newest research on alzheimer's disease

Lecanemab, the New Alzheimer’s Treatment: 3 Things To Know

BY CARRIE MACMILLAN July 24, 2023

Yale researcher discusses the recent FDA approval of a new Alzheimer's disease treatment.

[Originally published January 19, 2023. Updated: July 24, 2023.]

The Food and Drug Administration (FDA) recently granted full approval to a new Alzheimer’s treatment called lecanemab, which has been shown to moderately slow cognitive and functional decline in early-stage cases of the disease.

Alzheimer’s disease is a progressive disorder that damages and destroys nerve cells in the brain. Over time, the disease leads to a gradual loss of cognitive functions, including the ability to remember, reason, use language, and recognize familiar places. It can also cause a range of behavioral changes.

In January, the FDA gave the medication an accelerated approval based on amyloid plaque clearance. Christopher van Dyck, MD , director of Yale’s Alzheimer’s Disease Research Unit, was the lead author of a study published in the Jan. 5 issue of The New England Journal of Medicine that shared results of a Phase III clinical trial of lecanemab. (Dr. van Dyck is also a paid consultant for the pharmaceutical company Eisai, which funded the trials.)

Sold under the brand name Leqembi™ and made by Eisai in partnership with Biogen Inc., the drug is delivered by an intravenous infusion every two weeks. Lecanemab works by removing a sticky protein from the brain that is believed to cause Alzheimer’s disease to advance.

“It’s very exciting because this is the first treatment in our history that shows an unequivocal slowing of decline in Alzheimer’s disease,” says Dr. van Dyck.

This is the first time in two decades that the FDA has granted full approval to a drug for Alzheimer’s, but there is also a “black box” warning on the medication—the agency’s strongest caution—because of safety concerns.

We talked more with Dr. van Dyck, who answered three questions about the new treatment.

How effective is lecanemab for Alzheimer’s disease?

In a trial that involved 1,795 participants with early-stage, symptomatic Alzheimer’s, lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo.

“The antibody treatment selectively targets the forms of amyloid protein that are thought to be the most toxic to brain cells,” says Dr. van Dyck.

Study participants who received the treatment had a significant reduction in amyloid burden in imaging tests, usually reaching normal levels by the end of the trial. Participants also showed a 26% slowing of decline in a key secondary measure of cognitive function and a 37% slowing of decline in a measure of daily living compared to the placebo group.

“Would I like the numbers to be higher? Of course, but I don’t think this is a small effect,” says Dr. van Dyck. “These results could also indicate a starting point for bigger effects. The data appear encouraging that the longer the treatment period, the better the effect. But we’ll need more studies to determine if that’s true.”

They also beg the question about still-earlier intervention, adds Dr. van Dyck. Lecanemab is already being tested in the global AHEAD study for individuals who are still cognitively normal but at high risk of symptoms due to elevated levels of brain amyloid.

Yale currently has the largest number of participants in the AHEAD study, which is funded by the National Institutes of Health (NIH) and Eisai and is enrolling participants as young as 55. “We may see a larger benefit if we intervene before significant brain damage has occurred,” he says.

Is lecanemab safe?

The most common side effect (26.4% of participants vs. 7.4% in the placebo group) of the treatment is an infusion-related reaction, which may include transient symptoms, such as flushing, chills, fever, rash, and body aches. The majority (96%) of these reactions were mild to moderate, and 75% happened after the first dose.

“We can medicate those individuals in advance if we find they have those side effects repeatedly,” says Dr. van Dyck. “We can use medications such as diphenhydramine or acetaminophen. But this is generally not an issue.”

Another potential side effect associated with lecanemab was amyloid-related imaging abnormalities with edema, or fluid formation on the brain. This occurred in 12.6% of trial participants compared to 1.7% in the placebo group. “It’s usually asymptomatic when it occurs, but we can detect it on MRI scans. We often don’t stop dosing if we see it, unless there are symptoms, in which case we would pause infusions until it fully resolves,” Dr. van Dyck says.

It’s important to note that the studies with lecanemab show substantially lower rates of this side effect than do published trials of other, similar drugs such as aducanumab—they're at about a third of the rate, explains Dr. van Dyck. “So, for drugs in this class, I think lecanemab has a favorable safety profile,” he says.

Lastly, 17.3% of trial participants experienced amyloid-related imaging abnormalities with brain bleeding compared to 9% in the placebo group.

“Most of the time we're really talking about microhemorrhages that are in the order of millimeters,” says Dr. van Dyck. “People with Alzheimer's disease are more prone to these events because of the amyloid deposits in their blood vessels, but a catastrophic bleed is quite rare.”

The medication’s label includes warnings about brain swelling and bleeding and that people with a gene mutation that increases their risk of Alzheimer’s disease are at greater risk of brain swelling on the treatment. The label also cautions against taking blood thinners while on the medication.

When will lecanemab be available for Alzheimer’s disease treatment?

Eisai set the price for Leqembi at $26,500 per year, and it has reportedly been largely unavailable while FDA full approval was pending. That may change now that Medicare has said it will cover 80% of the cost.

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• Review Article
• Published: 04 September 2023

Emerging diagnostics and therapeutics for Alzheimer disease

• Wade K. Self   ORCID: orcid.org/0000-0003-1648-6124 1 &
• David M. Holtzman   ORCID: orcid.org/0000-0002-3400-0856 1  

Nature Medicine volume  29 ,  pages 2187–2199 ( 2023 ) Cite this article

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• Alzheimer's disease
• Diagnostic markers
• Drug development

Alzheimer disease (AD) is the most common contributor to dementia in the world, but strategies that slow or prevent its clinical progression have largely remained elusive, until recently. This Review highlights the latest advances in biomarker technologies and therapeutic development to improve AD diagnosis and treatment. We review recent results that enable pathological staging of AD with neuroimaging and fluid-based biomarkers, with a particular emphasis on the role of amyloid, tau and neuroinflammation in disease pathogenesis. We discuss the lessons learned from randomized controlled trials, including some supporting the proposal that certain anti-amyloid antibodies slow cognitive decline during the mildly symptomatic phase of AD. In addition, we highlight evidence for newly identified therapeutic targets that may be able to modify AD pathogenesis and progression. Collectively, these recent discoveries—and the research directions that they open—have the potential to move AD clinical care toward disease-modifying treatment strategies with maximal benefits for patients.

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Acknowledgements

We thank E. Franke for assistance with the generation of figures. We acknowledge support from US National Institute of Health grants RF1NS090934, RF1AG047644 and U19AG069701, the JPB Foundation, the Cure Alzheimer’s Fund and the Rainwater Charitable Foundation (all to D.M.H.).

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Self, W.K., Holtzman, D.M. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med 29 , 2187–2199 (2023). https://doi.org/10.1038/s41591-023-02505-2

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New drug donanemab is 'a turning point in the fight against Alzheimer’s'

Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, has called breakthrough Alzheimer's drug donanemab, 'a turning point', as the full trial results were revealed.

Full results about the Alzheimer's disease drug donanemab have been released today, supporting earlier trial results that suggested the breakthrough drug may slow down the progression of the disease.

Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said:   

“Dementia is the biggest killer in the UK and over 60% of people living with dementia are thought to have Alzheimer’s disease.

This is truly a turning point in the fight against Alzheimer’s and science is proving that it is possible to slow down the disease.

"Treatments like donanemab are the first steps towards a future where Alzheimer’s disease could be considered a long-term condition alongside diabetes or asthma.

"People may have to live with it, but they could have treatments that allow them to effectively manage their symptoms and continue to live fulfilled lives.

“Today’s full results support what we heard about donanemab back in May, that the drug is able to slow down the progression of Alzheimer’s disease by more than 20%. This study adds to the growing evidence that treating people as early as possible may be more beneficial, with the effects of donanemab greater in people who were at an earlier stage of the disease. 

'A defining moment'

Kate Lee, Alzheimer’s Society CEO said:

This is a defining moment for dementia research. But new treatments could mean nothing if we don’t fix dementia diagnosis .

"We estimate around 720,000 people in the UK could potentially benefit from these emerging new Alzheimer’s disease treatments if they’re approved for use here. But the NHS is simply not ready to deliver them.

“Everyone living with dementia deserves access to a speedy, accurate diagnosis to get the support and treatments they need, now and in the future.” 

Our CEO also shared her thoughts about the donanemab results on Twitter:

‘I know that there is so much to be done in order to ensure that we can get these drugs into people at the right time.’ Our Chief Exec @KateLeeCEO reacts to today’s donanemab news. Read our full comment at https://t.co/RnxF6fnRNH . pic.twitter.com/T1PPMefyQy — Alzheimer's Society (@alzheimerssoc) July 17, 2023

Early Alzheimer's diagnosis key

Dr Oakley added:

Diagnosis will be key to the access of any new treatments. We can’t have a situation where treatments are approved for use in the UK but people aren’t diagnosed early or accurately enough to be eligible.

"We need early, and accurate, diagnoses available for everyone and the NHS ready to roll out treatments such as donanemab and lecanemab if and when they are approved in the UK.  

“It’s also important to note that side effects did occur, although serious side effects only occurred in 1.6% of people receiving the drug.

"Regulators will need to balance these side effects against the benefits of the drug. We should also note that themajority of people who took part in this trial were white – it’s crucial that in future trials we see more diversity to prove that new drug treatments have similar effects for everyone living with Alzheimer’s disease. 

Just as we’ve seen a transformation in cancer treatment in recent decades, we’re really hopeful we’re on the same path for dementia.

"We’re so proud that research Alzheimer’s Society funded 30 years ago led to the breakthroughs we’re seeing today, and the research we’re funding now will be pivotal in unlocking more breakthroughs.  

“We will only see progress in clinical trials for new treatments if people from all backgrounds have the opportunity to join them.

"It’s not all about taking new drugs or having invasive tests, some trials are as simple as answering surveys and anyone over 18 in the UK can sign up."

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New breakthroughs on Alzheimer’s

MIT scientists have pinpointed the first brain cells to show signs of neurodegeneration in the disorder and identified a peptide that holds potential as a treatment.

• Anne Trafton archive page

Neuronal hyperactivity and the gradual loss of neuron function are key features of Alzheimer’s disease. Now researchers led by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, have identified the cells most susceptible to this damage, suggesting a good target for treatment. Even more exciting, Tsai and her colleagues have found a way to reverse neurodegeneration and other symptoms by interfering with an enzyme that is typically overactive in the brains of Alzheimer’s patients. 

In one study , the researchers used single-­cell RNA sequencing to distinguish two populations of neurons in the mammillary bodies, a pair of structures in the hypothalamus that play a role in memory and are affected early in the disease. Previous work by Tsai’s lab found that they had the highest density of amyloid beta plaques, abnormal clumps of protein that are thought to cause many Alzheimer’s symptoms. 

The researchers found that neurons in the lateral mammillary body showed much more hyperactivity and degeneration than those in the larger medial mamillary body. They also found that this damage led to memory impairments in mice and that they could reverse those impairments with a drug used to treat epilepsy.

In the other study , the researchers treated mice with a peptide that blocks a hyperactive version of an enzyme called CDK5, which plays an important role in development of the central nervous system. They found dramatic reductions in neurodegeneration and DNA damage in the brain, and the mice got better at tasks such as learning to navigate a water maze.

CDK5 is activated by a smaller protein known as P35, allowing it to add a phosphate molecule to its targets. However, in Alzheimer’s and other neurodegenerative diseases, P35 breaks down into a smaller protein called P25, which allows CDK5 to phosphorylate other molecules—including the Tau protein, leading to the Tau tangles that are another characteristic of Alzheimer’s.

Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs also interfere with other essential enzymes. The MIT team instead used a peptide—a string of amino acids, in this case a sequence matching that of a CDK5 segment that is critical to binding P25.

In tests on neurons in a lab dish, the researchers found that treatment with the peptide moderately reduced CDK5 activity. But in a mouse model that has hyperactive CDK5, they saw myriad beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. 

The treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein. Tsai hypothesizes that the peptide might confer resilience to cognitive impairment in the brains of people with Tau tangles.

“We found that the effect of this peptide is just remarkable,” she says. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”

The researchers hope the peptide could eventually be used as a treatment not only for Alzheimer’s but for frontotemporal dementia, HIV-induced dementia, diabetes-­linked cognitive impairment, and other conditions. 

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• Open access
• Published: 02 October 2023

Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update

• Li-Kai Huang 1 , 2 , 3   na1 ,
• Yi-Chun Kuan 2 , 3 , 4 , 5   na1 ,
• Ho-Wei Lin 6 &
• Chaur-Jong Hu   ORCID: orcid.org/0000-0002-4900-5967 1 , 2 , 3 , 4  

Journal of Biomedical Science volume  30 , Article number:  83 ( 2023 ) Cite this article

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Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.

Alzheimer disease (AD) represents a major global medical, social, and economic burden. The World Alzheimer Report 2022 revealed that more than 55 million people have AD or related conditions worldwide, and this number is projected to reach 82 million by 2030 and 138 million by 2050 [ 1 ]. Typically, AD first manifests as progressive memory decline accompanied or followed by other cognitive dysfunctions, such as visuospatial abnormalities, navigation difficulties, executive problems, and language disturbances. These cognitive impairments affect the performance of activities of daily living. During the course of AD, many behavioral and psychological symptoms of dementia (BPSD) occur [ 2 , 3 , 4 ].

Although the exact causes of AD remain unclear, the disease has two pathological hallmarks: plaques composed of amyloid-beta (Aβ) fibrils and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein [ 5 , 6 , 7 ]. The key event in AD pathogenesis is believed to be Aβ accumulation. Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms [ 8 ]. Brain atrophy, particularly in the hippocampus, is major indicator of early Aβ accumulation, particularly in the presubiculum [ 9 , 10 ]. Aβ accumulation was discovered to be crucial by three independent research groups in 1991 [ 11 , 12 , 13 ]. In familial AD, mutant autosomal-dominant genes, including the genes for amyloid precursor protein ( APP ), presenilin-1 ( PSEN1 ), and presenilin-2 ( PSEN2 ), encode the major proteins involved in amyloid metabolism [ 13 , 14 , 15 ]. Individuals with trisomy 21 (Down syndrome) have an extra copy of the APP gene, which may result in increased amyloid production and AD risk in middle age [ 16 ]. At present, the predominant theory regarding the cause of AD is the amyloid hypothesis; crucial advancements in AD therapy have been made on the basis of the proposed role of amyloid accumulation in the AD development. The United States Food and Drug Administration (US FDA) granted traditional approval for Leqembi (lecanemab-irmb) on July 6, 2023, for the treatment of AD [ 17 ]. The approval of this treatment not only affirms the pathophysiological significance of amyloid in AD but also marks a notable advance in clinical approaches to AD treatment, remedying the scarcity of new drugs in the market for nearly two decades.

Tau is a microtubule-associated protein that aids in microtubule assembly and stabilization. In AD, tau becomes hyperphosphorylated and aggregates to form paired helical filaments, a major component of NFTs within the neuronal cytoplasm. As the disease progresses, the gradual spread of tau pathology throughout brain regions has been suggested to be caused by the transfer of abnormal types of tau protein from one neuron to another [ 18 ]. The accumulation of NFTs might be initiated between the accumulation of Aβ and the development of clinical symptoms of AD [ 19 ]. NFTs and quantitative neuronal loss may be more closely correlated with disease severity and dementia progression than the amyloid plaque burden [ 20 , 21 , 22 ]. Positron emission tomography (PET) investigations have revealed a strong correlation between the binding characteristics of tau tracers and the severity of clinical manifestations in individuals with AD [ 23 ]. Molecular imaging modalities (PET) and cerebrospinal fluid (CSF) and blood–based biomarkers have extended the diagnostic scope of AD pathology to both clinical and even preclinical settings. The analysis of a combination of biomarkers such as amyloid, tau, and neurodegeneration (collectively, ATN classification) has been proposed by research on AD [ 24 , 25 ]. Furthermore, the exceptional diagnostic accuracy of plasma-based biomarkers has facilitated the clinical transition of fluid biomarkers from research settings to clinical practice. A recent presentation at the Alzheimer’s Association International Conference in 2023 highlighted the clinical and research applications of two fundamental AD biomarker categories, labeled as A and T. The A category pertains to biomarkers associated with the Aβ proteinopathy pathway, and the T category pertains to biomarkers linked to tau proteinopathy [ 26 ].

Aβ serves as a proinflammatory agent and triggers the nuclear factor κB (NF-κB) pathway in astrocytes, increasing complement C3 release. Subsequently, by binding to C3a receptors, C3 causes neuronal dysfunction and microglial activation [ 27 ]. In the early stage of AD, activated microglia may play a protective, anti-neuroinflammatory role by clearing amyloids and releasing nerve growth factors. However, activated microglia induce neurotoxic A1 astrocyte reactivity through the release of IL-1α, C1q, and TNF-α, resulting in a feedback loop of dysregulated inflammation in AD [ 28 ]. The excessive accumulation of Aβ or other toxic compounds activates proinflammatory phenotypes, resulting in neuronal damage [ 29 ]. Sustained inflammation has been observed in the brains of patients with AD [ 30 , 31 ]. The inadequate clearance of Aβ along with the aggregation of tau disrupts microglial defense mechanisms, resulting in sustained and harmful microglial activation [ 32 ]. The sequential occurrence of amyloid plaque formation, microglial activation, and the pathological phosphorylation and aggregation of tau proteins to form NFTs is the fundamental notion of the amyloid cascade–inflammation hypothesis. In the Multi-Ethnic Study of Atherosclerosis (multiple covariates were controlled for), vascular risk factor profiles and Aβ deposition significantly predicted cognitive decline [ 33 ]. Vascular risk factors can also lead to inflammation in the brain, which damages neuronal cells and further increases the likelihood of AD dementia [ 34 ].

The role of autophagy impairment is proposed in a novel hypothesis concerning plaque formation in AD. Among neurons that are compromised but still maintain some integrity, autophagic vacuoles (AVs) containing abundant Aβ are notably present. These AVs cluster within expansive membrane blebs, exhibiting a distinctive flower-like arrangement termed PANTHOS. These formations constitute the primary source of the majority of amyloid plaques found in mouse models of AD [ 35 ]. Neuroprotective therapies, including free radical scavengers, regeneration enhancers, and the suppression of excitable amino acid signaling pathways, have been proposed for preventing neuronal death or brain atrophy caused by amyloid, tau, and neuroinflammation [ 36 ]. Pathological evidence indicates that AD is also associated with degeneration in cholinergic neuron-rich regions, such as the nucleus basalis of Meynert, frontal cortex, and anterior and posterior cingulate cortex, which can lead to the symptoms of memory impairment and agitation. Acetylcholine (ACh) plays a vital role in memory function, including memory encoding, consolidation, and retrieval processes, and increasing Ach levels by using cholinesterase inhibitors (AChEIs) has become a standard therapy for the symptoms of AD [ 37 ].

Clinical trials of early or preventive interventions based on amyloid/tau theory and those targeting other pathophysiologies are ongoing or have been initiated. Many ongoing clinical trials on AD are focused on disease-modifying therapies (DMTs) that target the causes and can change the course of AD. The other trials involve symptomatic treatments—for example, enhancing cognitive function and relieving BPSD (Fig.  1 ). In this review, we summarize the new drugs being examined in ongoing trials (listed on ClinicalTrials.gov) and discuss the trends in and obstacles in AD clinical trials.

According to the amyloid hypothesis, the pathophysiology and clinical course of Alzheimer's disease progress as follows: amyloid accumulation, neuroinflammation, tau accumulation, brain metabolism dysfunction, brain atrophy, cognitive decline (from mild cognitive impairment to dementia), and the development of dementia symptoms. Novel drugs should target at least one of these events. AD Alzheimer's disease, aMCI amnestic mild cognitive impairment, BPSD behavioral psychological symptoms of dementia

Anti-amyloid therapy

Table 1 summarizes the US FDA approval status of anti-amyloid agents. Tables 2 and 3 summarize the ongoing phase 3 and phase 2 trials of anti-amyloid therapy respectively.

Aducanumab (brand name: Aduhelm) is a high-affinity, fully human immunoglobulin gamma 1 (IgG1) monoclonal antibody that binds to the N-terminus of Aβ fibrils and blocks amyloid aggregation [ 38 ]. In August 2015, two phase 3 clinical trials, namely ENGAGE and EMERGE studies, were initiated. These trials compared monthly intravenous infusions of aducanumab at one of three doses with infusions of placebo over 18 months, and the primary outcomes were cognitive and functional decline, which were assessed using the Clinical Dementia Rating (CDR) scale Sum of Boxes (CDR-SB). The secondary outcomes were other cognitive and functional measures. The trials were conducted in 150 centers across North America, Europe, Australia, and Asia. However, the findings of the EMERGE trial reached statistical significance, whereas the primary endpoint was not reached in the ENGAGE trial. An exploratory analysis revealed that a subgroup of the participants in the ENGAGE trial who received a high dose of aducanumab exhibited slow decline, which was similar to that observed among the participants in the EMERGE trial. The US FDA approved aducanumab in June 2021 on the basis of the data of the EMERGE and ENGAGE trials. Both trials presented evidence of an intermediate effect of the drug on biomarkers, indicating amyloid removal, which is likely linked to the clinical benefit of aducanumab. Further trials must be conducted to confirm the potential benefit of aducanumab [ 39 ]. The phase 3b/4 ENVISION trial (NCT05310071), which began in 2022, will enroll 1,512 patients with early AD who will receive either monthly doses of aducanumab of up to 10 mg/kg or placebo for 18 months. The aim of the trial is to determine the efficacy of aducanumab in delaying cognitive and functional decline in comparison with placebo, which would be determined on the basis of CDR-SB scores. The secondary endpoints of the trial include scores on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) 13, Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL)–Mild Cognitive Impairment Version, Integrated Alzheimer’s Disease Rating Scale (iADRS), Mini-Mental State Examination, and Neuropsychiatric Inventory. The trial intends to recruit 18% of its participants from Black and Latinx populations in the United States and will have a long-term follow-up of up to 4 years, with results expected by 2026. The EMBARK trial (NCT04241068) is a phase 3b open-label study including 1,696 participants from previous aducanumab trials (from trials 221AD103, 221AD301, 221AD302, and 221AD205) that will assess aducanumab safety and tolerability over 100 weeks after a wash-out period. Participants will receive an intravenous infusion of aducanumab at 10 mg/kg monthly for 2 years, and eligible participants will continue to receive the infusion for another 52 weeks during the long-term extended treatment period. The primary outcomes are safety and tolerability, and the efficacy endpoints are the same as those in the EMERGE and ENGAGE trials, and Caregiver Global Impression of Change evaluations will be conducted every 6 months. All participants will undergo volumetric magnetic resonance imaging (MRI) scans, and a subset of the study population will undergo biomarker testing, including amyloid PET, tau PET, and CSF testing.

Lecanemab (brand name: Leqembi), a humanized IgG1 antibody derived from mAb158, selectively binds to soluble Aβ protofibrils [ 40 ]. The US FDA approved it on January 6, 2023, through an accelerated approval pathway on the basis of evidence of amyloid removal in a phase 2 trial (NCT01767311) and because it had a likelihood of having clinical benefits [ 41 ] A double-blind, placebo-controlled phase 2 trial recruited 856 patients with AD with mild cognitive impairment (MCI) or mild dementia and verified amyloid pathology through amyloid PET or CSF Aβ1-42 [ 42 ]. The results revealed a significant and dose-dependent reduction of amyloid plaques in the lecanemab group (10 mg/kg, intravenous infusion every 2 weeks) from baseline to week 79 compared with the placebo group. At the time of writing this paper, three phase 3 clinical trials on lecanemab are underway. The first trial, Clarity AD (NCT03887455), was initiated in March 2019 and was conducted at 250 sites around the world. It reported favorable outcomes for all primary and secondary measures, including ADAS-Cog14, AD Composite Score (ADCOMS), and ADCS-MCI-ADL scores [ 43 ]. The second trial is AHEAD 3–45 (NCT04468659), which was initiated in July 2020 as a 4-year trial comprising two substudies, one of which is A3, and the other one is A45. A3 is enrolling 400 people whose amyloid levels are below the brain-wide threshold for positivity; participants will receive 5 mg/kg lecanemab titrated to 10 mg/kg or placebo every month for 216 weeks. A45 is enrolling 1,000 cognitively healthy participants with positive amyloid PET scans, and they will receive lecanemab titrated to 10 mg/kg every 2 weeks for 96 weeks, followed by 10 mg/kg every month through week 216. The trial is expected to run until October 2027. The third phase 3 clinical trial is the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Next Generation trial (DIAN-TU-001 (E2814), NCT05269394), in which a combination of lecanemab and the anti-tau antibody E2814 (phase 2) will be administered to 168 people with familial AD mutations. On July 6, 2023, Leqembi (lecanemab-irmb) received traditional approval from the US FDA for the treatment of AD based on Phase 3 data from the Clarity AD clinical trial [ 17 ].

The appropriate use recommendations (AURs) for lecanemab and aducanumab highlight the importance of patient selection, surveillance for adverse events, and clinician preparedness [ 44 , 45 ]. The AURs for both drugs have several similarities with respect to age criteria, biomarker requirements (positive amyloid PET or CSF findings indicative of AD), diagnosis (MCI due to AD or mild AD dementia), and MRI exclusion criteria (e.g., microhemorrhages and cortical infarction). The AURs also emphasize the importance of monitoring for amyloid-related imaging abnormalities (ARIAs), which can occur in patients receiving these drugs. APOE genotyping is recommended for informing risk discussions with candidate participants because APOE4 allele carriers, especially APOE4 homozygotes, are at a high risk of ARIAs. Patients receiving treatment must have care partners or family members who can provide necessary support and who clearly understand the nature and requirements of the therapy. Discontinuation of treatment is recommended in the following situations: when a patient is taking drugs with associated risks, such as anticoagulation agents for conditions like atrial fibrillation, deep vein thrombosis, or pulmonary embolism; or when any of the following conditions occur: a hypercoagulable state, or the development of any of the following: cerebral macrohemorrhage, multiple areas of superficial siderosis, more than 10 instances of microhemorrhages since treatment initiation, severe symptoms of ARIAs, or two or more episodes of ARIAs.

Donanemab is a humanized monoclonal antibody developed from mouse mE8-IgG2a. It recognizes Aβ (3–42), an aggregated form of Aβ found in amyloid plaques [ 46 ]. It was discovered to be bound to approximately one-third of amyloid plaques in postmortem brain samples of patients with AD or Down syndrome, and it strongly reacted with the plaque core [ 47 ]. In the phase 2 TRAILBLAZER-ALZ study, the safety, tolerability, and efficacy of donanemab alone and in combination with the Beta-Secretase 1 (BACE1) inhibitor LY3202626 (developed by Eli Lilly and Company) were evaluated over 18 months. The trial met its primary endpoint of delaying decline—which was determined on the basis of iADRS scores—by 32% compared with placebo. Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers [ 48 ]. Donanemab reduced the tau burden in the temporal, parietal, and frontal lobes and significantly decreased plasma pTau217 by 24% in the treatment group, whereas the placebo group exhibited a 6% increase in plasma pTau217 at the end of the trial [ 49 ]. At the time of writing this paper, five phase 3 trials of donanemab are underway: TRAILBLAZER-ALZ 2, TRAILBLAZER-ALZ 3, TRAILBLAZER-ALZ 4, TRAILBLAZER-ALZ 5 and TRAILBLAZER-ALZ 6. The TRAILBLAZER-ALZ 2 (NCT04437511) trial was initially started in June 2020 as a phase 2 safety and efficacy trial, and 500 patients with early AD were recruited. Inclusion criteria of TRAILBLAZER-ALZ 2 are similar to those of TRAILBLAZER-ALZ: a ≥ 6-month history of worsening memory and positive amyloid (flortaucipir) PET. The trial was subsequently extended to a phase 3 trial with 1,800 participants. The primary outcome is iADRS, and the effectiveness of treatment is being measured using a disease-progression model rather than solely on the basis of changes at the final time point. Trial results for 1,736 participants were published to report donanemab’s impact on early symptomatic AD. Using PET imaging to categorize individuals into groups with low/medium or high tau pathology load, the study spanned 18 months and assessed cognitive and functional scales. Donanemab achieved significant cognitive improvement in the low/medium tau group (iADRS change: − 6.02 vs. − 9.27 placebo) and combined population (change: − 10.2 vs. − 13.1 placebo). The drug notably reduced decline by 60% in patients with early-stage AD, supporting the efficacy of short-term dosing. Twenty-four outcomes were evaluated, with significant findings for 23 outcomes. Adverse effects included amyloid-related imaging problems (24% donanemab vs. 2.1% placebo) and infusion-related reactions (8.7% donanemab vs. 0.5% placebo). The study findings indicated the potential of donanemab to slow AD progression, particularly in the early stage [ 50 ]. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months ( p  = 0.04 vs. placebo), thus demonstrating clinical efficacy [ 51 ]. TRAILBLAZER-ALZ 3 (NCT05026866) is a placebo-controlled phase 3 prevention trial that was started in August 2021. The trial plans to enroll 3,300 cognitively healthy people aged 50–55 years who are at high risk of AD, as determined by elevated plasma pTau217 levels and Telephone Interview for Cognitive Status-modified scores. The primary outcome is the time to clinical progression, which is measured using global CDR scores. Participants are to be monitored every 6 months until cognitive impairment is noted (i.e., a score above 0 on the CDR for two consecutive evaluations) in 434 participants. The trial has a decentralized design and is being conducted at more than 200 sites in the United States, Japan, and Puerto Rico until November 2027. TRAILBLAZER-ALZ 4 (NCT05108922) is a phase 3, open-label, head-to-head comparison of amyloid clearance by either donanemab or aducanumab that began in November 2021 after the US FDA approval of aducanumab. The trial enrolled 200 people with early symptomatic AD, as indicated by a global CDR score of 0.5 or 1, at 31 sites in the United States. The primary outcome is the percentage of participants who achieve complete amyloid plaque clearance after 6 months for each treatment group, with clearance determined using amyloid (florbetapir) PET. The trial has 17 secondary outcomes, which are all related to amyloid PET measurements at up to 18 months. The preliminary results were presented at the 2022 Clinical Trial of AD (CTAD) conference: 38% of the patients on donanemab exhibited amyloid levels below the amyloid positivity threshold after 6 months, whereas only 2% of the patients on aducanumab has such findings. Plasma pTau217 levels decreased by 25% for the participants receiving donanemab, but not at all for those receiving aducanumab. The side effect of ARIA-edema occurred in 22% of the participants in both groups. TRAILBLAZER-ALZ 5 (NCT05508789) is being conducted to assess the safety and efficacy of donanemab in individuals with early symptomatic AD. The trial started in October 2022; 1,500 participants will be recruited by using the same criteria as those of TRAILBLAZER-ALZ 2 from 148 sites across China, Korea, Taiwan, and Europe; and the trial is expected to run until mid-2025. Participants will be administered monthly infusions of either donanemab or placebo, and the primary outcome will be measured on the basis of iADRS score changes after 18 months. TRAILBLAZER-ALZ 6 (NCT05738486) is a phase 3b study that will assess the impact of various dosing regimens of donanemab on the occurrence and severity of ARIA-E (ARIA with edema or effusion) in 800 adults with early symptomatic AD. The study also seeks to identify participant characteristics that predict the risk of ARIA-E. The trial is divided into four arms, each with a distinct donanemab dose.

