Barnett_2025_Alzheimers.Dement_21_e70486

INTRODUCTION: Underlying drivers of Alzheimer's disease (AD) remain unknown, though several distinct risk exposures share a common pathological progression. METHODS: The cellular and molecular consequences of two common midlife AD risk factors-heavy alcohol use and obesity-were compared to uncover novel mediators that contribute to AD. RESULTS: Both AD risk exposures reduced levels of neuronal lysosomal acid lipase (LAL), which contributed to AD pathology and cognitive decline. LAL was lost with age in mice and humans with greater losses in AD and inverse associations with amyloid beta (Abeta). LAL loss preceded Abeta pathology in AD mice, and neuronal LAL knockdown enhanced pathology and cognitive decline. In human AD brain, robust reductions in LAL protein were found with indications of a transcriptional mechanism. LAL gene therapy reduced pathology and improved cognition and affect in vivo. DISCUSSION: LAL loss is an age-related contributor to AD pathology that can be targeted therapeutically. HIGHLIGHTS: The loss of lysosomal acid lipase (LAL) contributes to Alzheimer's disease progression. LAL is lost is normal aging and Alzheimer's disease risk exposures. LAL loss is greater in human Alzheimer's brain and predicts the extent of pathology. LAL gene therapy blunts Alzheimer' pathology, improving cognition and mood with age.