Week 4, December 2024: Evolving Hypotheses in Alzheimer's Research

Alzheimer’s research has undergone transformative changes in recent years, characterized by breakthroughs, controversies, and a reevaluation of long-held theories. 

Recently, BioArctic announced a global license agreement with Bristol Myers Squibb for BioArctic’s PyroGlutamate-amyloid-beta antibody program, including BAN1503 and BAN2803. Their antibody program consists of novel antibodies targeting a specific truncated, pyroglutamate modified form of amyloid-beta. Monomers of PyroGlu-Aβ are highly prone to aggregate, leading to the formation of harmful aggregates which cause debilitating cognitive and other symptoms in Alzheimer’s disease. 

The rollout of anti-amyloid antibodies such as Eisai and Biogen’s Leqembi (lecanemab) and Eli Lilly’s Kisunla (donanemab) marks a milestone in disease-modifying treatments. However, skepticism lingers regarding their efficacy and the foundational amyloid hypothesis. While these antibodies modestly slow disease progression (~30%), their limited benefits, high cost, and risks of amyloid-related imaging abnormalities (ARIA) have prompted calls for combination therapies targeting multiple pathways, including tau proteins and neuroinflammation. Emerging technologies, such as Roche’s Brainshuttle platform and Aliada Therapeutics’ MODEL system, aim to enhance drug delivery across the blood-brain barrier, addressing a key limitation of current treatments. 

The amyloid hypothesis remains a central, albeit contested, focus in Alzheimer’s research. Findings supporting the theory have come under scrutiny following allegations of data manipulation in foundational studies, such as the argument that Aβ*56 (an oligomer of Aβ proteins) is responsible for the memory loss seen in Alzheimer’s. Critics have argued that amyloid accumulation may be a response to neural damage rather than a primary driver of Alzheimer’s, and that the antibodies are overly toxic with minimal effects on patients. Still, proponents cite data from Leqembi and Kisunla trials as proof of concept for amyloid-targeting strategies, even as new avenues, such as tau-focused therapies, gain momentum. 

At the 2024 Clinical Trials of Alzheimer’s Disease conference, researchers emphasized combination therapies as a promising frontier. Anti-amyloid antibodies paired with anti-tau, anti-inflammatory agents, or metabolic-targeting drugs could improve outcomes. Gene therapies are also gaining traction, with Lexeo Therapeutics reporting encouraging Phase I/II data on LX1001, a one-time therapy delivering protective APOE2 alleles to mitigate risks associated with APOE4 genotypes. 

The broader neuroscience space reflects Alzheimer’s research’s highs and lows, with significant progress tempered by setbacks. On November 25, Alector revealed that its investigational antibody AL002, developed in partnership with AbbVie, did not significantly slow clinical progression in Alzheimer’s patients. This disappointing outcome led to a layoff of around 17% of the company’s workforce. On the same day, Cassava Sciences disclosed that its Alzheimer’s candidate, simulfilam, failed to meet all pre-specified co-primary, secondary, and exploratory biomarker endpoints in a Phase III trial. This result follows allegations of "data manipulation" concerning the drug.