Reducing CETP activity prevents memory decline in an Alzheimer’s disease mouse model
Epidemiological studies have shown that lower activity of the cholesteryl ester transfer protein (CETP) correlates with reduced Alzheimer's disease (AD) risk. While small-molecule CETP inhibitors like evacetrapib have previously been assessed for cardiovascular diseases, their involvement in AD has not been investigated. Here, we establish CETP as a novel pharmacological target for AD treatment. Using CETP transgenic mice crossed to a mouse model of amyloidosis and administering evacetrapib, we provide evidence that CETP inhibition maintained memory independent of classic AD markers, likely through maintained vascular health, while increasing hippocampal cholesterol and altering plasma lipoproteins. Using proteomic data of cerebrospinal fluid (CSF) from cognitively unimpaired individuals at risk for AD in the PResymptomatic EValuation of Experimental or Novel Treatments for AD (PREVENT-AD) cohort, we confirm that our mouse model reflects physiological changes in pre-symptomatic human subjects. We propose the repurposing of CETP inhibitors as an effective therapeutic strategy to delay or prevent cognitive impairment in AD.
Authors
- Robert S. Kiss (ORCID: https://orcid.org/0000-0002-9189-0365)
- Megan S. Katz
- Jasmine Phénix (ORCID: https://orcid.org/0000-0002-5762-6376)
- Judes Poirier (ORCID: https://orcid.org/0000-0002-8018-4545)
- William A. Pastor (ORCID: https://orcid.org/0000-0003-4176-5299)
- Lisa Marie Munter (ORCID: https://orcid.org/0000-0001-5736-1462)
- Anja Kerksiek (ORCID: https://orcid.org/0009-0002-6162-6106)
- Aaron Ernesto Marure-Rojano (ORCID: https://orcid.org/0000-0001-7502-7249)
- Dieter Lütjohann (ORCID: https://orcid.org/0000-0002-7941-8308)
- Antonio Vázquez Cobá
- Isabel Sarty
- Hannah Nie
- Clara S Berger
- Indie Jerry
Institutions
- Bell (Canada) (CA)
- University Hospital Bonn (DE)
- Douglas Mental Health University Institute (CA)
- McGill University Health Centre (CA)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- William Osler Health System (CA)
- McGill University (CA)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-08-03
- DOI
- https://doi.org/10.1038/s44321-026-00482-w
- Primary Topic
- Nuclear Receptors and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- McGill University
- Weston Brain Institute
- Fondation Jean-Louis Lévesque
- Canada Foundation for Innovation
- Canada First Research Excellence Fund
- Alzheimer Society Research Program
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé