Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ε4 on memory decline in older adults

Abstract

Apolipoprotein ε4 (ApoE4) is a strong genetic risk factor for sporadic Alzheimer’s disease (AD) and memory decline in older adults. A single-nucleotide polymorphism in the cholesteryl ester transfer protein (CETP) gene (isoleucine to valine; V405) is associated with slower memory decline and a lower risk of AD. As both genes regulate cholesterol, we hypothesized that the favorable CETPV405 allele may buffer the effect of ApoE4 on memory decline in older adults. Using linear regression, we examined the interactive effect of ApoE4 by CETPV405 on memory decline among 909 community-dwelling, nondemented, older adults (≥70 years) from the Einstein Aging Study. Episodic memory was measured using the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+ir). There was a significant ApoE × CETP interaction on decline in pFCSRT+ir scores (p=0.01). ApoE4 carriers experienced faster decline than non-carriers among CETPI405I homozygotes (p=0.007) and in CETPI405V heterozygotes (p=0.015), but not in CETPV405V homozygotes (p=0.614). Results suggest that the CETPV405 allele buffers ApoE4-associated memory decline in a gene dose-dependent manner.

Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

“…This suggests that the variants in the PRS may compensate for the strong disease/mortality risk-increasing effect exerted by the APOE-ε4 allele; however, replication in a large and independent data set is needed to confirm this finding. A number of studies described this effect in dementia, and although the results did not strongly replicate across different studies, several variants (eg, rs5882 in the CETP gene and rs4934 in the SERPINA3 gene) were reported to exhibit buffering effects with respect to APOE-ε4 ( 41 , 42 ).…”

HDL from an Alzheimer's disease perspective

“…However, the most recent phase III trial of the potent CETP inhibitor anacetrapib had no adverse effects and reduced major coronary events [143]. CETP inhibitors may be especially useful for repurposing for Alzheimer's disease as certain CETP polymorphisms are associated with Alzheimer's disease risk and memory decline, particularly in APOE4 carriers [144–146].…”

The cholesteryl ester transfer protein (CETP) raises cholesterol levels in the brain

“…Based on these findings, several studies investigated whether CETP polymorphisms could decrease the risk for Alzheimer’s disease, an aging-associated neurodegenerative disease. Indeed, protective effects of CETP polymorphisms at early Alzheimer’s disease stages were reported, particularly in carriers of the strongest genetic risk factor, the ε4 allele of the A PO E4 ( 16 , 17 , 18 , 19 ). ApoE is the predominant lipoprotein of the brain, in contrast to the blood where there are several apolipoprotein-defined lipoprotein families ( 20 ).…”