Remternetug is a monoclonal antibody that recognizes a pyroglutamated form of Aβ that aggregates into amyloid plaques. In August 2022, Eli Lilly and Company initiated a phase 3 trial called TRAILRUNNER-ALZ1 (NCT05463731) that will randomize 600 patients with early symptomatic AD across 75 sites in the United States and 2 sites in Japan into groups receiving the antibody or placebo through intravenous infusion or subcutaneous injection for 1 year. The primary outcome is the percentage of patients whose amyloid plaques are cleared by the end of the treatment period. The secondary outcomes include the measurement of amyloid clearance, pharmacokinetics, and treatment-emergent anti-drug antibodies. The study also plans to conduct a year-long, blinded crossover extension. An additional safety cohort of 640 patients will receive open-label remternetug for 1 year.

Solanezumab is a humanized monoclonal antibody that targets the mid-domain of the Aβ peptide for increasing Aβ clearance [ 52 ]. Phase 3 trials of solanezumab, including EXPEDITION-1 and EXPEDITION-2, which enrolled 2,052 patients with mild-to-moderate AD, did not reveal improvements in ADAS-Cog11 and ADCS-ADL scores, which were the primary outcome measures. Similarly, the phase 3 trial EXPEDITION-3 demonstrated that 400 mg solanezumab administered every 4 weeks did not have significant effects on cognitive decline in patients with mild AD [ 52 ]. A4 (NCT02008357) is a phase 3 prevention trial focused on slowing memory and cognitive decline in elderly individuals without cognitive impairment or dementia. A4 is using a sensitive cognitive battery—the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite—and was initiated in February 28, 2014. On March 8, 2023, Eli Lilly and Company reported that solanezumab did not slow cognitive decline or clear amyloid plaques in individuals with preclinical AD in the A4 study. DIAN-TU-001 (NCT01760005) is another ongoing phase 3 clinical trial that is testing the combination of solanezumab and gantenerumab in 210 asymptomatic and mildly symptomatic carriers of autosomal-dominant mutations in AD genes. However, on February 10, 2020, the study investigators announced that the primary endpoint was not achieved in the trial, namely treatment-related changes on the DIAN-Multivariate Cognitive Endpoint. The results indicated that the solanezumab-treated group had greater cognitive decline on some measures relative to placebo, and that solanezumab treatment did not exert any beneficial effects on downstream biomarkers, whereas gantenerumab significantly reduced amyloid plaques, CSF total tau, and phospho-tau181 and attenuated increases in neurofilament light chain [ 53 ]. The participants were offered an open-label extension with high-dose gantenerumab because of its positive effects on imaging and other biomarkers, such as normalized CSF Aβ42, and because it reduced CSF total tau and pTau181 levels.

ALZ-801 is a prodrug of tramiprosate, a small molecule of anti-Aβ oligomers and an aggregation inhibitor [ 54 ]. The phase 3 trial APOLLOE4 (NCT04770220) is evaluating the safety and efficacy of ALZ-801 for patients with early AD and carrying the homozygous ε4 allele on the apolipoprotein E gene ( APOE4/4 ). The recruited patients are receiving 265 mg ALZ-801 or placebo twice daily for 18 months. The trial started in May 2021. The primary endpoint is ADAS-Cog scores, and the secondary endpoints are scores of the Disability Assessment for Dementia, CDR-SB, and Amsterdam-iADL. The biomarkers of interest include the hippocampal volume, as determined through MRI and based on CSF and plasma pTau181 levels. Another phase 2 trial (NCT04693520) is investigating the effects of oral ALZ-801 administered to participants with early AD who have the APOE4/4 or APOE3/4 genotype with biomarkers of core AD pathology. The study is also assessing the efficacy, safety, and tolerability of ALZ-801.

Simufilam (PTI-125) is a drug that binds to filamin, a scaffolding protein that stabilizes the interaction between soluble Aβ42 and the α7 nicotinic acetylcholine receptor [ 55 ]. Two phase 3 trials, namely RETHINK-ALZ (NCT04994483) and REFOCUS-ALZ (NCT05026177), were commenced in November 2021. Both are safety and efficacy studies of simufilam and have enrolled participants with mild-to-moderate AD. RETHINK-ALZ will randomize 750 participants with AD and CDR scores of 0.5, 1, or 2 into groups receiving either placebo or 100 mg of simufilam twice a day for 1 year (52 weeks). The coprimary outcomes of this trial are ADAS-Cog12 and ADCS-ADL scores, and the trial is set to run through October 2023. REFOCUS-ALZ will randomize 1,083 participants into groups receiving placebo or 50 or 100 mg of simufilam (1:1:1) for 76 weeks. The primary outcome measures are similar to those of the RETHINK-ALZ trial. A phase 3 trial of simufilam (NCT05575076) was started in November 2022 to assess the long-term safety and tolerability of simufilam in participants with mild-to-moderate AD. That open-label extension study is intended to assess the long-term safety and tolerability of simufilam 100 mg twice daily in patients who have completed the RETHINK-ALZ or REFOCUS-ALZ Phase 3 clinical trials. The primary outcome measure is adverse event monitoring from baseline to week 52.

Varoglutamstat (PQ912) is a glutaminyl cyclase inhibitor that reduces pGlu-Aβ generation [ 56 ]. Glutaminyl cyclase catalyzes the cyclization of an exposed glutamate at the N-terminus of Aβ, resulting in the formation of toxic pGlu-Aβ, a major component of amyloid plaques. Two ongoing phase 2 clinical trials, namely VIVA-MIND and VIVIAD, are evaluating the safety, tolerability, and efficacy of varoglutamstat in participants with MCI and mild dementia due to AD. VIVA-MIND (NCT03919162) is a phase 2A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of varoglutamstat, with a stage gate to phase 2B. Phase 2A involves an adaptive dosing evaluation of three doses of varoglutamstat or placebo for ≥ 24 weeks. VIVIAD (NCT04498650) is a phase 2B, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study being conducted to evaluate the safety, tolerability, and efficacy of varoglutamstat in 259 participants with MCI and mild dementia due to AD.

ABBV-916 is a monoclonal antibody to Aβ. It recognizes N-terminal truncated Aβ modified with pyroglutamate at position 3 (N3), a form of Aβ that is aggregated into amyloid plaques. A two-stage phase 2 trial of ABBV-916 is ongoing (NCT05291234). Stage A is a multiple ascending dose study, and participants have a 25% chance of receiving placebo. Stage B is a proof-of-concept study, and participants have a 20% chance of receiving placebo. The first 6 months of the study are a double-blinded period, which is to be followed by a 2-year extension period in which all participants receive ABBV-916. Approximately 195 participants aged 50–90 years are to be enrolled at approximately 90 sites across the world. The participants are to receive intravenous doses of ABBV-916 or placebo once every 4 weeks for 24 weeks and are to be followed up for an additional 16 weeks.

CT1812 is a ligand that targets the component 1 subunit of the sigma2/progesterone membrane receptor. It functions as a negative allosteric regulator, reducing the affinity of oligomeric Aβ and interfering with Aβ-induced synaptic toxicity [ 57 ]. START(COG0203) study (NCT05531656) is a phase 2, multicenter, randomized, double-blind, placebo-controlled trial that was initiated in September 2022 for evaluating the efficacy and safety of CT1812. START is comparing the effects of CT1812 (100 or 300 mg) with those of placebo over 18 months in 540 people with MCI or mild dementia due to AD. The SHINE (COG0201) study (NCT03507790) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 36-week phase 2 study of two doses of CT1812 in adults with mild-to-moderate AD. The study is evaluating the safety, tolerability, pharmacokinetics, and efficacy of CT1812.

Anti-tau therapy

Table 4 summarizes the ongoing phase 2 trials of anti-tau therapy.

Bepranemab (UCB0107) is a monoclonal IgG4 antibody that targets a central tau epitope. An ongoing phase 2 trial (NCT04867616) enrolling 421 participants with prodromal or mild AD is investigating the safety, tolerability, and efficacy of bepranemab. After an 80-week double-blinded treatment period, the participants are eligible to enter a 48-week open-label extension period, in which they are to receive bepranemab treatment for 44 weeks. Subsequently, they are to participate in a safety evaluation visit 20 weeks after the last infusion. The primary outcome measure is the CDR-SB score.

JNJ-63733657 is a humanized IgG1 monoclonal antibody that targets the microtubule-binding region of tau and prevents the cell-to-cell propagation of pathogenic tau aggregates. The AUTONOMY trial (NCT04619420) is an ongoing phase 2, randomized, double-blind, placebo-controlled, parallel-group multicenter study. Participants with early AD symptoms and a positive tau PET scan are randomized to groups receiving JNJ-63733657 or placebo. This trial is enrolling 420 participants and is expected to be completed by November 2025. The primary outcome measure is clinical decline, as determined using the iADRS.

ACI-35 is a liposome-based vaccine that targets pathological conformations of phosphorylated tau. A phase 1b/2a multicenter, double-blind, randomized, placebo-controlled trial (NCT04445831) was conducted to evaluate the safety, tolerability, and immunogenicity of various doses, regimens, and combinations of tau-targeting vaccines in individuals with early AD. The vaccines tested were JACI-35.054 and ACI-35.030 at various dose levels. The findings were presented at the 2022 CTAD conference. The results indicated that participants who received ACI-35.030 exhibited a strong and sustained immune response against pathological tau proteins (pTau) and nonphosphorylated tau (ePHF), particularly in the mid- and low-dose groups. Recipients of JACI-35.054 also displayed a robust immune response against ePHF and pTau, but without a clear dose–effect relationship. The trial has been conducted across nine centers in Finland, Sweden, the Netherlands, and the United Kingdom and is expected to be completed by October 2023.

E2814 is a monoclonal IgG1 antibody that targets an HVPGG epitope in the microtubule-binding domain of tau, prevents cell-to-cell propagation, and mediates the clearance of pathogenic tau proteins. The DIAN-TU-001 (E2814) trial (NCT05269394) is a phase 2/3 multicenter, randomized, double-blind, placebo-controlled platform trial of potential disease-modifying therapies with biomarker, cognitive, and clinical endpoints. The trial is enrolling patients with dominantly inherited AD. The study design involves the use of the anti-amyloid antibody lecanemab. Some participants are receiving a matching placebo plus lecanemab, whereas others are receiving concurrent therapy with E2814 plus lecanemab.

LY3372689 is a small-molecule inhibitor of O-GlcNAcase, which promotes tau glycosylation and prevents tau aggregation [ 58 ]. A phase 2 trial (NCT05063539) was initiated in September 2021 for assessing the safety, tolerability, and efficacy of LY3372689 in 330 patients with early symptomatic AD with progressive memory changes for ≥ 6 months and who met the criterion of having a positive flortaucipir-PET scan.

BIIB080 is a tau DNA/RNA-based antisense oligonucleotide that inhibits the translation of tau mRNA into protein, thus suppressing tau expression. CELIA (NCT05399888) is an ongoing phase 2 trial that is aiming to determine whether BIIB080 can delay AD progression in comparison with placebo and to identify the most effective dose of BIIB080. In March 2019, Biogen/Ionis performed a 4-year open-label extension trial of quarterly injections for individuals who completed the randomized portion of the trial. The initial data of this trial were reported at the Alzheimer’s Association International Conference (2021), revealing no serious adverse events from the intrathecal injection of BIIB080 at either of three doses every month for 3 months or two high-dose injections 3 months apart. BIIB080 led to a dose-dependent reductions of 30%–50% in total tau and pTau181 levels in CSF.

Neuroprotectors and cognitive enhancers

Table 5 summarizes the ongoing phase 3 trials for therapies other than anti-amyloid/tau treatment.

The active metabolite of fosgonimeton (ATH-1017) is a positive modulator of hepatocyte growth factor (HGF)/MET signaling [ 59 ]. A phase 3 trial of fosgonimeton (NCT04488419) was initiated in September 2020 and is expected to be completed in February 2024. This study is evaluating the safety and efficacy of fosgonimeton in participants with mild-to-moderate AD, with double-blind, parallel-arm treatment implemented for 26 weeks. The primary outcome measure is the overall treatment effect of fosgonimeton, as measured using the Global Statistical Test, which combines cognition (ADAS-Cog) and function (ADCS-ADL) scores.

AR-1001 selectively inhibits phosphodiesterase 5 and suppresses cGMP hydrolysis, resulting in the activation of protein kinase G and the increased phosphorylation of the cAMP-responsive element-binding protein at Ser133. It can rescue long-term potentiation impairment and cognitive dysfunction in animal models of AD [ 60 ]. A phase 3 trial of AR-1001 (NCT05531526) was started in December 2022 and is estimated to be completed in December 2027. The study aims to evaluate the efficacy and safety of AR1001 in participants with early AD. The primary outcome measure is the change in the CDR-SB from baseline to week 52.

BPDO-1603 is a potential cognitive-enhancing drug for AD, but its mechanism of action remains unknown [ 61 ]. A phase 3 trial of BPDO-1603 (NCT04229927) was started in February 2020 and is estimated to be completed in March 2023. The study has been undertaken to evaluate the efficacy and safety of BPDO-1603 in patients with moderate-to-severe AD. The primary outcome measures are the change in Severe Impairment Battery total scores from baseline to week 24, and CIBIC-plus total scores at week 24.

Buntanetap is a novel translational inhibitor of multiple neurotoxic proteins, including APP, tau, and α-synuclein, by enhancing the binding of the atypical iron response element in the 5′UTR regions of the mRNA of the neurotoxic proteins to iron regulatory protein 1 [ 62 ]. In February 2023, phase 2 and 3 trials (NCT05686044) were initiated to measure the efficacy and safety of three doses of buntanetap in comparison with placebo in participants with mild-to-moderate AD. The primary outcome measures are ADAS-Cog and ADCS Clinical Global Impression of Change (ADCS-CGIC) scores.

Caffeine is an adenosine receptor antagonist that has been reported to be associated with slower cognitive decline and lower cerebral amyloid accumulation [ 63 ]. A phase 3 trial of caffeine (NCT04570085) was started in March 2021 to evaluate the efficacy of 30 weeks of caffeine intake in comparison with placebo on cognitive decline in patients with mild-to-moderate AD dementia (Mini-Mental State Examination scores: 16–24). The primary outcome measure is changes in neuropsychological test battery scores between the randomized value and the value after 30 weeks of treatment.

Hydralazine may have anti-neurodegenerative effects because it activates the Nrf2 pathway, which involves more than 200 antioxidant proteins; improves mitochondrial function; and increases respiration capacity and the production of adenosine triphosphate; hydralazine also activates autophagy, which aids in the clearance of intracellular aggregates [ 64 , 65 , 66 ]. A phase 3 trial of hydralazine (NCT04842552) was started in August 2021 and is anticipated to be completed in December 2023. The study is comparing the effects of 75 mg hydralazine versus placebo in patients with mild-to-moderate AD. Various cognitive and function tests, including olfactory tests, biochemical analyses, and adverse effect monitoring, are being conducted regularly during follow-up.

