Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration

Alzheimer's disease (AD) is a progressive neurodegenerative disorder in the elderly, characterized by extracellular amyloid β‑ (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs). Impaired autophagy, the cellular pathway for degrading damaged organelles and misfolded proteins, and cellular senescence, permanent cell cycle arrest with proinflammatory secretions, have emerged as key contributors to AD pathogenesis.

We performed a narrative review of recent mechanistic and preclinical studies investigating (1) autophagic flux and its role in Aβ and tau clearance; (2) the accumulation and secretory phenotype of senescent cells in the aging brain; (3) interactions between autophagy impairment and senescence; and (4) the efficacy of autophagy enhancers (e.g., rapamycin and metformin) and senolytic agents in rodent models of AD.

Defective autophagosome-lysosome fusion in AD causes autophagic vacuole buildup with amyloid precursor protein and β‑secretase, boosting Aβ generation and hindering tau clearance, promoting neurofibrillary tangles. In AD models, senescent neurons and microglia release pro‑inflammatory cytokines (SASP), fueling neuroinflammation and synaptic dysfunction. Decline in autophagy induces senescence and blocks clearance in a vicious cycle. Rapamycin and metformin restore autophagic flux, reduce Aβ and tau pathologies, and improve memory. Senolytics clear senescent cells, reduce inflammation, and rescue cognition.

Dysregulated autophagy and cellular senescence interact to drive the progression of AD. Targeting these pathways with autophagy-boosting drugs and senolytic agents holds promise for disease-modifying therapies aimed at halting or reversing neurodegeneration in Alzheimer's disease.