Genetic Moderation of the Association of β-Amyloid With Cognition and MRI Brain Structure in Alzheimer Disease
Bibliographic record
Abstract
Objectives: There is considerable heterogeneity in the association between increasing amyloid β (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer’s 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 examine an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in two large cohorts. Methods: In 2953 cognitively-unimpaired participants from the A4 study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer’s Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer’s 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 A4, four genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of three variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β =-2.29, SE=0.40, pFDR=0.02, nearest gene ARPP21; rs71567499, β =-2.16, SE=0.38, pFDR=0.02, nearest gene PPARD; rs10974405, β =-1.68, SE=0.29, pFDR=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, pFDR=0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both A4 and ADNI. In 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 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. Conclusion: 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 A4 and accelerated cognitive decline as well as brain atrophy in ADNI may help to identify those at the highest risk of accelerated progression of Alzheimer’s disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".