Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer's Disease Spectrum.

TitleAssociation of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer's Disease Spectrum.
Publication TypeJournal Article
Year of Publication2021
AuthorsNilsson NIV, Picard C, Labonte A, Köbe T, Meyer P-F, Villeneuve S, Auld D, Poirier J
JournalGenes (Basel)
Volume12
Issue11
Date Published2021 Nov 17
ISSN2073-4425
Abstract

Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer's disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32-63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering -value thresholds for inclusion in the score, sex, and statin use. This optimized score (-value threshold of 1 × 10 for inclusion in the score) explained 18.2% of the variance in TC levels in statin free females compared to 6.9% in the entire sample and improved prediction of hypercholesterolemia (receiver operator characteristics analysis revealed area under the curve increase from 70.8% to 80.5%). The TC-PGS was further evaluated for association with AD risk and pathology. We found no association between the TC-PGS and either of the AD hallmark pathologies, assessed by cerebrospinal fluid levels of Aβ-42, p-Tau, and t-Tau, and 18F-NAV4694 and 18F-AV-1451 positron emission tomography. Similarly, we found no association with the risk of developing amyloid pathology or becoming cognitively impaired in individuals with amyloid pathology.

DOI10.3390/genes12111805
Alternate JournalGenes (Basel)
PubMed ID34828411
PubMed Central IDPMC8623969
Grant ListPJT-153287 / CAPMC / CIHR / Canada
MOP-126062 / CAPMC / CIHR / Canada
PJT-178210 / CAPMC / CIHR / Canada
PJT-162091, / CAPMC / CIHR / Canada
FRQ-264732 / / Fonds de Recherche du Québec - Santé /
U01 AG024904 / AG / NIA NIH HHS / United States
JLL-01 / / Fondation J.L. Levesque /