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

Abstract

Background and objectives: There is considerable heterogeneity in the association between increasing β-amyloid (Aβ) 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 Aβ, brain structure, and cognitive performance in 2 large cohorts.

Methods: In 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.

Results: In the A4 study, 4 genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β = -2.29, SE = 0.40, p _FDR = 0.02, nearest gene ARPP21; rs71567499, β = -2.16, SE = 0.38, p _FDR = 0.02, nearest gene PPARD; and rs10974405, β = -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 Aβ SUVR (β = 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 Aβ SUVR (β = -1.01, SE = 0.21, t = -4.90, p < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (χ² = 15.3, p = 0.004) and atrophy over time (χ² = 26.8, p < 0.001), with increasing Aβ SUVR.

Discussion: Patterns 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.

Figure 1. Genome-wide Significance in the A4

Genome-wide significance in the A4. A4 = Anti-Amyloid Treatment in Asymptomatic Alzheimer disease.

Figure 2. Regional Loci

Regional plots of each genetic variant's locus in the A4. Selected variant shown in purple. R² values are color coded to reflect the magnitude of linkage disequilibrium. A4 = Anti-Amyloid Treatment in Asymptomatic Alzheimer disease.

Figure 3. PACC Scores in A4

PACC Scores are plotted against 18F-Florbetapir SUVRs for each of the 4 variants in the A4. Separate curves are shown for participants carrying the minor allele of the genetic variant (GV+) and noncarriers (GV−). Shaded regions indicate 95% CIs. A4 = Anti-Amyloid Treatment in Asymptomatic Alzheimer disease; PACC = Preclinical Alzheimer Cognitive Composite.

Figure 4. PACC Scores and Structural MRI

Cross-sectional PACC scores for participants in the A4 are plotted against 18F-Florbetapir SUVRs by carrier status for the variant rs76366637 in the upper left panel. Longitudinal PACC scores for participants in the ADNI are plotted over time in the upper right panel, with estimated curves and 95% CIs for 4 groups: low amyloid GV carriers in blue, low amyloid GV noncarriers in black, high amyloid GV noncarriers in gold, and high amyloid GV carriers in red. SUVRs were modeled continuously, though specific SUVRs are used for the purpose of depiction. Similarly, in the bottom row, longitudinal ventricular volumes for ADNI participants are plotted over time with estimated curves and 95% CIs for the same 4 groups. A4 = Anti-Amyloid Treatment in Asymptomatic Alzheimer disease; ADNI = Alzheimer Disease Neuroimaging Initiative; GV = genetic variant; PACC = Preclinical Alzheimer Cognitive Composite; SUVR = standardized uptake value ratio.