Sustaining Drug Discovery Amid the Limits of Alzheimer's Disease Immunotherapies

Accumulation of insoluble extracellular amyloid-β (Aβ) plaques and intraneuronal fibrillary hyperphosphorylated tau fibrils in the brain are widely believed to contribute to the progressive neurodegeneration and neuronal loss characteristic of the Alzheimer's disease and the associated dementia. Anti-amyloid immunotherapies that reduce cerebral Aβ burden in affected individuals have been approved based on biological outcomes from clinical trials. However, the extent to which Aβ clearance translates into improved meaningful clinical, cognitive, and functional benefit versus risk and cost is unclear based on available data. Here, the critical barriers that limit the impact of anti-amyloid immunotherapies, including aducanumab, lecanemab, and donanemab, are discussed. Treatment slows cognitive decline by ∼20-30% in certain patient subsets, but absolute improvements in cognitive and functional outcomes remain modest. Independent analyses of how treatment impacts health span suggests statistically significant trial results may not translate into significant real-world benefit. Response is most significant in cases of early-stage disease where levels of copathology tau are low. Edema and brain hemorrhage occur frequently, particularly in carriers of APOE-e4 alleles, an established genetic risk factor for Alzheimer's disease, raising safety concerns which led to some regulators banning treatment in this patient group. Strict clinical trial eligibility criteria, high treatment costs relative to patient benefit, intensive during-treatment monitoring, and the absence of population-level screening programs further limit treatment accessibility and generalizability. Emerging evidence of accelerated brain atrophy and immunotherapy tolerance further complicates benefit-risk consultation. Sustaining drug- discovery pipelines by exploring combination therapies, tau-targeted approaches, drug repositioning, and novel small molecules through will be essential to provide comprehensive treatment options and personalized treatment plans for affected patients.