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Author: Jean-Claude Muller, Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT 25.4

Alzheimer’s disease : Beyond the beta amyloid hypothesis

Summary

Alzheimer’s disease is a complex pathology involving neurons, microglia, astrocytes and blood barrier vessels. The precise causality of each of these cells and their fine entanglements in triggering the disease are still far of being fully understood . Recently two amyloid antibody drugs, Leqembi (lecanemab), developed by Biogen and Eisai, and Kisunla (donanemab), developed by Eli Lilly, were approved in the US and in some other countries but not in Europe .The two drugs were cleared for patients with mild cognitive impairment on the basis of clinical studies showing that they were able to slow the progression of the disease by neutralising and eliminating amyloid-beta aggregates in the brain.

Leqembi and Kisunla are the first so-called “disease modifying drugs” to be approved for Alzheimer’s disease. But there are not a panacea. Both drugs are moderately active and carry boxed warnings for a side effect known as amyloid related imaging abnormalities (ARIA) which can cause bleeding and affects patients with a specific genetic profile. Although these approvals are a significant step forward, there is still work to be done to address the complexity of this neurodegenerative disease.

This article which was published in a different format in the February 2025 issue of MedNous www.mednous.com presents work underway on candidate diagnostics, new concepts and late-stage therapies, to deliver a new generation of Alzheimer’s treatments.

Introduction

In 1999, when the researcher Dale Schenk published a paper giving arguments for the use of an immunotherapy to treat Alzheimer’s disease there was hope that a breakthrough was near. This was the amyloid beta hypothesis which posited that the disease could be treated by reducing the build-up of these plaques in the brain. However the first human trial of Schenk’s hypothesis had to be stopped. It was unsafe.

This didn’t stop the next generation of researchers from continuing to test the hypothesis in the years that followed. A new threshold was reached in 2023 when Leqembi (lecanemab), an antibody drug developed by Biogen Inc and Eisai Co Ltd, was given an accelerated approval by the US Food and Drug Administration for the treatment Alzheimer’s disease. Six months later this accelerated approval was converted into a full FDA authorisation. The drug was cleared on the basis of studies showing that it was able to slow the progression of the disease by neutralising and eliminating amyloid-beta aggregates in the brain. In January of this year Leqembi was given a new indication as a maintenance treatment, meaning that patients could continue to take it after 18 months by intravenous administration once every four weeks.

Kisunla (donanemab), also an antibody drug directed against amyloid beta and developed by Eli Lilly and Co, was approved in the US in 2024. The approval is for patients with mild cognitive impairment or a mild dementia stage of disease on the basis of evidence that the drug slowed clinical decline, especially for patients at an earlier stage of the disease.

Leqembi and Kisunla are the first, and thus far only, disease modifying drugs to be approved for Alzheimer’s disease. But there are limitations. Both drugs carry boxed warnings in the US for a side effect known as amyloid related imaging abnormalities (ARIA) which can cause bleeding and affects patients with a specific genetic profile. In Europe, the European Commission is withholding approval of Leqembi because of concerns about the risk minimisation measures for ARIA on the label.

Although the approvals are a significant step forward, there is still work to be done to address the highly complex pathology of Alzheimer’s disease. Fortunately, these efforts are now getting resources and attention. In this article, we discuss work underway, on candidate diagnostics, new concepts and late-stage therapies, to deliver a new generation of Alzheimer’s treatments. The first is to develop reliable biomarkers for the disease. Current clinical outcome assessments of patients do not accurately differentiate between Alzheimer’s disease and other neurological disorders which trigger memory impairment. Measures such as the Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) focus on episodic memory. But spatial memory, attention and executive function need to be better measured. Not surprisingly, the FDA recently updated its draft guidance, noting that traditional clinical outcome assessment tools may lack the sensitivity to detect early cognitive impairment. This raises the question of whether a single biomarker can identify the various forms of the disease and which biomarker would be the most relevant to reliably identify onset of the disease.

Among recent positive news is a finding by researchers in Sweden of a specific form of the protein tau that can be detected in a blood sample and predict the presence of the disease with a high degree of accuracy. This is phosphorylated Tau-217. Located in neurons, tau proteins bind to the internal skeleton-like structure of microtubules giving neurons their shape and transporting nutrients. Individuals with Alzheimer’s develop tangles of tau in the brain. Hyperphosphorylated forms of tau can be identified in the cerebrospinal fluid. Although tau accumulation appears to be secondary to the appearance of beta-amyloid plaques, only phosphorylated tau correlates with impaired memory and other cognitive symptoms of the disease. The Roche Group has developed an assay for detecting p-Tau 217 which received a breakthrough device designation from the FDA in April 2014.

