Genetic Risk Score for Alzheimer’s Disease Predicts Brain Volume Differences in Mid‐ and Late‐life in UK Biobank Participants

Abstract

AbstractBackgroundGenetic risk variants for late‐onset Alzheimer’s disease (LOAD) predict brain atrophy, cognitive changes, and dementia onset in late‐life. Little is known about the association between LOAD genetic variants and regional brain volumes in middle aged adults. Further understanding of when associations emerge across mid‐to‐late‐life may point to the earliest manifestations of LOAD.MethodWe studied 41,435 UK Biobank participants aged 45‐80 who enrolled 2007‐2010, had no dementia at baseline, and subsequently underwent a brain MRI (3‐Tesla scanner). A genetic risk score for LOAD (LOAD‐GRS) was calculated as a weighted sum of 27 variants previously confirmed to be genome‐wide significant predictors of LOAD dementia including APOE. MR images underwent standardized quality control and data processing by UK Biobank. Volumes (both hemispheres combined) for 38 regions of interest (ROIs) were derived from Freesurfer (Version 6.0) packages for subcortical segmentation and cortical parcellation with the Desikan‐Killiany‐Tourville atlas. We examined associations of LOAD‐GRS with each ROI tested whether effects differed across age using linear regression with an interaction between age and LOAD‐GRS. A cross‐validated model determined the earliest age at which trends in MRI volume diverged between those with low compared to high LOAD‐GRS. All models adjusted for sex, genetic ancestry, and intracranial volume.ResultUsing a Bonferonni correction (p<0.05/38=0.0013]), 4 of 38 regional volumes had significant interactions between age and LOAD‐GRS, all indicating that for people with 1 SD higher genetic risk of LOAD, older age was more strongly associated with smaller brain volumes than among people with lower LOAD genetic risk. Significant regions included the amygdala (‐172.6 mm3/SD; 95%CI=‐176.7,‐168.5); hippocampus (‐351.9 mm3/SD; 95%CI=[‐359.9,‐343.9], nucleus accumbens (‐87.7 mm3/SD; 95%CI=‐89.4,‐86.0], and thalamus (‐526.4 mm3/SD; 95%CI=[‐538.2,‐514.6]. Best fitting model‐based age‐curves for people with high versus low LOAD‐GRS scores began to diverge around age 45 for the nucleus accumbens, hippocampus, and thalamus and after age 51 for the amygdala.ConclusionGenetic factors that increase risk of LOAD begin to predict lower brain volumes as early as middle age, decades prior to average age of dementia onset. Our findings prioritize particular brain regions that may help predict LOAD onset, including the hippocampus, amygdala, nucleus accumbens, and thalamus.