Reviewing the Current State of Immunotherapy for Alzheimer's Disease
After long years of failure, the treatment of Alzheimer's disease through clearance of protein aggregates in the brain has been reinvigorated by minor degrees of success. The results are poor in the grand scheme of things, and come with risk of severe side-effects, but once a disease can be at least slowed, there is a renewed interest in improving on that starting point. It remains the case that the contributing causes of Alzheimer's disease remain poorly understood, however, and it may turn out to be much more preventable than thought. Assays to detect the earliest stages of the condition are now demonstrated, and promising work suggests that persistent viral infection may be an important factor that could be addressed via more widespread use of existing antiviral therapies.
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Amyloid-β (Aβ), tau, and neuroinflammation are immunotherapy targets focused on by industries for AD intervention. Passive immunotherapy targeting Aβ was launched decades ago and has reached milestone progress with full approval of lecanemab by the FDA very recently. While the development of monoclonal antibody (mAb) drugs targeting tau or immune modulators is at an early stage, several preclinical and clinical studies have shown promising results.
Here, we review characteristics, clinical trial data, and mechanisms of action for mAbs targeting key players in AD pathogenesis, including Aβ, tau, and neuroinflammation modulators. For the anti-Aβ strategy, it should be noted that even the mAbs (lecanemab and donanemab) only showed efficacy in patients with early AD. This may be because other factors, such as tau, have important contributions to neuronal loss in the later stages of AD. In support of this notion, donanemab only showed efficacy in AD patients with low/medium tau pathology.
Therefore, it is important to elucidate the clinical effect of anti-Aβ mAbs on neuronal loss, and it is worth testing the combined immunotherapy strategy targeting both Aβ and tau in patients with moderate symptoms or medium/severe tau pathology in the future. In addition, efficient Aβ-targeted immunotherapy is associated with a high incidence of ARIA and brain atrophy, and the underlying mechanisms need to be clarified. For anti-tau immunotherapy, most of the mAbs recognizing the N-terminal epitopes failed in clinical trials. The industries have now focused on developing mAbs targeting the tau mid-region or phosphorylated tau, which may be able to stop tau seeding and spreading.