Separately, recent data from Roche for a candidate diagnostic showed that the test could rule out amyloid pathology in a broad population with cognitive impairment. The test had a high negative predictive value of 96.2% based on a 23.4% prevalence of amyloid positivity as identified by positron emission tomography scans with 91% sensitivity and 69.8% specificity. In a prepared statement on 31 October 2024, Matt Sause, chief executive of Roche Diagnostics said the test results suggest that a fast and simple blood test could reliably rule out amyloid pathology.

Taking biomarker discovery to holistic level, Thomas K. Karikari assistant professor of psychiatry, has described how his team at the University of Pittsburgh, US, created a platform that can simultaneously analyse 116 biomarkers involved in the onset and progression of Alzheimer’s disease. The biomarkers include various forms of phosphorylated tau as well as cerebrovascular inflammatory markers, synaptic disorder markers and abnormal glial activity. A simplified version of this platform would be extremely useful for the medical community (1). For example, a platform based on simple blood levels could help develop relevant models of disease progression for the assessment of the clinical efficacy of a candidate drug and the follow-up of asymptomatic trial participants.

New clinical data 

There is no shortage of clinical activity in the Alzheimer’s field both testing the amyloid beta hypothesis and other targets. The candidate therapies are both monoclonal antibodies and small molecule drugs.

Roche is testing the amyloid hypothesis in a large Phase 3 study that incorporates a new approach to delivery. Trontinemab is a new version of the antibody therapy gantenerumab which has been engineered to cross the blood-brain barrier using new technology. Using this approach, gantenerumab binds to a receptor on the endothelial cells that make up the blood-brain barrier leading to endocytosis and release into the brain (2). Initial findings show that trontinemab is able to clear beta-amyloid in the brain much faster than other amyloid-directed antibodies. Scientists at Roche believe that the speed of amyloid reduction is an important feature for the efficacy of the drug. At a conference in Madrid in late October 2024, Roche reported data from a dose-finding study in which the antibody quickly rid the brain of plaques. There were three cases of mild ARIA. However, there was also one death after a second dose. Accordingly, Roche has updated exclusion criteria for ongoing and future trials (3). An ongoing Phase 3 trial should confirm the speed of amyloid clearance. The clinical benefits are expected to appear as soon as week 12 of treatment.

In other developments, UCB SA reported in October 2024 that Phase 2a data from a study of bepranemab, an anti-tau antibody for Alzheimer’s, showed no beneficial effect compared with the primary endpoint which was a rating on a dementia scale. However, in relation to two secondary endpoints it was able to slow the rate of tau accumulation versus placebo by 33% to 58% and slow cognitive decline by 21% to 25% versus placebo on a cognitive subscale. Three other tau antibodies: simerinemab from AC Immune SA; gosuranemab from Biogen Inc and zagotenemab from Eli Lilly and Co have failed in clinical trials in similar settings.

Also in October, a candidate small molecule Alzheimer’s treatment from Athira Pharma Inc did not reach statistical significance for the primary endpoint in a Phase 2/3 trial, while an Alzheimer’s trial of an antagonist of the orexin-2 receptor being run by Johnson & Johnson Inc was discontinued.

However, AC Immune has moved on from the simerinemab failure and is now testing the hypothesis that an anti-tau vaccine has the potential to become a disease modifying agent to delay or prevent the onset of cognitive impairment. This theory is being tested in a trial of ACI-35-030 which received a ‘fast track’ designation from the FDA in July 2024. The Phase 2b trial is enrolling participants with preclinical Alzheimer’s disease who have yet to show clinical symptoms (4). The drug is partnered with Janssen Pharmaceuticals Inc “The Phase 2b ReTain study is the first time any active immunotherapy is being tested in a preclinical AD population,” Andrea Pfeifer, the chief executive said in a statement on 25 July 2024.

AC Immune also received a ‘fast track’ designation for ACI-24-060, an active amyloid antibody immunotherapy which is in a Phase 1b/2 trial for patients with prodromal Alzheimer’s disease as well as adults with Down syndrome. This drug is partnered with Takeda Pharmaceutical Co Ltd.

