BACKGROUND:Cognitive decline, and more specifically Alzheimer's Disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized in the diagnosis of cognitive decline which assess executive function, short- and long-term memory, cognitive flexibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids.
OBJECTIVE:We will examine the potential moderating effect of main species of ω3 polyunsaturated fatty acids (PUFA) on an individual's genetically conferred risk of cognitive decline.
METHODS:The Offspring cohort from the Framingham Heart Study was cross-sectionally analyzed in this genome wide interaction study (GWIS). Our sample included all individuals with red blood cell ω3-PUFA, genetic, cognitive testing (via Trail Making Tests), and covariate data (N = 1,620). We used linear mixed effects models to predict each of the three cognitive measures (TMT-A, TMT-B, TMT-D) by each ω3-PUFA, single nucleotide polymorphism (SNP) (0, 1 or 2 minor alleles), ω3-PUFA by SNP interaction term, and adjusting for sex, age, education, APOE-ε4 genotype status and kinship (relatedness).
RESULTS:Our analysis identified 31 unique SNPs from 24 genes reaching an exploratory significance threshold of 1×10-5. Fourteen of the 24 genes have been previously associated with the brain/cognition and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identified: DAB1, SORCS2, SERINC5, OSBPL3, CPA6, DLG2, MUC19, and RGMA have been associated with both cognition and circulating lipids. We identified 22 unique SNPs for which individuals with the minor alleles benefit substantially from increased ω3 fatty acid levels and 9 unique SNPs for which the common homozygote benefits.
CONCLUSIONS:In this GWIS of ω3-PUFA species on cognitive outcomes, we identify 8 unique genes with plausible biology suggesting individuals with specific polymorphisms may have greater potential to benefit from increased ω3-PUFA intake. Additional replication in prospective settings with more diverse samples are needed.