Loss of lysosomal acid lipase contributes to Alzheimer's disease pathology and cognitive decline
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Abstract
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 β (Aβ). LAL loss preceded Aβ 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.
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Reduced lipophagy has been shown to contribute to the progression of AD in disease mouse models.
“Similarly, reduced lipophagy has been shown to contribute to the progression of AD in disease mouse models77.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [77]
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Cuní-López, C., Root, J. T., Hao, Y., Blomberg, N., Koppes-den Hertog, S. J., Sacks, D., Trujillo, A. E., Ghirlando, R., Kowal, I., Epstein, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-76565-6
- Authors
- Barnett, A. M., McNair, E. M., Dawkins, L., Zou, J., Nikolova, V. D., Moy, S. S., Sutherland, G. T., Stevens, J., Colie, M., Katemboh, K., Kellner, H., Ho, K., Damian, C., DeCastro, S., Vetreno, R. P., & Coleman, L. G.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- The University of Sydney (AU)
- Corresponding author
- Coleman, Leon G.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2025-07
- Volume
- 21
- Issue
- 7
- Pages
- e70486-e70486
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC12271982
- OpenAlex
- W4412493138
- Cited by
- 12
- References
- 17
- Citations by year
- 2026: 9 · 2025: 3
- FWCI
- 6.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
- Funders
- National Institute of Child Health and Human Development (P50HD103573)
- National Institute on Aging (AG072894)
- National Institute on Alcohol Abuse and Alcoholism (R24AA012725, R01AA028924, K08AA024829, K01AA025713)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- lysosomal acid lipase, Alzheimer's disease
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