Among the less conventional approaches is a move by Merck & Co Inc to repurpose Belsomera, a small molecule drug approved by the FDA in 2014 to treat insomnia, and in 2020 to treat sleep disorders in Alzheimer’s disease. Based on evidence that the drug, an orexin-2 antagonist, decreased tau phosphorylation and amyloid-beta concentrations in the central nervous system, Merck is assessing whether it can successfully act as an agent for the prevention of Alzheimer’s disease.

Another unusual approach is being undertaken by the Burke Neurological Institute in the US, in partnership with the Alzheimer’s Disease Cooperative Study, to investigate the therapeutic potential of benfotiamine, a synthetic version of vitamin B1 or thiamine.as a treatment for early Alzheimer’s disease. Benfotiamine can increase blood thiamine up to 100 times the normal level in humans The brain tissue in Alzheimer’s patients shows a thiamine deficiency. The trial is investigating whether increasing thiamine levels with the drug will slow cognitive decline in people with the disease.

Separately, Sinaptica Therapeutics Inc is developing a non-invasive neuromodulation therapy for Alzheimer’s disease using repetitive transcranial magnetic stimulation targeting the default mode network, which is the primary functional brain network most impacted by the disease. Delivery of the first clinical system for validation and use in clinical trials is expected in March. The treatment is reminiscent of one used by astronauts in space to stimulate their muscles and bones.

In December 2024 the European Medicines Agency accepted an application from Anavex Life Sciences Corp to review blarcasemine, a small molecule drug that activates the sigma-1 receptor and restores cellular homeostasis, including impaired autophagy enhancement. In an article in the Journal of Prevention of Alzheimer’s Disease, of January 2025, data from a trial leading up to the application showed clinical progression on a primary endpoint and no safety issues. Separately, researchers are investigating glucagon-like peptide 1 receptor agonists, currently approved for obesity, as possible agents in preventing Alzheimer’s disease. And scientists in Finland are investigating how changes in lifestyle, including losing weight, could affect the disease.

Recent late-stage developments

New concepts, new hypotheses, new findings

The Icelandic mutation. More than a decade ago, scientists discovered a mutation in which nearly one in 100 Icelanders were thought to be a carrier of a gene that is protective against Alzheimer’s disease. This Icelandic variant, A673T, was much more common in dementia-free elderly Icelanders than in people with Alzheimer’s. The variant was also found to protect against cognitive decline in the elderly (5). The effect of the A673T variant on amyloid precursor protein (APP) processing has been investigated in vitro but not in vivo. In a study led by Sho Shimohama et al, in the Journal of Neuroscience in November 2024, researchers used a mouse model carrying the Icelandic mutation, APP-A673T, devoid of a Swedish mutation that is located at the same site but with a different effect, to find out whether it had any impact on Alzheimer’s pathology. They discovered that APP-A673T significantly downregulated beta-cleavage and reduced the production of amyloid-beta and amyloid pathology in the brains of the animals. It also reduced neuroinflammation and neuritic alterations. The authors conclude that inhibition of the interaction between APP and the BACE1 enzyme could be a possible therapeutic approach. They even suggest that in vivo gene editing might be possible treatment for individuals identified at high risk of the disease (6). 

Insulin resistance. Several studies have shown that the brain’s insulin-binding receptors are impaired in Alzheimer’s disease. These receptors are mainly located in the blood-brain barrier (BBB) with little evidence of their appearance in brain cells. The inability of insulin to cross the barrier has led to the conclusion that insulin acts on brain function by binding to receptors located on blood vessels. Post-mortem brain samples from Alzheimer’s patients have shown a considerable reduction of insulin binding receptors in the brains of these individuals. The activation of these receptors was downregulated and responded poorly to increased levels of insulin. It is therefore possible that an increase in beta-amyloid may contribute to insulin resistance by preventing insulin from binding to its receptors and/or by promoting the degradation of these receptors in the blood-brain barrier. It remains to be understood how insulin resistance to the blood-brain barrier contributes to cognitive decline and how stimulating these receptors would improve clinical outcomes. These features are an incentive for researchers to discover drugs that do not need to cross the blood-brain barrier.

