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Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model.

Overview

Authors: Jasmine Phénix1,2,3, Isabel Sarty4,5,6,7, Megan S Katz8,9, Antonio Vázquez Cobá1,2,3,4, Aarón Ernesto Marure Rojano1,2,3, Hannah Nie8,9, Anja Kerksiek10, Indie Jerry1,2,3, Clara S Berger1,2,3, Robert S Kiss11, Dieter Lütjohann10, William A Pastor8,9, Judes Poirier5,6,7, Lisa Marie Munter1,2,3,4, The PREVENT-AD Research Group
ORCID iDs: Isabel Sarty, Aarón Ernesto Marure Rojano, William A Pastor, Lisa Marie Munter
  1. Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, McGill University,Montreal, QC Canada
  2. Cell Information Systems group, Bellini Life Sciences Complex, Montreal, QC Canada
  3. Centre de Recherche en Biologie Structurale (CRBS), 3649 Promenade Sir William Osler, Montreal, QC Canada
  4. Integrated Program in Neuroscience, McGill University,Montreal, QC Canada
  5. Centre for Studies on the Prevention of Alzheimer’s Disease, Verdun, QC Canada
  6. Molecular Neurobiology Unit, Douglas Mental Health University Institute, Research Centre,Verdun, QC Canada
  7. Department of Psychiatry, Faculty of Medicine and Health Sciences, McGill University,Montreal, QC Canada
  8. Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University,Montreal, QC Canada
  9. The Rosalind & Morris Goodman Cancer Institute, McGill University,Montreal, QC Canada
  10. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn,Bonn, Germany
  11. Division of Cardiology, Department of Medicine, Faculty of Medicine and Health Sciences, Research Institute of the McGill University Health Centre, McGill University,Montreal, QC Canada
Institutions: McGill University (Canada); Douglas Mental Health University Institute (Canada); University Hospital Bonn (Germany); Research Institute of the McGill University Health Centre (Canada)
Journal: EMBO molecular medicine, volume 18, issue 9, pages 3597-3618
Dates: received 25 March 2025; accepted 25 June 2026; published online 3 August 2026; in print September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44321-026-00482-w · PMID 42547584 · PMCID PMC13562521 · OpenAlex W4404134333
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2024.11.05.621935
Status: data only
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Preprocessing, fMRI & imaging
Keywords: Neuroscience
MeSH: Alzheimer Disease*, Cholesterol Ester Transfer Proteins*, Memory Disorders*, Animals, Cholesterol, Disease Models, Animal, Humans, Male, Memory, Mice, Mice, Transgenic (* major topic)
Topic: Nuclear Receptors and Signaling (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Canadian Institutes of Health Research (PJT-162302, PJT-175306, PJT-186080, PJT 153287, PJT-178210); Weston Brain Institute (RR172187); Canada Foundation for Innovation (32565); Société Alzheimer | Alzheimer Society Research Program (ASRP) (17-02); Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-04645); Fonds de Recherche du Québec - Santé (356162); Jeanne and Jean-Louis Lévesque Foundation; Secretaría de Ciencia, Humanidades, Tecnología e Innovación (Secihti, Conacyt), Ciudad de México, México (1017734); Canada First Research Excellence Fund (Fonds d'excellence en recherche Apogée Canada); McGill University Goodman Cancer Institute Entrance Award; Fonds de Recherche du Québec - Santé
Citations: not cited yet (Europe PMC); 143 references in the paper
Research resources: RRID:SCR_017697

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Other data links

Data availability

The RNAseq dataset generated during the current study is available at the Geo repository with accession number GSE314221 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314221).

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00482-w (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00482-w).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 1 keyword, 11 MeSH terms, 11 funders, 137 references, 1 RRID.

Cite

This paper

Phénix, J., Sarty, I., Katz, M. S., Vázquez Cobá, A., Marure Rojano, A. E., Nie, H., Kerksiek, A., Jerry, I., Berger, C. S., Kiss, R. S., Lütjohann, D., Pastor, W. A., Poirier, J., Munter, L. M., & The PREVENT-AD Research Group. (2026). Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model. EMBO molecular medicine, 18(9), 3597-3618. https://doi.org/10.1038/s44321-026-00482-w

BibTeX

@article{phenix2026reducing,
author = {Phénix, Jasmine and Sarty, Isabel and Katz, Megan S and Vázquez Cobá, Antonio and Marure Rojano, Aarón Ernesto and Nie, Hannah and Kerksiek, Anja and Jerry, Indie and Berger, Clara S and Kiss, Robert S and Lütjohann, Dieter and Pastor, William A and Poirier, Judes and Munter, Lisa Marie and {The PREVENT-AD Research Group}},
title = {{Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model}},
journal = {EMBO molecular medicine},
year = {2026},
month = aug,
volume = {18},
number = {9},
pages = {3597--3618},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/s44321-026-00482-w},
url = {https://doi.org/10.1038/s44321-026-00482-w},
pmid = {42547584},
pmcid = {PMC13562521}
}

RIS

TY - JOUR
AU - Phénix, Jasmine
AU - Sarty, Isabel
AU - Katz, Megan S
AU - Vázquez Cobá, Antonio
AU - Marure Rojano, Aarón Ernesto
AU - Nie, Hannah
AU - Kerksiek, Anja
AU - Jerry, Indie
AU - Berger, Clara S
AU - Kiss, Robert S
AU - Lütjohann, Dieter
AU - Pastor, William A
AU - Poirier, Judes
AU - Munter, Lisa Marie
AU - The PREVENT-AD Research Group
TI - Reducing CETP activity prevents memory decline in an Alzheimer's disease mouse model
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/08/03
VL - 18
IS - 9
SP - 3597
EP - 3618
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/s44321-026-00482-w
UR - https://doi.org/10.1038/s44321-026-00482-w
LA - en
ER -

CSL-JSON

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