This study investigates the role of macroautophagy in Alzheimer's disease (AD). Macroautophagy, a lysosomal pathway for the turnover of organelles and long-lived proteins, is crucial for cell survival and longevity. The researchers found that macroautophagy is induced early in AD, before the accumulation of β-amyloid (Aβ) deposits in the presenilin 1/Aβ precursor protein (PS1/APP) mouse model of AD. Autophagosomes and late autophagic vacuoles (AVs) accumulate in dystrophic dendrites, indicating impaired maturation of AVs to lysosomes. AVs in the brain are identified as a major reservoir of intracellular Aβ, containing APP, β-cleaved APP, PS1, nicastrin, and γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells through the mammalian target of rapamycin kinase pathway results in parallel changes in AV proliferation and Aβ production. These findings link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and abnormal in AD. The study suggests that macroautophagy may contribute to Aβ generation and intracellular Aβ accumulation, potentially exacerbating AD pathology.This study investigates the role of macroautophagy in Alzheimer's disease (AD). Macroautophagy, a lysosomal pathway for the turnover of organelles and long-lived proteins, is crucial for cell survival and longevity. The researchers found that macroautophagy is induced early in AD, before the accumulation of β-amyloid (Aβ) deposits in the presenilin 1/Aβ precursor protein (PS1/APP) mouse model of AD. Autophagosomes and late autophagic vacuoles (AVs) accumulate in dystrophic dendrites, indicating impaired maturation of AVs to lysosomes. AVs in the brain are identified as a major reservoir of intracellular Aβ, containing APP, β-cleaved APP, PS1, nicastrin, and γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells through the mammalian target of rapamycin kinase pathway results in parallel changes in AV proliferation and Aβ production. These findings link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and abnormal in AD. The study suggests that macroautophagy may contribute to Aβ generation and intracellular Aβ accumulation, potentially exacerbating AD pathology.