Ballantyne, Christie M.

AbstractIntroductionExisting studies predominantly consider the association of late‐life lipid levels and subsequent cognitive change. However, midlife rather than late‐life risk factors are often most relevant to cognitive health.MethodsWe quantified the association between measured serum lipids in midlife and subsequent 20‐year change in performance on three cognitive tests in 13,997 participants of the Atherosclerosis Risk in Communities study.ResultsElevated total cholesterol, low‐density lipoprotein cholesterol, and triglycerides were associated with greater 20‐year decline on a test of executive function, sustained attention, and processing speed. Higher total cholesterol and triglycerides were also associated with greater 20‐year decline in memory scores and a measure summarizing performance on all three tests. High‐density lipoprotein cholesterol was not associated with cognitive change. Results were materially unchanged in sensitivity analyses addressing informative missingness.DiscussionElevated total cholesterol, low‐density lipoprotein cholesterol, and triglycerides in midlife were associated with greater 20‐year cognitive decline.

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

OBJECTIVE Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT), a measure of subclinical atherosclerosis. It is unclear if this association is causal. Using the principle of Mendelian randomization, we sought to explore the causal association between circulating glucose and IMT by examining the association of a genetic risk score with IMT. RESEARCH DESIGN AND METHODS The sample was drawn from the Atherosclerosis Risk in Communities (ARIC) study and included 7,260 nondiabetic Caucasian individuals with IMT measurements and relevant genotyping. Components of the fasting glucose genetic risk score (FGGRS) were selected from a fasting glucose genome-wide association study in ARIC. The score was created by combining five single nucleotide polymorphisms (SNPs) (rs780094 [GCKR], rs560887 [G6PC2], rs4607517 [GCK], rs13266634 [SLC30A8], and rs10830963 [MTNR1B]) and weighting each SNP by its strength of association with fasting glucose. IMT was measured through bilateral carotid ultrasound. Mean IMT was regressed on the FGGRS and on the component SNPs, individually. RESULTS The FGGRS was significantly associated (P = 0.009) with mean IMT. The difference in IMT predicted by a 1 SD increment in the FGGRS (0.0048 mm) was not clinically relevant but was larger than would have been predicted based on observed associations between the FFGRS, fasting glucose, and IMT. Additional adjustment for baseline measured glucose in regression models attenuated the association by about one third. CONCLUSIONS The significant association of the FGGRS with IMT suggests a possible causal association of elevated fasting glucose with atherosclerosis, although it may be that these loci influence IMT through nonglucose pathways.