Alterations in cholesterol metabolism–related genes in sporadic Alzheimer's disease

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Abstract

Genome-wide association studies have identified several cholesterol metabolism–related genes as top risk factors for late-onset Alzheimer's disease (LOAD). We hypothesized that specific genetic variants could act as disease-modifying factors by altering the expression of those genes. Targeted association studies were conducted with available genomic, transcriptomic, proteomic, and histopathological data from 3 independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Quebec Founder Population (QFP), and the United Kingdom Brain Expression Consortium (UKBEC). First, a total of 273 polymorphisms located in 17 cholesterol metabolism-related loci were screened for associations with cerebrospinal fluid LOAD biomarkers beta amyloid, phosphorylated tau, and tau (from the ADNI) and with amyloid plaque and tangle densities (from the QFP). Top polymorphisms were then contrasted with gene expression levels measured in 134 autopsied healthy brains (from the UKBEC). In the end, only SREBF2 polymorphism rs2269657 showed significant dual associations with LOAD pathological biomarkers and gene expression levels. Furthermore, SREBF2 expression levels measured in LOAD frontal cortices inversely correlated with age at death; suggesting a possible influence on survival rate.

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Picard, C., Julien, C., Frappier, J., Miron, J., Théroux, L., Dea, D., … Poirier, J. (2018). Alterations in cholesterol metabolism–related genes in sporadic Alzheimer’s disease. Neurobiology of Aging, 66, 180.e1-180.e9. https://doi.org/10.1016/j.neurobiolaging.2018.01.018

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