The multifaceted roles of apolipoprotein E4 in Alzheimer’s disease pathology and potential therapeutic strategies
Yongfeng Chen, Haiping Jin, Jia Chen, Jing Li, Mihnea‐Alexandru Găman, Zhenyou Zou
Abstract
Alzheimer's disease (AD), the most common dementia in the elderly, is marked by progressive cognitive decline and neurodegeneration. Core pathological hallmarks include amyloid-beta (Aβ) plaques, hyperphosphorylated tau aggregates, neuroinflammation, and metabolic dysfunction (e.g., impaired glucose utilization, mitochondrial deficits). Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for AD, interacts with these processes, yet its precise pathogenic mechanisms remain unclear. This review examines ApoE4's multifaceted contributions to AD pathogenesis, focusing on its roles in Aβ accumulation, tau hyperphosphorylation, neuroinflammatory activation, and metabolic dysregulation. We further evaluate emerging therapeutic strategies targeting these pathways, including ApoE4 modulation, anti-amyloid/tau interventions, and metabolic rescue approaches. Elucidating the molecular interplay between ApoE4 and AD pathology is critical for developing targeted therapies to modify disease progression and mitigate cognitive decline in patients.