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 p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 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.
Highlights
Alzheimer’s disease (AD), dementia, and cognitive impairment are multifactorial in nature, whose cause and progression are typically influenced by a combination of risk factors such as old age, genetics, and lifestyle factors [1]
Post-hoc analyses revealed that the proportion of females was higher in PREVENTAD and ROSMAP compared to ADNI (p’s ≤ 1.0 × 10−8) and that the proportion of APOEε4 carriers was significantly different between all cohorts (p’s ≤ 5.0 × 10−7)
We found no evidence for an association of the total cholesterol (TC)-PGS with cerebrospinal fluid (CSF) t-Tau in neither PREVENT-AD (tmain(16, 69) = 0.758, pmain = 0.451; tint(16, 69) = −0.111, pint = 0.912) nor ADNI (−1.393 ≤ t’s(19, 251) ≤ 1.533, p’s ≥ 0.127)
Summary
Alzheimer’s disease (AD), dementia, and cognitive impairment are multifactorial in nature, whose cause and progression are typically influenced by a combination of risk factors such as old age, genetics, and lifestyle factors [1]. In a study with nursing home residents, levels of blood TC were found to be significantly increased in pathologically defined AD patients, compared to individuals free from AD pathology [15,16]. When compared to non-demented subjects with atherosclerotic heart disease, TC levels were found to be increased in individuals with possible clinical or probable AD [17]. Contrary to these findings, one study found that TC levels were decreased in AD individuals compared to controls [18]
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