KarXT (xanomeline-trospium), comprised of muscarinic agonist xanomeline and muscarinic antagonist trospium, is designed to preferentially activate muscarinic receptor in the CNS and ameliorate the peripheral muscarinic side effects. It is reported that KarXT improves cognition in patients with AD and schizophrenia [ 67 ]. A 38-week phase 3 trial comparing the effects of KarXT (NCT05511363) and placebo in participants with psychosis associated with AD dementia was started in August 2022. The trial is analyzing the time from randomization to relapse (primary outcome) as well as the time from randomization to discontinuation for any reason and the safety and tolerability of KarXT (secondary outcomes).

Metformin, a commonly prescribed antidiabetic medication, has been reported to improve cognition or mood in many neurological disorders [ 68 , 69 ]. A phase 3 trial of metformin (NCT04098666) was started in March 2021 and is anticipated to be completed in April 2026. The primary outcome measure is the total recall of the Free and Cued Selective Reminding Test at 24 months.

Nilotinib is a tyrosine kinase inhibitor that preferentially targets discoidin domain receptors and can effectively reduce the occurrence of misfolded proteins in animal models of neurodegeneration by crossing the blood–brain barrier and promoting Aβ and tau degradation [ 70 ]. A phase 3 trial (NCT05143528) was initiated in February 2022 to investigate the safety and efficacy of nilotinib BE (bioequivalent) in individuals with early AD. The primary outcome measure is changes in CDR-SB scores between baseline and week 72.

Piromelatine is a melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptor agonist and was developed as a treatment for mild AD [ 71 ]. In May 2022, a randomized trial (NCT05267535) was initiated in 225 noncarriers of a specific polymorphism, and these participants with mild dementia due to AD are allocated at a ratio of 1:1 to receive piromelatine or placebo for 26 weeks. A 12-month extension involves treating the placebo group with piromelatine to assess the drug’s disease-modifying effects. The primary analysis will be conducted after the initial 26 weeks. If efficacy is not confirmed, the study is to end without the extension phase.

Semaglutide is a peptidic GLP-1 receptor agonist that may regulate the aggregation of Aβ in AD. GLP-1 receptors are involved in cognition, synaptic transmission in hippocampal neurons, and cell apoptosis; thus, they may serve as targets for exploring candidate drugs with neuroprotective and cognition-enhancing effects [ 72 ]. A phase 3 trial of semaglutide (NCT04777396) was started in May 2021 to investigate the efficacy of semaglutide in individuals with early AD. The primary outcome measure is changes in the CDR-SB score from baseline to week 104.

Tricaprilin, a semisynthetic medium-chain triglyceride, is hydrolyzed to octanoic acid after administration and is further metabolized to ketones, which serve as an alternative energy substrate for the brain [ 73 ]. Therefore, tricaprilin can be used as a ketogenic source for the management of mild-to-moderate AD. A phase 3 trial (NCT04187547) was started in June 2022 to evaluate the efficacy and safety of tricaprilin in participants with mild-to-moderate AD. The primary outcome measure is changes in ADAS-Cog scores from baseline to week 20.

Anti-neuroinflammation therapy

Masitinib, an oral tyrosine kinase inhibitor, exerts effects by inhibiting mast cell and microglia/macrophage activity, with significant CNS penetration [ 74 ]. It is currently undergoing a phase 3 trial (NCT05564169) with 600 participants, employing a randomized, double-blind, placebo-controlled, parallel-group design over 24 weeks, followed by a 24-week extension phase. Quadruple masking ensures blinding. The study aims to evaluate Masitinib as an adjunct therapy for mild to moderate AD. Estimated to conclude on December 15, 2025, the trial assesses primary outcomes through changes from baseline in ADAS-Cog-11 and ADCS-ADL scores, measuring cognitive and functional abilities, respectively.

NE3107 is an anti-inflammatory insulin sensitizer that can cross the blood–brain barrier and bind to ERK. NE3107 can selectively inhibit inflammation-driven ERK- and NF-κB-stimulated inflammatory mediators, including TNF-α, without disturbing their homeostatic functions [ 75 ]. A multicenter phase 3 trial (NCT04669028) was started in August 2021 to investigate the safety and efficacy of NE3107 at 20 mg that was orally administered twice daily versus placebo in adult participants with mild-to-moderate AD. The primary outcome measures are changes in ADAS-Cog12 and ADCS-CGIC scores from baseline to week 30 [ 76 ].

BPSD-relieving therapy

Masupirdine, a selective 5‐HT6 receptor antagonist with favorable physicochemical properties and absorption, distribution, metabolism, and excretion properties, may have beneficial effects on agitation, aggression, and psychosis in patients with moderate AD [ 77 ]. A phase 3 trial (NCT05397639) was started in November 2022 to evaluate the efficacy, safety, tolerability, and pharmacokinetics of masupirdine in comparison with placebo for treating agitation in participants with AD dementia. The primary outcome measure is the change in the score of the Cohen–Mansfield Agitation Inventory from baseline to week 12.

Nabilone is a partial agonist of cannabinoid receptor 1 (CB1) and CB2 in the brain and in peripheral tissues, and it has been reported to provide effective treatment for agitation in patients with AD [ 78 ]. A phase 3 trial (NCT04516057) was started in February 2021 to investigate whether nabilone is an effective treatment for agitation in AD patients. The primary outcome measure is agitation (Cohen–Mansfield Agitation Inventory) between baseline and week 8.

Phase 4 and repurposing trials

Table 6 summarizes ongoing phase 4 trials.

Escitalopram, a selective-serotonin reuptake inhibitor, is a commonly used antidepressant. It ameliorates cognitive impairment and could selectively attenuate phosphorylated tau accumulation in stressed rats by regulating hypothalamic–pituitary–adrenal axis activity and the insulin receptor substrate/glycogen synthase kinase-3β signaling pathway [ 79 ]. A phase 4 trial (NCT05004987) was started in February 2022 to investigate whether a reduction in depressive symptoms owing to the administration of escitalopram oxalate is associated with the normalization of AD biomarkers in CSF and inflammatory markers in the peripheral blood. The primary outcome measures are changes in CSF Aβ40 and Aβ42 levels, vascular dysfunction biomarker levels, and scores of the Montgomery–Asberg Depression Ratio Scale at week 8.

Sodium oligomannate (GV-971), a marine-derived oligosaccharide, can reconstitute the gut microbiota, reduce bacterial metabolite–driven peripheral infiltration of immune cells into the brain, inhibit amyloid-β fibril formation, and inhibit neuroinflammation in the brain, as demonstrated in animal studies [ 80 , 81 ]. A phase 4 trial (NCT05181475) was initiated in December 2021 to examine the long-term efficacy and safety of GV-971 as well as changes in blood and gut microbiota biomarkers and thereby validate its mechanism of action and establish guidance for the more rational use of drugs in clinical practice. The primary outcome measure is changes in ADAS-Cog11 scores from baseline to week 48. Another phase 4 trial was started in July 2022 and is comparing the efficacy and safety of memantine and GV-971 monotherapy and combination therapy in patients with moderate-to-severe AD. The primary outcome measure is changes in cognitive function at weeks 12, 24, 36, and 48.

Spironolactone, an aldosterone mineralocorticoid receptor antagonist, has been commonly used to treat cardiovascular diseases, including hypertension. It has anti-inflammatory effects on the peripheral tissues and central nervous system and therefore may have beneficial effects on neurological disorders [ 82 ]. A phase 4 trial (NCT04522739) was started in September 2022 to investigate whether spironolactone can be tolerated by older Black American adults with MCI and to determine its effect on memory and thinking abilities, as measured by participant performance on cognitive tests. The primary outcome measures are the number of adverse events and the attrition rate.

Published results

Among the clinical trials newly registered in the last 4 years, four articles pertaining to two trials have been published in peer-reviewed scientific journals. The characteristics of the published randomized controlled trials are summarized in Table 7 [ 43 , 53 , 83 , 84 ]. Two articles reported the results of NCT03887455 [ 43 , 84 ], and the other two reported the results of NCT01760005 [ 53 , 83 ]. The articles were published between 2018 and 2023. The results of both NCT03887455 (Clarity AD) and NCT01760005 have been discussed in the anti-amyloid section. The methodological quality of these studies is summarized in Table 8 . Both trials (NCT03887455 and NCT01760005) had a overall low risk of bias [ 43 , 53 , 83 , 84 ].

Our understanding of AD originated from clinical research, and how pathological findings are associated with clinical presentation of AD has continued to intrigue the neuroscience research community over the past century. DMTs have become the core of new drug development, and the accumulation of knowledge is leading to the evolution of diagnostic criteria and clinical outcome measurements. The view of clinical outcomes has shifted from considering them as solely determinative to considering them to be just one of the determinants. In accordance with the 2018 NIA-AA Research Framework criteria [ 25 ] or the new 2023 NIA-AA revised criteria for AD [ 26 ], the incorporation of biomarkers is necessary in clinical practice.

This review documented that in terms of the number of AD drug trials and the number of recruited participants, the majority of trials continue to focus on mechanisms involving amyloid and tau. Our 2020 report highlighted that due to the failure of early anti-amyloid trials to achieve their intended outcomes, particularly studies involving BACE inhibitors and monoclonal antibodies, some have questioned whether amyloid remains clinically relevant in AD. This shift in perspective has led to a change in the focus of research toward populations in the prodromal or preclinical stage with positive results for diagnostic biomarkers. Additionally, the validity of the amyloid hypothesis has been contested, resulting in a significant reduction in the number of anti-amyloid phase 3 trials since 2019. However, the targets of both phase 1 and phase 2 trials are diverse, with a noticeable increase in the number of phase 1 trials focusing on neuroprotection and phase 2 trials focusing on anti-neuroinflammation [ 85 ]. Since the positive outcomes in terms of slow decline in cognitive abilities in the lecanemab Clarity AD trial [ 43 ] and the donanemab trial TRAILBLAZER-ALZ [ 86 ], the impact of amyloid and consequent pathological alterations is likely to become the main focus of clinical trials. The incorporation of amyloid-related therapy either as an add-on or as a link to specific aspects of AD pathophysiology might become an important trend in clinical trials of new drugs in the future. However, despite this expansion of research areas, the scope of indications for novel anti-amyloid monoclonal antibody therapy remains limited. The mode of treatment administration and the high monitoring costs along with the need for specialized facilities and imaging scans remain challenges. Other unmet needs, such as addressing BPSD and enhancing cognitive function, necessitate pharmaceutical research. Examining drugs with diverse mechanisms necessitates thorough evaluation that extends beyond mere clinical measurements to encompass their intermediate impact on biomarkers. It is essential to investigate the potential synergy between a new drug and existing medications approved by the US FDA. This approach could even be extended to situations where adjuvant treatment, such as tau-related treatments, is provided after amyloid clearance has been achieved. Clinical trials related to AD have also exhibited a shift in focus toward the earlier stages of AD, such as MCI, or even cognitively healthy participants for developing prevention interventions.

Successful phase 3 trials such as Clarity AD (lecanemab) and EMERGE (aducanumab) have evaluated anti-amyloid treatment in mild AD (Fig.  2 ). Trials that do not target specific pathophysiologies are becoming fewer in all phases (Figs.  2 and 3 ). However, an increasing number of early-phase trials of therapies for symptoms, including cognitive enhancers and agents for relieving BPSD, are being conducted. This reflects the unmet clinical need for such therapies (Figs.  2 and 3 ). Similarly, an increasing number of phase 1 trials involving DMTs, particularly those targeting both anti-amyloid and anti-tau mechanisms, has been noted, indicating the importance of basic research (Fig.  3 ). Outcome measurement tools have also become more diverse, which has enabled meaningful improvements in AD and the efficacy of treatments to be clearly determined in clinical trials. Overall, the field of AD clinical trials is evolving, and additional promising treatments for AD are likely to be developed in the near future.

Trends in Phase 3 trials, 2020–2023, categorized according to event-related themes in ClinicalTrials.gov. Left: Number of Phase 3 trials. Right: Percentage of Phase 3 trials. A anti-amyloid therapy, B anti-tau therapy, C neuroprotection, D anti-neuroinflammation, E cognitive enhancer, F relief of behavioral psychological symptoms of dementia, G others, U undisclosed

Trends in Phase 1 and 2 trials, 2020–2023, categorized according to event-related themes in ClinicalTrials.gov. Left: Number of Phase 2 trials. Right: Number of Phase 1 trials; A anti-amyloid therapy, B anti-tau therapy, C neuroprotection, D anti-neuroinflammation, E cognitive enhancer, F relief of behavioral psychological symptoms of dementia, G others, U undisclosed

Availability of data and materials

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Abbreviations

Amyloid-beta

Acetylcholine

Cholinesterase inhibitors

• Alzheimer disease

Alzheimer’s Disease Assessment Scale–Cognitive Subscale

Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory–Mild Cognitive Impairment Version

Apolipoprotein gene

Amyloid precursor protein

Amyloid-related imaging abnormalities

Amyloid, tau, and neurodegeneration biomarkers

Appropriate use recommendations

Autophagic vacuoles

Beta-secretase 1

Behavioral psychological symptoms of dementia

Clinical Dementia Rating scale

Clinical Dementia Rating scale Sum of Box

Caregiver Global Impression of Change

Cerebrospinal fluid

Clinical Trial of AD

Disease-modifyung therapies

Integrated Alzheimer’s Disease Rating Scale

Immunoglobulin gamma 1

Mild cognitive impairment

Magnetic resonance imaging

Nuclear factor κB

Neurofibrillary tangles

Neuropsychiatric Inventory

Positron emission tomography

Presenilin-1

Presenilin-2

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Li-Kai Huang and Yi-Chun Kuan contributed equally to this work.

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PhD Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, No. 291, Zhong Zheng Road, Zhonghe District, New Taipei City, Taiwan

Li-Kai Huang & Chaur-Jong Hu

Taipei Neuroscience Institute, Taipei Medical University, New Taipei City, Taiwan

Li-Kai Huang, Yi-Chun Kuan & Chaur-Jong Hu

Dementia Center and Department of Neurology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan

Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Yi-Chun Kuan & Chaur-Jong Hu

Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan

Yi-Chun Kuan

School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

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LKH and YCK: Conducted literature search, developed the study concept and design, extracted information from trials and studies, and contributed to manuscript drafting and revision. HWL: Extracted information from trials and studies and contributed to manuscript drafting and revision. CJH: Contributed to the study concept and design, interpreted the data and information, finalized and revised the manuscript, and provided overall supervision of the entire project.

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Huang, LK., Kuan, YC., Lin, HW. et al. Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update. J Biomed Sci 30 , 83 (2023). https://doi.org/10.1186/s12929-023-00976-6

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DOI : https://doi.org/10.1186/s12929-023-00976-6

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New alzheimer’s study suggests genetic cause of specific form of disease.

Neurons with amyloid plaques.

Samantha Laine Perfas

Harvard Staff Writer

Findings eventually could pave way to earlier diagnosis, treatment, and affect search for new therapies

A recent study published in Nature Medicine offers evidence that genetics may be a direct cause of a specific form of Alzheimer’s disease and not merely a risk factor. While most patients currently do not have a clearly identified cause of this devastating illness, researchers found that people with two copies of the gene variant APOE4 are at extremely high risk of developing Alzheimer’s. The finding led them to recommend a new designation that takes this into account, which could lead to up to a fifth of Alzheimer’s patients being classified as having a genetically caused form of the disease. The shift eventually could lead to earlier diagnosis and treatment and affect the search for therapies. Reisa Sperling , a neurologist at Mass General Brigham and an author of the study, explains the importance of the findings. This interview has been edited for clarity and length.

Your study highlights a new, clearly identified genetic component to Alzheimer’s disease worthy of a new designation. Could you explain why that’s significant?

Designating this form of Alzheimer’s disease means a group of people who are extremely likely — I won’t say absolutely, but extremely likely — to develop Alzheimer’s could be treated earlier. This could really have an impact on preventing dementia.

