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

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 ris...

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Autores principales:	Nathalie I. V. Nilsson, Cynthia Picard, Anne Labonté, Theresa Köbe, Pierre-François Meyer, Sylvia Villeneuve, Daniel Auld, Judes Poirier, for the PREVENT-AD Research Group, Alzheimer’s Disease Neuroimaging Initiative
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	polygenic score Alzheimer’s disease cholesterol amyloid tau protein aging Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ebb65cee29624861a4bf683fb670e657
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spelling	oai:doaj.org-article:ebb65cee29624861a4bf683fb670e6572021-11-25T17:42:13ZAssociation of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum10.3390/genes121118052073-4425https://doaj.org/article/ebb65cee29624861a4bf683fb670e6572021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1805https://doaj.org/toc/2073-4425Midlife 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 <i>p</i>-value thresholds for inclusion in the score, sex, and statin use. This optimized score (<i>p</i>-value threshold of 1 × 10<sup>−6</sup> 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.Nathalie I. V. NilssonCynthia PicardAnne LabontéTheresa KöbePierre-François MeyerSylvia VilleneuveDaniel AuldJudes Poirierfor the PREVENT-AD Research GroupAlzheimer’s Disease Neuroimaging InitiativeMDPI AGarticlepolygenic scoreAlzheimer’s diseasecholesterolamyloidtau proteinagingGeneticsQH426-470ENGenes, Vol 12, Iss 1805, p 1805 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	polygenic score Alzheimer’s disease cholesterol amyloid tau protein aging Genetics QH426-470
spellingShingle	polygenic score Alzheimer’s disease cholesterol amyloid tau protein aging Genetics QH426-470 Nathalie I. V. Nilsson Cynthia Picard Anne Labonté Theresa Köbe Pierre-François Meyer Sylvia Villeneuve Daniel Auld Judes Poirier for the PREVENT-AD Research Group Alzheimer’s Disease Neuroimaging Initiative Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum
description	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 <i>p</i>-value thresholds for inclusion in the score, sex, and statin use. This optimized score (<i>p</i>-value threshold of 1 × 10<sup>−6</sup> 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.
format	article
author	Nathalie I. V. Nilsson Cynthia Picard Anne Labonté Theresa Köbe Pierre-François Meyer Sylvia Villeneuve Daniel Auld Judes Poirier for the PREVENT-AD Research Group Alzheimer’s Disease Neuroimaging Initiative
author_facet	Nathalie I. V. Nilsson Cynthia Picard Anne Labonté Theresa Köbe Pierre-François Meyer Sylvia Villeneuve Daniel Auld Judes Poirier for the PREVENT-AD Research Group Alzheimer’s Disease Neuroimaging Initiative
author_sort	Nathalie I. V. Nilsson
title	Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum
title_short	Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum
title_full	Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum
title_fullStr	Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum
title_full_unstemmed	Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum
title_sort	association of a total cholesterol polygenic score with cholesterol levels and pathological biomarkers across the alzheimer’s disease spectrum
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ebb65cee29624861a4bf683fb670e657
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Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum

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