P2‐076: Alzheimer’s Disease Genetic Risk Variants Beyond <i>Apoe</i> ε4 Predict Mortality in The Adult Changes in Thought (ACT) Study
Bibliographic record
Abstract
Longevity studies in older adults have identified APOEε4 as a risk factor for death. This risk may be partially mediated through Alzheimer’s disease (AD) incidence, as APOEε4 has the largest genetic effect on AD incidence and AD is a leading cause of death in older adults. We hypothesized that an AD genetic risk score (GRS) that incorporated other genetic variants associated with AD incidence may be associated with survival in older adults. 2,330 cognitively normal non-Hispanic white Group Health members aged ≥65 were enrolled in the ACT study, had available genetic data and were followed longitudinally. At biennial evaluations, a Cognitive Abilities Screening Instrument ≤85 triggered clinical and neuropsychological evaluation and consideration of a NINCDS-ADRDA criteria AD consensus diagnosis. We generated a weighted AD GRS based on the effect sizes of 19 non-APOE SNPs that achieved genome wide significance in a large meta-analysis (Lambert et al., Nature Genetics 2013). We used a Cox proportional hazards model to estimate the effect of the AD GRS and APOE on time to death, controlling for enrollment age, enrollment age, sex, 3 principal components of population substructure and study wave. In subsequent models, we controlled for CASI score at each visit and limited the analysis to those with an AD diagnosis. Mean AD GRS was -0.01 (sd=0.32). 25.7% of participants carried at least one APOEe4 allele. AD GRS was associated with mortality (HR=1.24; SE=0.10; P=0.02), but APOEε4 status was not (HR=1.03; SE=0.07; P=0.64). When we controlled for CASI score, AD GRS was no longer associated with mortality (HR=1.08; SE=0.05; P=0.52). When we limited the analysis to those with an AD diagnosis, AD GRS also was no longer associated with mortality (HR=0.94; SE=0.18; P=0.73). An AD GRS is associated with mortality, in addition to AD incidence. Our results suggest that the relationship between the AD GRS and mortality may be fully or partially mediated by cognitive changes, but not by AD disease progression.
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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 | 0.005 | 0.008 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.004 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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".