The second thing is there’s been an ongoing debate about whether Alzheimer’s disease has anything to do with amyloid plaques or not. And in this group, they begin to have buildup of amyloid plaques and tau tangles in their late 50s and early 60s, and the likelihood that they will develop symptoms of Alzheimer’s disease is extremely high. So it creates another link in our understanding of the disease process.

And finally, this is a bridge between the rare forms of genetically determined Alzheimer’s disease that are 100 percent penetrant and often affect people in their 40s and 50s. Those cases are often considered such a rarity that they’re not representative of Alzheimer’s disease. So people with two copies of APOE4 are a bit in the middle. This new study really suggests that their biomarkers are similar to what we see in these rare autosomal dominant diseases, and over 90 percent will develop Alzheimer’s pathology in their brains. It links the rare genetic forms of Alzheimer’s to what we call sporadic late-onset Alzheimer’s disease.

Part of this new classification would also make this type of Alzheimer’s one of the most common genetic disorders in the world. Are there benefits to having it classified that way?

I don’t know that I’m the best person to opine on that, but I certainly think there may be important reasons. For example, eventually getting insurance coverage for individuals who are below the age of 65 and need rapid evaluation and treatment for Alzheimer’s disease. Alzheimer’s disease often doesn’t get diagnosed in these individuals because people think they’re too young. Additionally, they may not have insurance coverage for all of the medications required for treatment.

I do think it is important that this is recognized as one of the more common genetic links to Alzheimer’s disease and leads the way to one day being able to treat people who have a strong family history and genetic predisposition. Then we can really think about being aggressive and treating patients early.

“Somehow, we have to turn these findings to — instead of being scary for people — being a sense of hope.” Reisa Sperling

We’ve known for a long time that there is a genetic component to Alzheimer’s disease. Is this one of the first studies to show such a specific genetic link?

No. As I mentioned there are these rare genes that we’ve known for more than 20 years that are very specific and cause Alzheimer’s disease at a much younger age. But this data really suggests that people who have two copies of this particular allele, APOE4, have such a high likelihood of developing Alzheimer’s disease.

So it’s not the first genetic link, but it is the first large study that convincingly says having two copies of this gene really increases the likelihood you will have Alzheimer’s disease. And it’s a more common gene; these other known genes are very rare. But with APOE4, it’s estimated that up to 15 percent of Alzheimer’s patients carry two copies of these alleles (although I will say that estimate is a little different across studies). It is much more common than these very rare autosomal dominant forms.

How common is it in the general population to have two copies of that gene?

Estimated, about 2 percent of the population, so it’s not that common. People having at least one copy of APOE4 is fairly common. Depending on which part of the world you’re from, that can be up to 25 percent. But having two copies is still pretty rare.

There is still so much that we don’t know about Alzheimer’s, but it does seem to be fueled by both genetic and environmental factors. In what ways does this research help push our understanding of the disease overall?

That’s a great question. And for me, this research really does provide support to both camps. One, the likelihood that people with these genes will develop amyloid plaque by the time they’re age 65 is somewhere between 75 and 95 percent. To me that suggests that it is genetically driven.

But there is a variability in the range of when people develop symptoms. And that suggests that there might be environmental or lifestyle factors that can make people’s brains more resilient, or conversely, more vulnerable. This research really supports both ideas that genetics is a major driver in Alzheimer’s disease, but you can modulate your risk of showing symptoms.

Would it be beneficial for people to know early on if they are carriers of these genes?

At this moment, I do not recommend that people who don’t have symptoms get genetic testing or blood-based biomarker testing. I hope that recommendation will change greatly over the next few years.

There are large-scale clinical trials, including the one I run . We’re recruiting people who have evidence of amyloid buildup, but don’t yet have symptoms, and we’re recruiting a lot of people with a family history and have copies of APOE4. If that study and other studies like it succeed in treating people before they have symptoms, then I would recommend testing and trying to get treatment as soon as possible.

But we don’t have that available right now, and I just think we don’t yet know what to do with that information before people have symptoms.

If this new classification did occur, what areas of further research would you be most excited to pursue?

Number one for me is we need to be able to offer treatments to those patients. Right now, there’s actually a black-box warning on some currently approved Alzheimer’s treatments that cautions treating people who have two copies of APOE4 because the risk of side effects is so great. I want to redouble my efforts to make sure we can offer disease-modifying medications in a safe way.

Number two is about the environment. I’m quite interested in what it is that modulates whether people get symptoms sooner rather than later, with this buildup of amyloid that’s genetically determined. How do we understand what factors were protective? That’s a very important area of research to help us understand what can modulate people’s risk of symptoms in the setting of a very strong genetic predisposition.

We talk about this in the study, but I think it’s also important to mention that these studies mostly observed white majority populations. And one of the things we desperately need to know is whether these findings are also true in more ethnic and racially diverse populations. There is some evidence that APOE4 might have a slightly different effect on amyloid in populations who come from communities of color.

Similarly, there are slight differences in the sex effects: Women APOE4 carriers have more likelihood of developing symptoms. I think it’s really important to get more information on representative populations, especially from communities of color, and really help us develop treatments that will work best for everybody.

For people who have Alzheimer’s or loved ones with Alzheimer’s, how do these findings offer hope or shed light on the disease?

This is another tool to be able to find people who have Alzheimer’s disease at an earlier stage and treat them earlier. My dad and my grandfather died of this disease, and I’m a clinical neurologist. When I see people with symptoms, I think this is helping us learn about the underlying causes and will help us in accelerating to find good treatments.

I think it will both help the next generation of people who are likely to develop Alzheimer’s disease, but it will also help us treat people who already have Alzheimer’s disease symptoms because every little bit of information helps us develop better treatments for all.

I really hope this research doesn’t have the effect of just scaring people. I hope it will instead say, “These are important clues so that we can treat people earlier and hopefully prevent dementia.”

Somehow, we have to turn these findings to — instead of being scary for people — being a sense of hope. I hope this means we will be able to find people and treat them before they develop symptoms.

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Alzheimer’s Breakthrough: Researchers Discover Novel Way To Potentially Halt Disease Progression

Innovative research from Mount Sinai has also identified new pathways for research.

Researchers at the Icahn School of Medicine at Mount Sinai have achieved a major breakthrough in Alzheimer’s disease research. Their study identifies a promising method that could potentially slow or even stop the progression of the disease. Focusing on the role of reactive astrocytes and the plexin-B1 protein in Alzheimer’s disease, the research offers vital insights into how brain cells communicate. This opens up new avenues for innovative treatment approaches. The findings were published on May 27 in the journal Nature Neuroscience .

This groundbreaking work is centered on the manipulation of the plexin-B1 protein to enhance the brain’s ability to clear amyloid plaques, a hallmark of Alzheimer’s disease. Reactive astrocytes, a type of brain cell that becomes activated in response to injury or disease, were found to play a crucial role in this process. They help control the spacing around amyloid plaques, affecting how other brain cells can access and clear these harmful deposits.

“Our findings offer a promising path for developing new treatments by improving how cells interact with these harmful plaques,” said Roland Friedel, PhD, Associate Professor of Neuroscience, and Neurosurgery, at Icahn Mount Sinai and a senior author of the study. The research was driven by the analysis of complex data comparing healthy individuals to those with Alzheimer’s, aiming to understand the disease’s molecular and cellular foundations.

Broad Implications and Validation of Gene Network Models

Hongyan Zou, PhD, Professor of Neurosurgery, and Neuroscience, at Icahn Mount Sinai and one of the study’s lead authors, highlighted the broader implications of their findings: “Our study opens new pathways for Alzheimer’s research, emphasizing the importance of cellular interactions in developing neurodegenerative disease treatments.”

One of the study’s most significant achievements is its validation of multiscale gene network models of Alzheimer’s disease. “This study not only confirms one of the most important predictions from our gene network models but also significantly advances our understanding of Alzheimer’s. It lays a solid foundation for developing novel therapeutics targeting such highly predictive network models,” said Bin Zhang, PhD, Willard T.C. Johnson Research Professor of Neurogenetics at Icahn Mount Sinai and one of the study’s lead authors. By demonstrating the critical role of plexin-B1 in Alzheimer’s disease, the research underscores the potential of targeted therapies to disrupt the disease’s progression.

The research team emphasizes that while their findings mark a significant advance in the fight against Alzheimer’s, more research is needed to translate these discoveries into treatments for human patients.

“Our ultimate goal is to develop treatments that can prevent or slow down Alzheimer’s progression,” Dr. Zhang added, outlining the team’s commitment to further exploring the therapeutic potential of plexin-B1.

Reference: “Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease” by Yong Huang, Minghui Wang, Haofei Ni, Jinglong Zhang, Aiqun Li, Bin Hu, Chrystian Junqueira Alves, Shalaka Wahane, Mitzy Rios de Anda, Lap Ho, Yuhuan Li, Sangjo Kang, Ryan Neff, Ana Kostic, Joseph D. Buxbaum, John F. Crary, Kristen J. Brennand, Bin Zhang, Hongyan Zou and Roland H. Friedel, 27 May 2024, Nature Neuroscience . DOI: 10.1038/s41593-024-01664-w

This study is supported by the NIH National Institute on Aging (NIA) grants U01AG046170 and RF1AG057440 and is part of the NIA-led Accelerating Medicines Partnership – Alzheimer’s Disease (AMP-AD) Target Discovery and Preclinical Validation program. This public-private partnership aims to shorten the time between the discovery of potential drug targets and the development of new drugs for Alzheimer’s disease treatment and prevention.

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Seven recent papers amplify advances in Alzheimer’s research

Alzheimer's Disease Biomarkers Dementias Neuroscience

AMP AD uses an open-science research model that makes all data and methods rapidly available to the research community at large through the data sharing infrastructure, the AD Knowledge Portal. Since the Portal’s launch in 2015, more than 3,000 researchers world wide from the academic, biotech, and pharmaceutical industry sectors have used the data resources for research on Alzheimer’s and related dementias.

Alzheimer’s is a complex disease, and as it slowly develops, many normal biological processes in the brain and the body go awry, from inflammation, to blood vessels damage and neuronal death. Seven recent AMP AD reports showcase research advances related to the discovery of new drug candidate targets, identification of molecular subtypes of the disease, and new potential biomarkers that can serve as the basis for a precision medicine approach to therapy development.

Identifying ATP6VA1 gene as a candidate target for treatment: Researchers at the Icahn School of Medicine at Mount Sinai in New York generated several types of molecular data from 364 brain donors at different stages of Alzheimer’s. Using network modeling, a way to show data and its relationships, the team identified large sets of genes associated with the disease. Among the thousands of molecular changes associated with Alzheimer’s, the expression of a set of neuronal genes (neuronal network) was the most disrupted. Their analyses identified ATP6VA1 as a master regulator gene of this neuronal network and demonstrated that increasing its expression genetically, or by using a pharmacologic agent, led to improving neuronal function in cultured cells and in flies. These findings were published in Neuron and pave the way for new drug discovery efforts targeting ATP6VA1 .

Finding and validating VGF gene as key regulator of Alzheimer’s: Another AMP AD study led by researchers at Icahn School of Medicine identified the VGF gene and protein as having a key role in protecting the brain against Alzheimer’s. This discovery was made possible by combining computational analyses that integrate large human Alzheimer’s molecular datasets, clinical features of Alzheimer’s, DNA variation, and data on gene- and protein expression with experimental studies in mouse models. The findings provide a new target for researchers seeking to develop drugs to treat or prevent Alzheimer’s. The report of the discovery of this gene as a key driver and its validation in mouse studies was published in Nature Communications .

Identifying different types of microglia associated with Alzheimer’s: An AMP AD research team at Columbia University conducted a study that measured the expression of genes in individual microglial cells purified from human brain samples obtained at autopsy and during neurosurgical procedures. This single cell profiling technology identified several molecular subtypes of microglia based on the pattern of gene expression. Follow-up validation studies in post mortem brain tissue showed that this microglia subtype was less abundant in Alzheimer's brains compared to control brains. These results, published in Nature Communications , will help design larger, more specific studies of the role of microglia subtypes in Alzheimer’s.

Using data to unfold and predict disease process: An AMP AD team led by researchers at Sage Bionetworks in Seattle used innovative computational approaches to make predictions about the sequence of molecular changes that lead to Alzheimer’s. The team used RNA sequencing data collected from a large collection of post-mortem tissue from Alzheimer’s and control brains. This modeling method, called the manifold learning method, predicted early-stage disease processes, such as RNA-splicing, mitochondrial function, and protein transport. Additionally, the method predicted several distinct molecular subtypes of late-onset Alzheimer’s. These predictions speak to the complex nature of the disease and the need to verify these observations in longitudinal studies where molecular signatures can be linked to different clinical features of the disease. These findings were published in Nature Communications .

Network modeling identifies molecular subtypes of Alzheimer’s: Using a large collection of human brain samples from different studies, a team led by researchers at Icahn School of Medicine also analyzed RNA sequencing data and identified three major molecular subtypes of Alzheimer’s. The subtypes, which are independent of age and disease stage, and are replicated across multiple brain regions, show how different combinations of biological pathways lead to brain degeneration. With further research and validation in larger groups, these molecular subtypes may help reveal how Alzheimer’s progresses and potential ways to slow or stop it. Their findings were published in Science Advances .

Identifying new biomarkers in spinal fluid: AMP AD researchers at Emory University identified groups of proteins (protein panels) associated with Alzheimer’s that could be identified in both brain and spinal fluid. These overlapping protein panels detected in the spinal fluid reflected changes in multiple biological process in the brain. The researchers found this by measuring 3,500 proteins in spinal fluid, and 12,000 proteins in a collection of postmortem brain samples, from patients with Alzheimer’s and cognitively normal study participants. The study also showed that these changes in the protein expression pattern were specific for Alzheimer’s. This work lays the foundation for the discovery of new fluid biomarkers for Alzheimer’s. These findings were published in Science Advances .

Investigating how being female may increase risk of Alzheimer’s: Duke University researchers and members of the Alzheimer’s Disease Metabolomic Consortium (ADMC) participating in the AMP AD program, analyzed the changes in the levels of 180 metabolites in the blood from more than 1,500 people who took part in the NIA-supported Alzheimer’s Disease Neuroimaging Initiative . The researchers reported that there are differences in a subset of blood metabolites associated with Alzheimer's based on sex and ApoE4 status. ApoE4 is the strongest Alzheimer's risk factor gene. Women with Alzheimer’s who carry the ApoE4 gene have a distinct metabolic pattern in blood. These metabolic changes suggest that females have a greater impairment of brain energy production than males. Dissecting metabolic differences in Alzheimer’s can identify specific pathways within specific patient subgroups and guide the way to personalized medicine.

The data and methods from the above studies are available and can be accessed by researchers across the world through the AD Knowledge Portal . The portal is the data repository for the AMP AD Target Discovery Program, and other NIA-supported team-science programs operating under open-science principles. Now in its sixth year, AMP AD is demonstrating the power of open science to enable the scientific community to investigate difficult scientific questions and jumpstart new drug discovery projects.

The AMP AD research teams are funded by NIA grants U01AG046152, U01AG046170, U01AG046139, U01AG046161, R01AG046171, R01AG046174, U19AG010483, U01AG042791, U01AG061357, U01AG061359, U01AG061835, and U24AG061340.

