Genetics
The CETP rs5882 variant predicts white matter microstructure, with opposite effects in young versus older adults (Neurobiol Aging 2014)
Original title: Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure
Because myelin is highly sensitive to cholesterol and abnormal cholesterol levels raise Alzheimer's disease risk, researchers examined how cholesterol-related genetic variants affect brain white matter using diffusion and anatomic MRI at 4 Tesla in 403 young adults (mean age 23.8 plus or minus 2.4 years). Higher serum cholesterol and HDL cholesterol were significantly associated with higher fractional anisotropy, and among 18 cholesterol-related SNPs linked to Alzheimer's disease risk, the CETP variant rs5882 had the largest individual effect, with increased G-allele dosage associated with higher fractional anisotropy and lower radial and mean diffusivity across the whole brain. A follow-up analysis in 78 older individuals (mean age 74.3 plus or minus 7.3 years) found rs5882 associated with white matter changes in the opposite direction, suggesting cholesterol-related genes exert age-dependent effects on brain white matter integrity.
Original abstract
Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4 years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4 Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3 years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.