Macroautophagy, a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. This study shows that neuronal macroautophagy is induced early in Alzheimer’s disease (AD) and before extracellular β-amyloid (Aβ) deposits appear in the PS1/APP mouse model of β-amyloidosis. Autophagosomes and late autophagic vacuoles (AVs) accumulate in dystrophic dendrites, indicating impaired maturation of AVs to lysosomes. AVs are enriched in γ-secretase components and contain APP and β-cleaved APP, suggesting they are a major source of intracellular Aβ in AD. Modulating macroautophagy by inducing or inhibiting it affects AV proliferation and Aβ production. These findings link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and abnormal in AD. Macroautophagy is involved in degrading mutated and aggregated proteins implicated in neurodegenerative diseases, including Parkinson’s and Huntington’s disease. Defective removal of these proteins is linked to disease progression, and stimulating macroautophagy in Huntington’s disease models reduces abnormal protein aggregation and improves neurological function. However, sustained overactivity during embryonic development or in pathological states can lead to caspase-independent cell death. Despite its importance in cell survival, macroautophagy’s role in AD has been limited. Recent immuno-EM analyses show that autophagosomes and late AVs appear in neurons in AD brains and accumulate in dystrophic neurites, suggesting progressive dysfunction of macroautophagy-mediated protein turnover. In AD, neuronal atrophy and loss are preceded by intraneuronal neurofibrillary tangles and extracellular Aβ deposits. Aβ is generated from APP cleavage by β- and γ-secretase. APP, β-cleaved APP, PS1, and nicastrin are found in purified AVs from wild-type APP yeast artificial chromosome mice, suggesting AVs may generate Aβ. This study demonstrates that macroautophagy is induced in the brain at early stages of sporadic AD and in the PS1/APP mouse model. In the PS1/APP model, macroautophagy induction is evident before Aβ deposition, and AVs accumulate abnormally in dystrophic neurites, indicating impaired maturation to lysosomes. AVs are enriched in γ-secretase components and contain APP and βCTF, making them a major source of intracellular Aβ in AD. Modulating macroautophagy in neuronal and nonneuronal cell lines shows it is a previously unrecognized pathway for Aβ generation under conditions of AV accumulation. Early and persistent induction of macroautophagy and later pathological accumulation of AVs in AD and related mouse models link β-amyloidogenic and neurodegenerative mechanisms in AD. Macroautophagy is induced earlyMacroautophagy, a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. This study shows that neuronal macroautophagy is induced early in Alzheimer’s disease (AD) and before extracellular β-amyloid (Aβ) deposits appear in the PS1/APP mouse model of β-amyloidosis. Autophagosomes and late autophagic vacuoles (AVs) accumulate in dystrophic dendrites, indicating impaired maturation of AVs to lysosomes. AVs are enriched in γ-secretase components and contain APP and β-cleaved APP, suggesting they are a major source of intracellular Aβ in AD. Modulating macroautophagy by inducing or inhibiting it affects AV proliferation and Aβ production. These findings link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and abnormal in AD. Macroautophagy is involved in degrading mutated and aggregated proteins implicated in neurodegenerative diseases, including Parkinson’s and Huntington’s disease. Defective removal of these proteins is linked to disease progression, and stimulating macroautophagy in Huntington’s disease models reduces abnormal protein aggregation and improves neurological function. However, sustained overactivity during embryonic development or in pathological states can lead to caspase-independent cell death. Despite its importance in cell survival, macroautophagy’s role in AD has been limited. Recent immuno-EM analyses show that autophagosomes and late AVs appear in neurons in AD brains and accumulate in dystrophic neurites, suggesting progressive dysfunction of macroautophagy-mediated protein turnover. In AD, neuronal atrophy and loss are preceded by intraneuronal neurofibrillary tangles and extracellular Aβ deposits. Aβ is generated from APP cleavage by β- and γ-secretase. APP, β-cleaved APP, PS1, and nicastrin are found in purified AVs from wild-type APP yeast artificial chromosome mice, suggesting AVs may generate Aβ. This study demonstrates that macroautophagy is induced in the brain at early stages of sporadic AD and in the PS1/APP mouse model. In the PS1/APP model, macroautophagy induction is evident before Aβ deposition, and AVs accumulate abnormally in dystrophic neurites, indicating impaired maturation to lysosomes. AVs are enriched in γ-secretase components and contain APP and βCTF, making them a major source of intracellular Aβ in AD. Modulating macroautophagy in neuronal and nonneuronal cell lines shows it is a previously unrecognized pathway for Aβ generation under conditions of AV accumulation. Early and persistent induction of macroautophagy and later pathological accumulation of AVs in AD and related mouse models link β-amyloidogenic and neurodegenerative mechanisms in AD. Macroautophagy is induced early