The studies outlined here were also supported by the following NIA grants (in order of appearance):

• ATP6VA1: NIA grants U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, and R01AG068030
• VGF: NIA grants U01AG046170, R01AG046170, RF1AG054014, RF1AG057440, R01AG057907, R01AG055501, U01AG046161, P50AG025688, 5R01AG053960, and 5R01AG062355
• Microglia: NIA grants U01AG046152, R01AG036836, R01AG048015, and RF1AG057473
• Disease process: NIA grants U54AG054345, RF1AG057443, P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, P50AG016574, R01AG032990, U01AG046139, R01AG018023, U01AG006576, U01AG006786, R01 AG025711, R01AG017216, and R01AG003949
• Subtypes: U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, R01AG068030, P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, U01AG52411, K01AG062683, and U01AG058635
• Spinal fluid biomarkers: NIA grants R01AG053960, R01AG057911, R01AG061800, RF1AG057471, RF1AG057470, R01AG061800, R01AG057911, R01AG057339, U01AG046161, and U01AG061357
• Female risk: NIA grants U01AG024904, P30AG10161, R01AG15819, R01AG17917, U01AG46152, U01AG61356, R01AG059093, R01AG046171, RF1AG051550, and U01AG024904, RF1AG058942, R01AG057452, R03AG054936, and RF1AG061872

These AMP AD activities relate to NIH’s AD+ADRD Research Implementation Milestone 2.A , “Create new research programs that use data-driven, systems-based approaches to integrate the study of fundamental biology of aging with neurobiology of aging and research on neurodegeneration, AD and AD-related dementias to better understand the mechanism(s) of vulnerability and resilience in AD across all levels of biologic complexity (from cellular to population level) and to gain a deeper understanding of the complex biology and integrative physiology of healthy and pathologic brain aging;” Milestone 9.B , "Accelerate the development of the next generation CNS imaging ligands and biofluid molecular signatures targeting a variety of disease processes (neuroinflammation, bioenergetic/metabolic compromise, oxidative stress, synaptic pathology) that can be used as research tools or developed into diagnostic, prognostic, theragnostic or target engagement biomarkers;" and Milestone 9.F , “Initiate studies to develop minimally invasive biomarkers for detection of cerebral amyloidosis, AD and AD-related dementias pathophysiology.”

References:

Wang M, et al. Transformative network modeling of multi-omics data reveals detailed circuits, key regulators, and potential therapeutics for Alzheimer's disease . Neuron . 2021;109(2):257-272.e14. doi:10.1016/j.neuron.2020.11.002.

Beckmann ND, et al. Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease . Nature Communications. 2020;11(1): 3942. doi:10.1038/s41467-020-17405-z.

Olah M, et al. Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease . Nature Communications . 2020;11(1):6129. doi:10.1038/s41467-020-19737-2.

Mukherjee S, et al. Molecular estimation of neurodegeneration pseudotime in older brains . Nature Communications . 2020;11(1):5781. doi:10.1038/s41467-020-19622-y.

Neff RA, et al. Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets . Science Advances . 2021;7(2):eabb5398. doi: 10.1126/sciadv.abb5398.

Higginbotham L, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease . Science Advances . 2020;6(43):eaaz9360. doi:10.1126/sciadv.aaz9360.

Arnold M, et al. Sex and APOE ε4 genotype modify the Alzheimer's disease serum metabolome . Nature Communications . 2020;11(1): 1148. doi:10.1038/s41467-020-14959-w.

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Alzheimer's researchers are looking beyond plaques and tangles for new treatments.

Jon Hamilton

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation. Matt York/AP hide caption

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation.

The field of Alzheimer's research is branching out.

After decades of focusing on the sticky amyloid plaques and tangled tau fibers associated with the disease, brain researchers are searching for other potential causes of impaired memory and thinking.

That search is on full display this week at the Alzheimer's Association International Conference in San Diego, where sessions are exploring factors including genes, brain injury, clogged arteries and inflammation.

A group of researchers from Seattle even unveiled a highly detailed atlas showing how different types of brain cells change in Alzheimer's. The goal is to help scientists identify new approaches to treatment.

"Certainly, plaques and tangles are a hallmark," says Maria Carrillo , chief science officer of the Alzheimer's Association. "It doesn't mean plaques are the cause of cell death."

Plaques are clumps of a protein called beta-amyloid that appear in the spaces between neurons. Tangles are made up of a protein called tau that appears inside a neuron.

Both proteins tend to accumulate in the brains of people with Alzheimer's. But their role in killing brain cells is still unclear.

Carrillo says the Alzheimer's field needs to look to cancer research where a deeper understanding of the disease has led to better treatments.

The shift comes after a series of experimental drugs have succeeded in removing amyloid plaques and tau tangles from the brain, but failed to halt the disease.

The Food and Drug Administration has approved one amyloid drug, Aduhelm, but is still evaluating whether it actually helps patients.

An Alzheimer's Atlas

The study that produced the atlas is emblematic of how researchers are recalibrating.

"What we're trying to do with this study is to look at cell vulnerability early on in disease, before [people] have plaques and tangles, before they have cognitive impairment," says Dr. C. Dirk Keene , a neuropathologist at the University of Washington.

To create the atlas, Keene and a team of researches analyzed more than a million cells from 84 brains donated by people who'd signed up for Alzheimer's research projects run by the University of Washington and Kaiser Permanente Washington Research Institute.

The brains came from donors "at all different stages of disease" Keene says, "so we can pinpoint what's happening from the earliest levels all the way through to people with advanced disease."

The effort is funded by the National Institute on Aging and grew out of the federal BRAIN initiative launched by President Obama in 2013.

The atlas came from the realization that "If we want to treat diseases of an extremely complex cellular organ, you need to understand that organ much better than we do," says Ed Lein , a senior investigator at the Allen Institute for Brain Science, which played a key role in analyzing the brain tissue.

So the team spent years studying cells in healthy brains before looking at brains affected by Alzheimer's.

"We've defined what a normal adult brain looks like," Lein says, "and now we can use that knowledge and look for changes that are happening in specific kinds of cells."

Future Alzheimer's Treatments Aim To Do More Than Clear Plaques From The Brain

Finding vulnerable brain cells.

At the Alzheimer's meeting, the team described changes they saw in more than 100 types of cells taken from the cortex — an area of the brain which is important to memory and thinking.

One finding was that neurons that make connections within the cortex itself were much more likely to die than those that connect to distant areas of the brain.

"What we're seeing is a profound effect on cortical circuitry that very plausibly is the reason we have cognitive decline," Lein says.

If so, a treatment designed to protect those vulnerable neurons might prevent declines in memory and thinking linked to Alzheimer's.

The team also found a proliferation of brain cells that contribute to inflammation. These included certain immune cells and a type of cell that responds to injury.

"So while the neurons are lost, the non-neuronal cells are actually increasing and changing" Lein says.

The finding supports the idea that inflammation plays an important role in Alzheimer's, and that anti-inflammatory drugs might help protect the brain.

The Seattle team hopes other scientists will use the brain cell atlas to come up with new treatments for Alzheimer's.

"We've created an open-access resource where the whole community can come and look at this data," Lein says. "They can mine it to speed up progress in the field as a whole."

Speeding up progress is one reason Kyle Travaglini , a researcher at the Allen Institute, jumped at the chance to work on the Alzheimer's project.

"My grandmother started developing Alzheimer's disease when I was just going off to college," says Travaglini, who received his PhD in 2021.

Travaglini says the atlas project is appealing because it isn't based on a preconceived idea about what causes Alzheimer's.

"It's like looking at the same disease that everyone has been looking at but in an entirely different way," he says.

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New Alzheimer's studies reveal disease biology, risk for progression and the potential for a novel blood test

by Boston University School of Medicine

The failure to diagnose Alzheimer's disease—the most common form of dementia in the elderly—at an early stage of molecular pathology is considered a major reason that treatments fail in clinical trials. Previous research to molecularly diagnose Alzheimer's disease yielded "A/T/N" central biomarkers based on the measurements of proteins, β-amyloid ("A") and tau ("T"), and "N" encompassing neurodegeneration. A/T/N can be measured in brain tissue, by in vivo brain imaging techniques, and by analysis of cerebrospinal fluid and plasma.

Alzheimer's disease is thought to be triggered by combinations of genetic and environmental risk factors. Blood-based biomarkers such as plasma microRNAs (miRNAs)—molecules that regulate genome-environment interactions and control the expression of genes governing brain functions which deteriorate in Alzheimer's—could offer advantages of cost-savings, accessibility and decreased invasiveness.

Two new papers by a team of researchers at Boston University, the Indiana University School of Medicine and the Alzheimer's Disease Neuroimaging Initiative (ADNI), and the German Center for Neurodegenerative Diseases (DZNE) in Goettingen, Germany, published in Alzheimer's & Dementia demonstrate that evaluating microRNAs in blood can be used not only to diagnose mild cognitive impairment (MCI), but also, critically, to predict the conversion from MCI to dementia due to Alzheimer's disease. Moreover, the researchers uncovered microRNA candidate molecular biomarkers that associate with current amyloid, tau, and neurodegeneration (A/T/N) Alzheimer's biomarkers.

"Our papers are the result of a successful collaboration that tied the technology developed by professor Andre Fischer in Germany's DZNE to reliably measure the levels of microRNA in human plasma, and the power of blood samples obtained from hundreds of ADNI participants participating in a simulated clinical trial taking place at about 60 medical centers across the US and Canada," said Ivana Delalle, MD, Ph.D., professor of pathology & laboratory medicine at Boston University Chobanian & Avedisian School of Medicine, and one of four senior authors.

Our discovery is important, because unlike the current A/T/N biomarkers, microRNAs may serve as blood molecular biomarkers years before Alzheimer's disease manifests clinically, thus identifying the time window for effective prevention or early intervention to stop the progression of Alzheimer's."

The other senior authors are Andre Fischer, Ph.D., DZNE speaker and professor of epigenetics of neurodegenerative diseases at University Medical Center Goettingen, Germany; Kwangsik Nho, Ph.D., professor of radiology and imaging sciences at the IU School of Medicine; and Andrew J. Saykin, PsyD, Raymond C. Beeler Professor of Radiology and director of the Center for Neuroimaging and the Indiana Alzheimer's Disease Research Center at the IU School of Medicine.

The researchers examined miRNA expression in the plasma samples of three diagnostic groups of participants—cognitively normal, mildly cognitively impaired and dementia due to Alzheimer's disease patients. They found that when combined with neuropsychological testing, plasma microRNAome evaluation helps predict which aging individuals concerned about cognitive decline will progress to develop Alzheimer's.

"These findings provide a path toward a better understanding of the molecular mechanisms driving plaques, tangles and atrophy, and may provide clues for the next generation of therapeutic targets," Saykin said.

While these are exciting times with novel therapies for Alzheimer's disease entering clinical care, the researchers note that those therapies will only work in a real-world setting if patients at risk are identified as early as possible.

"MicroRNAs are ideal biomarkers since they are not only very stable, but also control entire molecular pathways, thereby ensuring cellular homeostasis. As such, one microRNA can simultaneously control many proteins belonging to a certain pathway," Fischer said.

"Therefore, the analysis of a few microRNAs can inform about complex pathological changes reflecting multiple pathways, such as neuroinflammation, metabolic changes, or synapse dysfunction. Thus, we need biomarkers that allow screening applicable in a point-of-care setting. Our studies are an important step in this direction."

"We have laid the groundwork for further investigations into the role of microRNAs in Alzheimer's disease pathogenesis," Nho said. "We envision that once specific miRNA signatures are further confirmed, the analysis of blood miRNAs will be transferred to simple assay formats, enabling the adoption of blood miRNAome analysis in clinical practice."

The researchers said improved tools for the early detection of Alzheimer's are indispensable for developing prevention and treatment strategies for the disease that is causing enormous suffering and burdens on health care systems around the world.

Alzheimer's & Dementia (2024). alz-journals.onlinelibrary.wil … ll/10.1002/alz.14230

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New class of Alzheimer's drugs showing promise in patients in early stage of disease

Topic: Alzheimer's and Dementia

Melbourne grandmother Jan Cody was not eligible for the new drug trial but now has hope. ( ABC News: Loretta Florance )

For decades scientists and families have been frustrated by the intractable nature of Alzheimer's disease.

Key points:

• A study showed donanemab could slow Alzheimer's disease progression by 35pc in patients in the earliest stages of the disease
• Geriatrician Michael Woodward says the medical community is excited by the results
• The donanemab study findings were similar to those of its predecessor lecanemab

As the population ages and more people develop the devastating condition, there have been no new treatments coming onto the market and for many, no hope in sight.

That was until two years ago.

In a short time, decades of research has started to come to fruition, with at least three new drugs demonstrating the first glimmers of promise.

The latest is called donanemab, with the findings of a global trial involving 1,700 patients presented at a major Alzheimer's conference in The Netherlands.

Sixteen Australians took part in the trial at eight sites in Victoria and New South Wales.

The drug, from pharmaceutical giant Eli Lilly, was able to slow Alzheimer's disease progression by 35 per cent in patients in the earliest stages of the disease.

Across the whole study, there was a 22 per cent slowdown in the disease's progress at the 18-month mark.

Sixteen Australians took part in the donanemab trial. ( Supplied: Eli Lilly )

Michael Woodward, a geriatrician who has been involved in Alzheimer's research for decades, was at the Alzheimer's conference and said the medical community was excited by the results.

"I would regard this as the end of the beginning in Alzheimer's therapies," he said.

"The word breakthrough is used perhaps a little too often, but this is a major breakthrough.

"We now have three drugs that have been shown that can critically slow down the decline."

How does the new drug work?

Donanemab is a monoclonal antibody designed to clear the brain of amyloid plaque, which experts believe plays a role in Alzheimer's disease.

Researchers have long been trying to work out whether a protein called beta-amyloid plaque (BAP) or another protein called tau is responsible for Alzheimer's, or a combination of the two.

Those in the study were all in the early stages of Alzheimer's and aged between 60 and 85.

At the 12-month mark, the researchers said 47 per cent had no evidence of amyloid plaques, compared with 29 per cent in the placebo group.

Associate Professor Stephen Macfarlane says donanemab has shown positive results in three of his patients. ( Supplied )

Patients also did not need indefinite treatment, with injections being able to reduce amyloid to non-existent levels where they would not re-accumulate for many years.

Stephen Macfarlane had three patients in the study through his work with The Dementia Centre at HammondCare in Victoria.

He said the medication was the equivalent of slowing the rate of the disease by seven and a half months compared to someone who was not taking it.

"These drugs slow the progression of the disease, they don't cause people to improve," Dr Macfarlane said.

He said it was the most promising drug in two decades for Alzheimer's research.

"It's the most effective, and the safety data seems to be on a par with similar drugs," he said.

The findings show there was a risk of brain bleeding and swelling in a subset of patients, including 1.6 per cent of participants who experienced serious forms, and three who died.

"Bearing in mind that Alzheimer's disease is a fatal and otherwise untreatable illness, some degree of risk is inherent in the process," Dr Macfarlane said.

Drug follows on heels of another, lecanemab

The donanemab study findings were similar to those of its predecessor lecanemab, sold under the brand name Leqembi.

It reduced cognitive decline by 27 per cent in patients with early Alzheimer's in a study published last year.

Lou Coenen is among the Australian patients in a lecanemab trial.

This drug from Japanese drug maker Eisa is being tested in four trials that include Australian sites across 18 locations.

The 72-year-old was diagnosed with Alzheimer's about five years ago and had a family history of the disease.

"You just start feeling your thinking doesn't work quite as fast," Mr Coenen said.

"You start to wonder why."

He decided to take part in a clinical trial of lecanemab through the KaRa Institute of Neurological Diseases to help give back to the health community.

He says he does notice a difference on the medication.

It is allowing him to spend more time with his wife and family and still participate in community activities such as The Men's Shed.

