VARIABILITY IN APOE-TOMM40-PVRL2 LOCUS AND OTHER GENOMIC REGIONS CONTRIBUTES TO COGNITIVE PERFORMANCE IN A POPULATION BASED STUDY OF RUSSIAN ELDERLY

Abstract

Genetic variability contributes to the age of onset of the late onset Alzheimer's disease as well as to cognitive performance in normal subjects. A set of 62 single nucleotide variants was tested in respect to Montreal Cognitive Assessment (MoCA) total score in 708 older subjects randomly selected from a large urban elderly population from Tomsk, Russia. Volunteers were identified through the local centralized medical care system and were invited for neurocognitive assessment as a part of a study of normal aging of the brain. Detailed information was collected on 2000+ individuals, including demographics, medical history, and family history. 62 SNPs in 45 genes previously reported to be associated with cognitive performance and/or Alzheimer's disiease in multiple GWAS or meta-analysis studies were genotyped in two multiplex reactions using MALDI-TOF mass spectrometry. Mean age was 72±5 years (from 56 to 90), 77.1% of the sample were female. Age (r=-0.338,p<0.001) and education (r=+0.422,p<0.001) significantly influenced MoCA total score, but male and female subjects performed similarly. Arterial hypertension was reported by 82.4% of participants, 42.9% reported hypercholesterolemia, 38.4% were obese, 32.3% had one or more other cardiovascular conditions (defined as history of heart attack, pacemaker, or valve replacement), 28.5% had atrial fibrillation, 19.3% reported type 2 diabetes, and 8.5% survived stroke. MoCA scores corrected for covariates were subjected to analysis of variance in order to estimate the contribution of genetic factors to variability of cognitive functions. 11 out of 62 SNPs were significantly associated with the variance of MoCA scores. Most significant contribution was found for APOC3-APOE-TOMM40-PVRL2 gene cluster located on chromosome 19q13.32. 8.6% of the MoCA scores variance is attributable to the cumulative effect of linked genetic markers at this 41 kb locus. The effect of single SNPs at this cluster varied from 0.7% to 1.8%. Other significant signals were detected for variants at CSMD1, CNTNAP2, SORL1, FBXO40, DCHS2,and ACSM1 loci. This study confirms the significant contribution of genetic variation of APOE-TOMM40 linked markers and points out to several novel loci associated with the cognitive performance in normal elderly population. (The work was supported by the Russian Science Foundation project#16–14–00020).