Alzheimer’s Disease: Hypotheses and therapies

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by dementia and progressive cognitive decline. Despite decades of research, the fundamental causes of Alzheimer’s remain unclear and expect to be multifactorial. Among numerous hypotheses, the amyloid cascade hypothesis, suggesting that the accumulation of beta-amyloid (Aβ) peptides triggers a cascade of pathological events, including tau hyperphosphorylation, synaptic dysfunction, and neuronal death, remains the core framework due to recent breakthroughs in its related drugs. At the same time, emerging evidences also promote the attention on other contributing factors such as tau pathology, neuroinflammation, mitochondrial dysfunction, and genetic predispositions, particularly involving APOE-ε4 and TREM2 variants. In addition, non-AD co-pathologies, such as Lewy body disease, cerebrovascular pathology, and TDP-43 proteinopathy, would further complicate disease progression, especially in elderly patients. This review critically examines and elaborates on most of the current human understanding of the etiology of AD, involves different AD treatment interventions designed based on different understandings, and emphasizes new strategies for personalized and combination therapy aimed at preventing or reversing disease progression.