Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants

Abstract

INTRODUCTIONWe estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle‐aged and older adults.METHODSAmong 45,616 dementia‐free participants aged 45–80, linear regressions tested whether genetic risk score for AD (AD‐GRS) had age‐dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume.RESULTSAD‐GRS modified the estimated effect of age (per decade) on the amygdala (−0.41 mm3 [−0.42, −0.40]); hippocampus (−0.45 mm3 [−0.45, −0.44]), nucleus accumbens (−0.55 mm3 [−0.56, −0.54]), thalamus (−0.38 mm3 [−0.39, −0.37]), and medial orbitofrontal cortex (−0.23 mm3 [−0.24, −0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD‐GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices.DISCUSSIONAPOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

Age-related polygenic effects of Alzheimer's disease on brain structures and cognition in middle aged and elderly adults from UK Biobank

“…Our results are in concordance with prior investigations which suggested potential correlations between the AD-PRS and the pathological progression within the hippocampal region [12,15] and structural alterations in the brain [16-18]; moreover, our results are consistent with ndings from post-mortem examinations indicating age-related impacts of AD-PRS on the entorhinal cortex and frontal lobes [13]. Additionally, our study revealed that AD-PRS-associated degenerative alterations occur earlier in deeper brain regions, a phenomenon that has been corroborated by a recent study based on the UKB cohort [17], con rming the hypothesized spreading pattern of pathological proteins of AD [2,50].…”

“…Although APOE gene polymorphism has been acknowledged as the most powerful genetic factor contributing to sporadic AD, the dependence of APOE effects from the in uence of AD-PRS on changes in brain structures in preclinical stages remains unclear. Studies supporting the dependence have demonstrated associations between APOE and levels of pathological markers in CSF [54], as well as links to WM integrity and WMHV [21], and suggested that the exclusion of APOE loci or regions from AD-PRS would decrease its statistical power in explaining variations in brain volumes [17,55] and WM integrity [16]. Conversely, other studies suggested that the effects of the AD-PRS on Aβ burden [14,19], tau burden [13,14,56], brain structure changes [13,16,21] and cognitive function [18, 56] might be independent of APOE.…”

“…In addition to single genes, AD-GWASs have enabled the assessment of individualised risk through calculating the polygenic risk score for AD (AD-PRS), which incorporates risk pro les from multiple Single Nucleotide Polymorphisms (SNPs) across the entire genome [10,11]. The AD-PRS has been shown to correlate with neuropathological markers [12][13][14], brain structural degeneration [15][16][17], and cognitive decline [13,15,18] along the continuum of AD, with the ability to enhance the e cacy of prediction models [19,20]. However, the ndings on the associated brain regions and the dependence of the AD-PRS on APOE remain inconsistent, likely stemming from variations in study samples and statistical methodologies.…”

“…However, the ndings on the associated brain regions and the dependence of the AD-PRS on APOE remain inconsistent, likely stemming from variations in study samples and statistical methodologies. For instance, while the hippocampus has been implicated as a region that is sensitive to the genetic risk for AD [15][16][17][18], a very recent study reported no signi cant between-group differences on hippocampal volumes among APOE genotypes (N = 28,494) [21].…”

“…Large-scale gene-neuroimaging datasets, such as the UK Biobank (UKB) [22], have facilitated the exploration of ageing-related differences in brain structures among individuals with various risk levels. Recent investigations conducted based on the UKB cohort revealed regionspeci c differences in grey matter (GM) volumes between individuals with high and low AD-PRS, with these distinctions becoming notable starting around 50 years old (N = 45,616) [17]. However, the ageing-dynamic effects of AD-PRS on brain structures and cognitive outcomes remain to be quanti ed.To address these gaps, we analysed data from 29,645 cognitively intact ageing individuals in the UKB, integrating multimodal neuroimaging markers, multidimensional cognitive assessments, and the AD-PRS derived from approximately ve million SNPs.…”