"I know compared to other people this is working," he said. "But I don't have a comparative of another me that says otherwise."

On June 30 Australia's Therapeutic Goods Administration (TGA) started work to consider approving lecanemab in Australia.

This drug has shown similar results to donanemab in patients with early Alzheimer's but also comes with risks of brain swelling and bleeding in a small subset of patients.

Melbourne grandmother Jan Cody had to give up work and other activities after realising she had Alzheimer's disease. ( ABC News: Loretta Florance )

How much will it cost?

New Alzheimer's drugs to the market are predicted to be hugely expensive for governments because of the significant time and cost they took to develop.

Leqembi is priced at about $US26,500 ($39,974) for a year's supply of infusions every two weeks but there is no potential price for donanemab yet, which will involve monthly injections.

"That's going to be a big challenge," Dr Woodward said.

"But we've got to look also at the savings. The total cost of care for Alzheimer's disease is probably closer to about $6-7 billion per year in Australia."

Dr Macfarlane said the drug would also mean Australia would need to revamp its Alzheimer's infrastructure so PET scans were more available for early diagnoses, regular hospital infusions were easier to access, and patients were diagnosed much sooner.

"We know in Australia that on average there's about a three-year delay between people first experiencing symptoms of memory loss and actually receiving a diagnosis," he said.

Biogen drug caused controversy

The drugs follow the groundbreaking but controversial release of Biogen's Aducanumab in 2021.

It is another monoclonal antibody that also works by removing the build-up of amyloid plaque proteins.

It was controversial because of the way the research was structured and the pharmaceutical company's relationship with US regulators.

In June this year the Therapeutic Goods Administration found the drug did not meet its safety and efficacy requirements for approval in Australia and Biogen withdrew its application.

Latest findings bring hope for patients

For Melbourne grandmother Jan Cody, the first sign she knew her memory was failing was when her three children met to discuss her declining mental state.

Victorian grandmother Jan Cody has noticed improvements since beginning treatment for Alzheimer's disease. ( Supplied )

The 75-year-old had to give up her work as a psychologist, as well as cooking and driving.

"My world just shrank. There's really no medication to take," she said.

She has been involved in some Alzheimer's trials but was not eligible for donanemab.

"The slowing it down takes a long time," she said. "So one really doesn't know whether you're going to last."

"But now I do have a glimmer of hope."

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In 2 papers, researchers describe potential new neurodegenerative disease treatment approach

William McEwan, Ph.D., spent years unraveling how an antiviral protein, tripartite motif-containing 21 (TRIM21), protects our cells from infection. Working in the lab of Leo James, Ph.D., McEwan and collaborators realized that TRIM21 marks viruses to be destroyed by the cell’s waste disposal system —but only activates when enough of the proteins cluster together.

McEwan and James have now taken advantage of TRIM21’s cluster activation by turning it against another protein with a penchant for aggregation: the misfolded tau protein that causes Alzheimer’s and other neurodegenerative diseases. In two new papers, they demonstrate how two TRIM21-based techniques can remove tau tangles inside of mouse neurons while leaving healthy tau alone and improve mobility in a mouse model of Alzheimer’s disease.

“These two articles by the groups of William McEwan and Leo James are very interesting,” Einar Sigurdsson, Ph.D., a neuroscientist at NYU Grossman School of Medicine, and colleagues wrote in a forthcoming commentary that Sigurdsson shared in advance with Fierce Biotech. “Both of these potential therapies are successful in clearing pathological tau.”

Our cells normally use TRIM21 as a last line of defense against viruses that manage to breach the cell membrane. Once McEwan, now at the UK Dementia Research Institute at the University of Cambridge, understood how TRIM21 is activated by bunching together, he saw its potential to go after tau aggregates right away.

“It's only when it's forced to cluster on the surface of a virus that it becomes activated,” McEwan told Fierce in an interview. “We asked whether this could therefore allow us to encode specificity for aggregates.” In a 2017 study, he found that TRIM21, combined with antibodies that target tau, could effectively destroy tangles of misfolded tau protein in human cells.

To turn TRIM21 into a treatment, McEwan and James, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, needed to make the molecule smaller and simpler. They first isolated the part of the protein that does the antiviral dirty work, called the RING domain, and then linked it to two different tau-targeting molecules: a miniature antibody (nanobody) called F8-2 and tau protein itself.

The team engineered genes to code for the RING constructs and delivered them to mice using an adenovirus vector, commonly used in gene therapy. Injecting the RING-nanobody gene into mice with pathogenic tau, either directly into their brains or in their tails (depending on the vector), successfully cleared the aggregated proteins from their brains while not decreasing overall tau levels. The results were published in Science on Aug. 29.

In the other study, the team used tau protein itself as bait, because the misfolded tau seen in Alzheimer’s stick together and turn healthy tau pathological. This RING-Bait gene therapy also cleared tau tangles in mouse brains, and treated mice were able to walk more quickly and with more coordination. These results appeared in Cell on Sept. 13.

“It would have been interesting to see how [the two techniques] compare under identical conditions,” Sigurdsson and colleagues said in their commentary. “The antibody approach would seem to be safer because of better specificity and the RING-domain could possibly be cleaved to some extent from the mutant tau, which could then become pathological.”

“It's a hypothetical possibility” that the tau bait could separate from RING, McEwan said. “We didn't see evidence of that in our study, but it's definitely something you would want to keep an eye out for.”

Recent years have seen a boom in therapies that go after tau, which is a tougher target than the other main neurodegenerative protein—amyloid beta—because it mostly sits inside of brain cells rather than outside of them. Sigurdsson recently published a paper on a gene therapy that produces tau-targeting antibodies , and, in July, AC Immune presented preclinical data on a new class of antibody-drug conjugates that the biotech thinks has “landmark” potential.

McEwan said he’s looking to set up a company to develop other TRIM21-based degrader molecules. He also plans to continue using the new RING techniques to study the basic biology of tau in neurodegenerative disease.

“What really pays is the molecular understanding of the pathogenesis of the disease and the molecular pathways that could be applied to treat it,” McEwan said. “The investment that charities and governmental bodies have put into basic research is beginning to come to fruition.”

New Alzheimer’s Studies Reveal Disease Biology, Risk for Progression, and Potential for Novel Blood Test

The failure to diagnose Alzheimer’s disease, the most common form of dementia in the elderly, at an early stage of molecular pathology is considered a major reason why treatments fail in clinical trials. Previous research to molecularly diagnose Alzheimer’s disease yielded “A/T/N” central biomarkers based on the measurements of proteins, β-amyloid (“A”) and tau (“T”), and “N” encompassing neurodegeneration. A/T/N can be measured in brain tissue, by in vivo brain imaging techniques, and by analysis of cerebrospinal fluid and plasma.

Alzheimer’s disease is thought to be triggered by combinations of genetic and environmental risk factors.   Blood-based biomarkers such as plasma microRNAs (miRNAs)—molecules that regulate genome-environment interactions and control the expression of genes governing brain functions which deteriorate in Alzheimer’s—could offer advantages of cost-savings, accessibility and decreased invasiveness.

Two new papers by a team of researchers at Boston University Chobanian & Avedisian School of Medicine, the Indiana University School of Medicine and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the German Center for Neurodegenerative Diseases (DZNE) in Goettingen, Germany, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association demonstrate that evaluating microRNAs in blood can be used not only to diagnose mild cognitive impairment (MCI) but also, critically, to predict the conversion from MCI to dementia due to Alzheimer’s disease. Moreover, the researchers uncovered microRNA candidate molecular biomarkers that associate with current Amyloid, Tau, and Neurodegeneration (A/T/N) Alzheimer’s biomarkers.

“Our papers are the result of a successful collaboration that tied the technology developed by professor Andre Fischer in Germany’s DZNE to reliably measure the levels of microRNA in human plasma, and the power of blood samples obtained from hundreds of ADNI participants participating in a simulated clinical trial taking place at about 60 medical centers across the US and Canada. Our discovery is important because, unlike the current A/T/N biomarkers, microRNAs may serve as blood molecular biomarkers years before Alzheimer’s disease manifests clinically, thus identifying the time window for effective prevention or early intervention to stop the progression of Alzheimer’s,” explained one of four senior authors Ivana Delalle , MD, PhD, professor of pathology & laboratory medicine at Boston University.

The other senior authors are Andre Fischer, PhD, DZNE speaker and professor of epigenetics of neurodegenerative diseases at University Medical Center Goettingen, Germany; Kwangsik Nho, PhD, professor of radiology and imaging sciences at the IU School of Medicine; and Andrew J. Saykin, PsyD, Raymond C. Beeler Professor of Radiology and director of the Center for Neuroimaging and the Indiana Alzheimer’s Disease Research Center at the IU School of Medicine. The work was funded by the National Institutes of Health’s National Institute on Aging multisite project RF1AG078299. “MicroRNAs as Diagnostic and Prognostic Biomarker of Alzheimer’s Disease” that supports the teams of researchers in multiple institutions.

The researchers examined miRNA expression in the plasma samples of three diagnostic groups of participants—cognitively normal, mildly cognitively impaired and dementia due to Alzheimer’s disease patients. They found that, when combined with neuropsychological testing, plasma microRNAome evaluation helps predict which aging individuals concerned about cognitive decline will progress to develop Alzheimer’s.

“These findings provide a path toward a better understanding the molecular mechanisms driving plaques, tangles and atrophy, and may provide clues for the next generation of therapeutic targets,” Saykin said.

While these are exciting times with novel therapies for Alzheimer’s disease entering clinical care, the researchers note that those therapies only will work in a real-world setting if patients at risk are identified as early as possible.

“MicroRNAs are ideal biomarkers since they are not only very stable but also control entire molecular pathways thereby ensuring cellular homeostasis. As such one microRNA can simultaneously control many proteins belonging to a certain pathway,” Fischer said. “Therefore, the analysis of a few microRNAs can inform about complex pathological changes reflecting multiple pathways, such as neuroinflammation, metabolic changes, or synapse dysfunction. Thus, we need biomarkers that allow screening applicable in a point-of-care setting. Our studies are an important step in this direction.”

“We have laid the groundwork for further investigations into the role of microRNAs in Alzheimer’s disease pathogenesis,” Nho said. “We envision that once specific miRNA signatures are further confirmed, the analysis of blood miRNAs will be transferred to simple assay formats enabling the adoption of blood miRNAome analysis in clinical practice.”

The researchers said improved tools for the early detection of Alzheimer’s are indispensable for developing prevention and treatment strategies for the disease that is causing enormous suffering and burdens health care systems around the world.

These findings appear online in Alzheimer’s & Dementia in two papers. Find them here and here .

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Alzheimer's treatments: what's on the horizon.

Despite many promising leads, new treatments for Alzheimer's are slow to emerge.

Current Alzheimer's treatments temporarily improve symptoms of memory loss and problems with thinking and reasoning.

These Alzheimer's treatments boost the performance of chemicals in the brain that carry information from one brain cell to another. They include cholinesterase inhibitors and the medicine memantine (Namenda). However, these treatments don't stop the underlying decline and death of brain cells. As more cells die, Alzheimer's disease continues to progress.

Experts are cautious but hopeful about developing treatments that can stop or delay the progression of Alzheimer's. Experts continue to better understand how the disease changes the brain. This has led to the research of potential Alzheimer's treatments that may affect the disease process.

Future Alzheimer's treatments may include a combination of medicines. This is similar to treatments for many cancers or HIV / AIDS that include more than one medicine.

These are some of the strategies currently being studied.

Taking aim at plaques

Some of the new Alzheimer's treatments target clumps of the protein beta-amyloid, known as plaques, in the brain. Plaques are a characteristic sign of Alzheimer's disease.

Strategies aimed at beta-amyloid include:

Recruiting the immune system. Medicines known as monoclonal antibodies may prevent beta-amyloid from clumping into plaques. They also may remove beta-amyloid plaques that have formed. They do this by helping the body clear them from the brain. These medicines mimic the antibodies your body naturally produces as part of your immune system's response to foreign invaders or vaccines.

The U.S. Food and Drug Administration (FDA) has approved lecanemab (Leqembi) and donanemab (Kisunla) for people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease.

Clinical trials found that the medicines slowed declines in thinking and functioning in people with early Alzheimer's disease. The medicines prevent amyloid plaques in the brain from clumping.

Lecanemab is given as an IV infusion every two weeks. Your care team likely will watch for side effects and ask you or your caregiver how your body reacts to the drug. Side effects of lecanemab include infusion-related reactions such as fever, flu-like symptoms, nausea, vomiting, dizziness, changes in heart rate and shortness of breath.

Donanemab is given as an IV infusion every four weeks. Side effects of the medicine may include flu-like symptoms, nausea, vomiting, headache and changes in blood pressure. Rarely, donanemab can cause a life-threatening allergic reaction and swelling.

Also, people taking lecanemab or donanemab may have swelling in the brain or may get small bleeds in the brain. Rarely, brain swelling can be serious enough to cause seizures and other symptoms. Also in rare instances, bleeding in the brain can cause death. The FDA recommends getting a brain MRI before starting treatment. The FDA also recommends periodic brain MRIs during treatment for symptoms of brain swelling or bleeding.

People who carry a certain form of a gene known as APOE e4 appear to have a higher risk of these serious complications. The FDA recommends testing for this gene before starting treatment.

If you take a blood thinner or have other risk factors for brain bleeding, talk to your healthcare professional before taking lecanemab or donanemab. Blood-thinning medicines may increase the risk of bleeds in the brain.

More research is being done on the potential risks of taking lecanemab and donanemab. Other research is looking at how effective the medicines may be for people at risk of Alzheimer's disease, including people who have a first-degree relative, such as a parent or sibling, with the disease.

The monoclonal antibody solanezumab did not show benefits for individuals with preclinical, mild or moderate Alzheimer's disease. Solanezumab did not lower beta-amyloid in the brain, which may be why it wasn't effective.

Preventing destruction. A medicine initially developed as a possible cancer treatment — saracatinib — is now being tested in Alzheimer's disease.

In mice, saracatinib turned off a protein that allowed synapses to start working again. Synapses are the tiny spaces between brain cells through which the cells communicate. The animals in the study experienced a reversal of some memory loss. Human trials for saracatinib as a possible Alzheimer's treatment are now underway.

Production blockers. These therapies may reduce the amount of beta-amyloid formed in the brain. Research has shown that beta-amyloid is produced from a "parent protein" in two steps performed by different enzymes.

Several experimental medicines aim to block the activity of these enzymes. They're known as beta- and gamma-secretase inhibitors. Recent studies showed that the beta-secretase inhibitors did not slow cognitive decline. They also were associated with significant side effects in those with mild or moderate Alzheimer's. This has decreased enthusiasm for the medicines.

Keeping tau from tangling

A vital brain cell transport system collapses when a protein called tau twists into tiny fibers. These fibers are called tangles. They are another common change in the brains of people with Alzheimer's. Researchers are looking at a way to prevent tau from forming tangles.

Tau aggregation inhibitors and tau vaccines are currently being studied in clinical trials.

Reducing inflammation

Alzheimer's causes chronic, low-level brain cell inflammation. Researchers are studying ways to treat the processes that lead to inflammation in Alzheimer's disease. The medicine sargramostim (Leukine) is currently in research. The medicine may stimulate the immune system to protect the brain from harmful proteins.

Researching insulin resistance

Studies are looking into how insulin may affect the brain and brain cell function. Researchers are studying how insulin changes in the brain may be related to Alzheimer's. However, a trial testing of an insulin nasal spray determined that the medicine wasn't effective in slowing the progression of Alzheimer's.

