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: | , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/ebb65cee29624861a4bf683fb670e657 |
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| Sumario: | 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. |
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