Genes and Cognition, a recallable cohort to study Dementia/Alzheimer’s disease

Abstract

AbstractBackgroundDecades of research have not resulted in a cure for dementia/Alzheimer’s disease (AD). Most treatments have failed to benefit patients in clinical trials, potentially due to treatment being provided too late when brain damage is irreversible. There is an urgent need to understand the disease mechanism at the preclinical and prodromal stages of AD, which requires early identification of participants at risk of AD.MethodWe attempt to address this need by establishing an open cohort named Genes and Cognition (GC), nested within NIHR Bioresource (https://bioresource.nihr.ac.uk/) and comprising 21,051 healthy people aged 17‐85 who consented to be recalled for follow‐up studies. Participants took 11 cognitive tests (CTs) covering various domains of cognition. We examined the association between CT scores and demographic characteristics, explored phenotypic and genotypic correlations between CTs, and estimated SNP‐based heritability. In addition, AD polygenic risk (high vs low) was determined in 10,038 participants using 20 single nucleotide polymorphisms (SNPs) from Lambert et al. (PMID:24162737) to identify the earliest age with a noticeable score difference in CTs.ResultCT scores (higher score indicates poorer performance) were associated with age and gender differences were significant for each CT score. Significant linear trends were observed between CTs and educational attainment. Genetic correlations between tests were stronger than the phenotypic correlations. SNP‐heritability for CTs and general cognitive ability ranged from 8‐28%. We observed that three CTs (Reaction Time, Stroop Box, Stroop Ink) began deviating around age 55 between high (≥ 96th percentile) and low (≤ 95th percentile) AD polygenic risk groups, although not significant. Similar deviations in some CTs were observed among APOE E4 allele carriers compared to E3/E3 carriers. However, AD risk groups determined without including the APOE region indicated such deviation after age 65.ConclusionWe presented preliminary findings for the GC study cohort. Our results suggest that AD polygenic risk measured with or without APOE region may be less beneficial than the two APOE SNPs (rs429358 and rs7412) alone for the early identification of AD. Repeated CT measures would shed more light on this observation; therefore, we aim to investigate this with CTs repeated at two years intervals.