Studying the heart-head connection

Growing evidence suggests that brain health is closely linked to heart and blood vessel health. The risk of developing dementia appears to increase as a result of many conditions that damage the heart or arteries. These include high blood pressure, heart disease, stroke, diabetes and high cholesterol.

A number of studies are exploring how best to build on this connection. Strategies being researched include:

• Current medicines for heart disease risk factors. Researchers are looking into whether blood pressure medicines may benefit people with Alzheimer's. They're also studying whether the medicines may reduce the risk of dementia.
• Medicines aimed at new targets. Other studies are looking more closely at how the connection between heart disease and Alzheimer's works at the molecular level. The goal is to find new potential medicines for Alzheimer's.
• Lifestyle choices. Research suggests that lifestyle choices with known heart benefits may help prevent Alzheimer's disease or delay its onset. Those lifestyle choices include exercising on most days and eating a heart-healthy diet.

Studies during the 1990s suggested that taking hormone replacement therapy during perimenopause and menopause lowered the risk of Alzheimer's disease. But further research has been mixed. Some studies found no cognitive benefit of taking hormone replacement therapy. More research and a better understanding of the relationship between estrogen and cognitive function are needed.

Speeding treatment development

Developing new medicines is a slow process. The pace can be frustrating for people with Alzheimer's and their families who are waiting for new treatment options.

To help speed discovery, the Critical Path for Alzheimer's Disease (CPAD) consortium created a first-of-its-kind partnership to share data from Alzheimer's clinical trials. CPAD 's partners include pharmaceutical companies, nonprofit foundations and government advisers. CPAD was formerly called the Coalition Against Major Diseases.

CPAD also has collaborated with the Clinical Data Interchange Standards Consortium to create data standards. Researchers think that data standards and sharing data from thousands of study participants will speed development of more-effective therapies.

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• Cummings J, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimer's and Dementia. 2022; doi:10.1002/trc2.12295.
• Burns S, et al. Therapeutics of Alzheimer's disease: Recent developments. Antioxidants. 2022; doi:10.3390/antiox11122402.
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Stories from The University of Texas Health Science Center at Houston (UTHealth Houston)

Grants for $3.5M from TARCC fund new Alzheimer’s disease research at UTHealth Houston

Written by: Deborah Mann Lake | Updated: September 19, 2024

Studies by researchers at UTHealth Houston seeking to understand the underlying pathology of Alzheimer’s disease in order to discover new pathways to treatment have earned multiple awards totaling $3.5 million from the Texas Alzheimer’s Research and Care Consortium ( TARCC ).

A state-funded organization composed of 11 medical schools across the state, the goal of the TARCC is to fund Alzheimer’s-related projects within the member institutions and promote collaborative efforts. Rodrigo Morales, PhD, professor of neurology with McGovern Medical School at UTHealth Houston, is vice chair of the TARCC Steering Committee. 

Projects include the following UTHealth Houston faculty and fellows.

Andrey Tsvetkov, PhD, associate professor in the Department of Neurology: Until recently, the contribution of chromosomal sex to sex-associated differences in Alzheimer’s disease has been largely ignored. As females possess two X chromosomes, many genes that partially escape X inactivation could be expressed at higher levels in females. The ACSL4 gene is located on the X chromosome. Whether ACSL4 plays a role in Alzheimer’s disease has not been studied. The primary objective is to investigate whether ACSL4-dependent molecular mechanisms exhibit sexual dimorphism in healthy and Alzheimer’s disease-derived neurons and mouse models of Alzheimer’s disease. Since clinical research has demonstrated variable efficacy of therapeutic agents in male and female patients, identifying sex-specific mechanisms has significant translational relevance.

Tatiana Barichello, PhD, associate professor in the Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences: Delirium is a severe neuropsychiatric syndrome characterized by sudden confusion, attention deficits, and changes in sleep and psychomotor activity. This project explores whether delirium, caused either by infection or sterile surgery, contributes to Alzheimer’s disease progression by promoting gut dysbiosis (imbalanced gut bacteria) and neuroinflammation. The first aim explores how delirium-like states, induced by infection, or by surgery without infection, affect the brain’s amyloidosis and tangles (hallmarks of the disease). The second aim focuses on how delirium affects existing disease pathology. Through this study, we aim to clarify the link between delirium and Alzheimer’s disease, potentially paving the way for improved prevention and treatment strategies for those at risk.

Rodney M. Ritzel, PhD, assistant professor in the Department of Neurology :  Women with Alzheimer’s disease exhibit greater cognitive vulnerability, faster cognitive decline, and increased brain volume loss compared to men. The hormonal shifts during menopause may elevate the risk of disease-related brain changes, as early menopause is associated with a higher risk of dementia later in life. The initiation of amyloid β (Aβ) pathology aligns with this unique life transition in women. As the primary drivers of inflammaging in the brain, senescent microglia represent important therapeutic targets, which if left unchecked, could worsen Alzheimer’s disease progression. This proposal will explore the role of biological aging in the pathogenesis and progression of Alzheimer’s disease and as a potential driver of sexually dimorphic outcomes. We will determine if the accumulation of senescent cells precedes amyloidopathy, or vice versa, and whether males and females respond similarly to senolytic treatment.

Natalia Pessoa Rocha, PharmD, PhD, MSc, assistant professor in the Department of Neurology: One of the main challenges in the field of Alzheimer’s disease and related dementias is the absence of a noninvasive, early, and reliable way to diagnose the disease in a clinical setting. While cognitive symptoms are the primary clinical features, neuropsychiatric symptoms are very common and often appear in the early stages. As a result, mild behavioral impairment has been suggested as a diagnostic category to identify patients at a higher risk of developing dementia. The major goal of this project is to contribute to validating mild behavioral impairment in a neurobiological framework using innovative and sensitive biochemical tests capable of identifying early Alzheimer’s disease-related pathology in patients with mild behavioral impairment. Validating mild behavioral impairment as a prodromal phase of Alzheimer’s disease on a biological level could pave the way for earlier clinical identification and targeted interventions for patients in the very early stages.

Salvatore Saieva, PhD, postdoctoral research fellow in the Department of Neurology: Alzheimer’s disease pathology is mainly linked to cerebral nervous system alterations, yet compelling evidence shows the contribution of peripheral tissues in disease progression. Aβ deposits have been identified in peripheral tissues of patients, including skin, liver, and intestine, and Aβ seeds can accelerate Aβ brain deposition in mouse models when challenged through different peripheral routes of administration. Notably, our group recently demonstrated that the most efficient peripheral administration route of Aβ seeds is through eye drops. This information is suggestive of an active cross-talk between brain and eyes in the context of Alzheimer’s disease. Therefore, investigating the biochemical, functional, and pathological properties of ocular Aβ deposits may be relevant to understand the mechanisms underlying disease onset and progression.

Vijayasree V. Giridharan, PhD, MPharm, assistant professor in the Faillace Department of Psychiatry and Behavioral Sciences: Recent studies suggest that the innate immune system, particularly a group of cells called innate lymphoid cells (ILCs), can revitalize the aging brain and alleviate cognitive decline. Specifically, a subtype known as ILC2 has been shown to reduce brain inflammation and improve memory in animal models by releasing protective molecules. Our preliminary research indicates that inactive ILC2 cells accumulate in the blood-brain barrier during infection, contributing to memory decline. While ILC2’s impact on memory has been studied, its role in the development of amyloid plaques and tau tangles, the two major hallmarks of Alzheimer’s disease, remains unexplored. We hypothesize that harnessing ILC2 cells could enhance memory, mitigate harmful brain changes, and slow the progression of Alzheimer’s disease. Our findings could provide valuable insights into potential immune therapies for Alzheimer’s disease and related dementias.

Huihui Fan, MBBS, PhD, assistant professor in the Department of Neurology: As the population of older adults grows around the world, the incidence of Alzheimer’s disease is also intensifying. However, not all people older than 65 are affected equally. Compared to other ethnic groups, Latinos are about 1.5 times more likely than non-Hispanic whites to develop Alzheimer’s disease and other dementias and are projected to have the steepest increase in Alzheimer’s disease in the next few decades. Some of the known and suspected risk factors for Alzheimer’s disease, for example advanced age and vascular disease risk factors such as diabetes and hypertension, predominantly present in Latinos, and may lead to their greater risks. The TARCC cohort will be used to uncover novel peripheral DNA methylation biomarkers in Hispanic patients with mild cognitive impairment and Alzheimer’s disease.

Youngran Kim, PhD, assistant professor with UTHealth Houston School of Public Health: This study looks at how the first drug approved by the U.S. Food and Drug Administration for treating agitation in Alzheimer’s patients, called brexpiprazole, is affecting Medicare patients in Texas. Before this drug was approved, doctors often used other antipsychotics that weren’t officially approved for treating agitation in dementia patients. Now that brexpiprazole is approved, the study will seek to see if its use will increase, how it might change the way doctors treat patients, and what this means for both health care costs and patient outcomes. To do this, Medicare claims data from Texas will be examined.

Sithara Thomas, PhD, postdoctoral research fellow in the Vivian L. Smith Department of Neurosurgery: Traditionally, Alzheimer’s disease research has primarily focused on neuronal and glial dysfunctions. However, recent studies suggest that brain vascular factors play a significant role in the development and progression of the disease. While it is clear that vascular decline is associated with Alzheimer’s disease, it remains unclear whether this decline is a cause or a consequence of the disease. Additionally, the potential benefits of enhancing vascular functions in ameliorating disease pathology are still being investigated. By gaining a deeper understanding of the vascular role in Alzheimer’s disease, researchers may be able to overcome the limitations of current treatments by developing medications that target and rejuvenate vascular functions.

Keran Ma, PhD, assistant professor in the Department of Neurobiology and Anatomy: Alzheimer’s disease causes abnormal function of nerve cells (neurons) in the brain, which results in cognitive impairment. Interestingly, immune cells in the brain (microglia) are capable of modulating the activity of neurons. Studies that identify changes in the genome of Alzheimer’s disease patients implicated microglia as an important cellular culprit in the disease. One variation of a microglial gene found in patients, called TREM2, increases the risk of developing the disease. The hypothesis is that TREM2 gene variation alters microglia function, which in turn causes abnormal regulation of neuronal activity by microglia. The resulting erratic activity of neurons may then impair learning and memory and induce seizures. To test the hypothesis, researchers will compare neuron-microglia communication and neuronal function between healthy control mice and genetically altered mice with Alzheimer’s disease-like brain pathology and the Alzheimer’s disease TREM2 gene variant. The outcomes of this study will help to illuminate the mechanisms driving the miscommunication between neurons and microglia and the resulting effects on brain function and memory loss, which may help to identify new avenues of Alzheimer’s disease therapeutic intervention. 

Vijay Kumar M.J. Rao, MSc, PhD, postdoctoral fellow in the Department of Neurology: Unhealthy brain aging causes loss of memory, thinking skills, and the ability to perform simple daily tasks. These problems are caused by the changes in the DNA and RNA leading to their damage during aging. Various forms of DNA have been found, such as four-stranded DNA which is called G4-DNA. Similar structures are also present in RNA and called G4-RNA. These G4-DNA/RNA structures have recently been described and perform many functions inside the cells. However, the exact function of these G4-DNA/RNA structures in brain aging is not known. In a previous study, researchers at UTHealth Houston identified more G4-DNA/RNA structures in the brain cells of aged animals. The abnormal presence of these G4 structures causes severe damage to cells in the brain. This will reduce the blood supply and nutrients and kill the brain cells. Reducing these G4-DNA/RNA structures inside the neurons and astrocytes could slow the aging process and prevent the brain cells from dying. In this study, researchers will decrease the levels of these G4 structures inside the brain cells with a goal of designing new drugs to fight brain diseases.

The TARCC 2025 Scientific Symposium will be held Thursday, Jan. 23, 2025, in Austin, Texas. More information can be found here : https://ais.swmed.edu/redcap/surveys/?s=4DNFCKE3XXMYFTN8 .

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Canada has a chance to change the Alzheimer’s experience - let’s not squander it

Dr. Sharon Cohen is a behavioural neurologist and the medical director and site principal investigator of the Toronto Memory Program.

There are currently more than 450,000 Canadians living with dementia. These numbers will double by 2030 and increase to 1.7 million by 2050, according to the Alzheimer Society of Canada. Alzheimer’s disease is the most common cause of dementia and is chronic, progressive, severely disabling and ultimately fatal. It is one of the most feared diseases of our time.

As a neurologist and medical director of the Toronto Memory Program, I see every day the heartbreak of individuals who dread the loss of independence that comes with Alzheimer’s, and the dismay of becoming a burden on their families. I also see the despair of families witnessing their loved ones gradually slipping away.

However, Alzheimer’s disease affects more than the stereotyped patient, often seen as elderly, frail and confused. In early disease stages, with symptoms often conflated with “normal aging,” many individuals diagnosed with Alzheimer’s are still living independently in their own homes, contributing to society and being active members of their families. They may be working, driving, travelling, pursuing hobbies and having meaningful relationships with friends.

It’s time to shake off the stigma and myths that have surrounded this disease and have held people back. We need to acknowledge that there is hope and that new and emerging treatments are shaping the future of Alzheimer’s diagnosis and treatment. The valiant contributions of researchers and patients, including those across Canada, have remarkably led to the full approval of two disease-slowing treatments in the U.S. in the past year, and health regulators in Britain have just approved the first of these – lecanemab .

Sold under the brand name Leqembi, lecanemab is a treatment already approved in seven countries (including Japan, China, South Korea, Israel and the United Arab Emirates). This drug is indicated for those with mild cognitive impairment or mild dementia owing to Alzheimer’s disease – and it works. It robustly clears amyloids (abnormal protein deposits) from the brain and in turn slows decline in cognition, daily function and quality of life. It buys individuals precious time at the early stages of disease, when time is most valued, and reduces the risk of individuals progressing to more disabling, costly and distressing stages.

The British health authority deemed Leqembi safe and effective after conducting a careful review of the drug’s Phase-3 study data. This approval is significant and long-awaited, yet bittersweet, as Britain’s public payer, the National Institute for Health and Care Excellence (NICE), has issued initial guidance recommending against cost coverage. NICE’s recommendation may change as advocacy groups and expert clinicians make the case that the benefits of Leqembi are not trivial as NICE has suggested.

As we wait impatiently for Health Canada to issue its decision on approval for Leqembi, we, as Canadians, need to reframe how we view Alzheimer’s disease. This is a disease, like any other complex, progressive disease, that should be identified and treated early and for which individuals who can benefit are given access to life-enhancing treatments. Our approach to early diagnosis, and early intervention, should be no different for Alzheimer’s than for cancer or any other serious diseases, where buying time is critical and the assessment of benefit versus risk of treatment should consider a patient’s values and goals.

Unfortunately, in considering Alzheimer’s disease, we all too often demonstrate paternalistic, and frankly insulting, patterns of “overprotecting” individuals from potential side effects. There is a clear double standard when it comes to agency approvals and cost coverage for Alzheimer’s treatments compared with treatments for other diseases.

Treating any disease comes with risk. In cancer care, we call these “trade-offs,” i.e. is the treatment worth the risk for more time with loved ones? We should view Alzheimer’s disease in the same way and let patients decide what risk is acceptable for the benefit of slowing their disease.

Patients and families have a lot on the line. Slowing down the progression of Alzheimer’s disease means families can stay together longer, independence can be maintained and lives can continue to be lived vibrantly for longer periods. However, this disease does not wait for health regulators and payers to make decisions over months or years; it progresses relentlessly, and once the early stages have passed, the treatment opportunity for a drug like Leqembi is lost.

Let’s not deny legitimate treatment opportunities to Canadians. Let’s make sure that we have access to meaningful, early treatments for Alzheimer’s disease.

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