Autoimmunity. In late 2022, Donald Weaver published an article in Alzheimer’s & Dementia in which he argued that Alzheimer’s is an autoimmune disease, rejected the amyloid misfolding hypothesis and identified amyloid beta as a physiologically oligomerising cytokine-like immune-peptide which is part of a larger immunopathic concept of the disease (7). Autoimmunity is regarded as a chronic disorder of adaptive immunity which is highly specific, long lasting and remembered via autoantibodies. Innate autoimmunity responses are immediate, non-specific and not remembered. In Weaver’s hypothesis, when neurons are damaged, amyloid beta is released as an early responder cytokine, exhibiting antimicrobial properties and triggering an innate immunity cascade in which amyloid beta acts as a misdirected attack upon self-neurons, leading to a chronic, self-perpetuating cycle. According to this model, chronic pro-inflammatory cytokine release, tau aggregation, and mitochondriopathy with oxidative stress further contribute to disease progression.

Fungal infection. In late 2023, David Corry from Baylor College of Medicine in the US showed how Candida albicans, a yeast found in the gut, can access the brain and induce an infection that ultimately triggers Alzheimer’s disease. A chronic long-lasting infection could therefore be prodding the brain immune system and induce the disease. Studies with infected mice with the yeast showed that it disrupts the blood-brain barrier by secreting enzymes acting on amyloid precursor proteins and breaking it into amyloid beta like peptides. The group showed that the amyloid beta like peptides can also be generated from a source such as Candida albicans. This common fungus, which has been detected in the brains of people with Alzheimer’s disease and other chronic neurodegenerative disorders, has its own set of proteases that can generate the same toxic peptides that the brain generates endogenously.

Protein scaffolding. A recent report by scientists from the US Center for Neurodegenerative Disease, has proposed yet another hypothesis. This is that beta-amyloid may not be the only protein involved in the disease but rather a scaffolding for other proteins. This then raises the question of whether the scaffolding of proteins is the real culprit behind the damage to the brain cells of Alzheimer's patients. The report, which focused on Alzheimer’s brain proteomics, revealed that more than 20 proteins are capable of co-accumulating with beta-amyloid. The immediate question therefore is whether these proteins are simple markers of the disease, or are they aggravating factors. To study this further, the scientists focused on two proteins: midkine and pleiotrophine. The outcome was unambiguous: both accelerated beta-amyloid aggregation. The authors posit that amyloid-scaffolding is a central mechanism mediating downstream pathophysiology in Alzheimer’s disease. In other words, these proteins are involved in the process that leads to the brain damage characteristic of the disease and the linear amyloid cascade is again heavily challenged and even jeopardised. 

The missing link. What is still missing from these studies is the search for a link between ligand-target interactions and their biological responses. Some have already been identified in the gut but their links with the brain need to be further assessed. The bidirectional gut-brain connection involves the enteric nervous system, the vagus nerve, and the gut microbiome. There is a growing body of evidence that suggests that crosstalk between the gut and the brain influences cognitive function.

Conclusion
For the first time in many years the amyloid beta hypothesis is not the only concept to make the scene. The findings reported in this article, which all need to be validated or confirmed in well controlled human clinic trials, are promising. They illustrate that Alzheimer’s is a complex disease involving neurons, microglia, astrocytes and blood barrier vessels. New trials are expected to produce large amounts of data. This will require the use of digital technology to analyse the information fully and assess their intrinsic value. A successful treatment will certainly require more than one target. And like in oncology, it may need to be part of a double or even a triple therapy. According to Philippa Salter, neurology analyst at the consultancy, Global Data, future Alzheimer’s treatments will “entail the combinatory use of preventative, symptomatic and disease-modifying products.” Recent progress in the field has already opened new avenues, paving the way for the exploration of innovative clinical investigations and hopefully helping the rapid discovery of agents with a real clinical benefit to the more than 55 million Alzheimer's disease patients and their caregivers.

References:

1. Zeng, Xuemei et al, Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer’s disease, Molecular Neurodegeneration, 10 October 2024.

2. Therapeutics, Trontinemab, Alzforum, 10 January 2025.

3. Trontinemab data strengthen hope for brain shuttles, Alzforum, 8 November 2024.

4. AC Immune’s ACI-35.030 granted FDA fast track designation for Alzheimer’s disease, AC Immune press release, 25 July 2024.

5. Mutations, APP A673T (Icelandic), Alzforum, 8 November 2024.

6. Shimohama, Sho et al, The Icelandic mutation (APP-A673T) is protective against amyloid pathology in vivo, Journal of Neuroscience, November 2024.

7. Weaver, Donald, Alzheimer’s disease as an innate autoimmune disease (AD2): a new molecular paradigm, Alzheimer’s & Dementia, 27 September 2022.

Paris February 22, 2025

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