Genetic Moderation of the Association of & beta;-Amyloid With Cognition and MRI Brain Structure in Alzheimer Disease

Background and ObjectivesThere is considerable heterogeneity in the association between increasing & beta;-amyloid (A & beta;) pathology and early cognitive dysfunction in preclinical Alzheimer disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examined an array of genetic variants that may influence the relationships among A & beta;, brain structure, and cognitive performance in 2 large cohorts.MethodsIn 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment.ResultsIn the A4 study, 4 genetic variants significantly moderated the association between A & beta; load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing A & beta; SUVR (rs78021285, & beta; = -2.29, SE = 0.40, p(FDR) = 0.02, nearest gene ARPP21; rs71567499, & beta; = -2.16, SE = 0.38, p(FDR) = 0.02, nearest gene PPARD; and rs10974405, & beta; = -1.68, SE = 0.29, p(FDR) = 0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing A & beta; SUVR (& beta; = 0.71, SE = 0.13, p(FDR) = 0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both the A4 and ADNI. In the A4, rs76366637 was strongly associated with reduced PACC scores with increasing A & beta; SUVR (& beta; = -1.01, SE = 0.21, t = -4.90, p < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (& chi;(2) = 15.3, p = 0.004) and atrophy over time (& chi;(2) = 26.8, p < 0.001), with increasing A & beta; SUVR.DiscussionPatterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD.

Automated summary

This study found that certain genetic variations can modulate the relationship between Aβ and cognitive ability, explaining the heterogeneity in cognitive function in early AD. One specific genetic variant near the ARPP21 gene was associated with cognitive decline and accelerated brain atrophy, potentially identifying individuals at higher risk for AD progression.