Whole Genome Sequencing Analysis of Cognitively Wellderly Individuals Identifies Potential Protective Genetic Variants for Alzheimer’s Disease
Bibliographic record
Abstract
Abstract Background Genetic variants that confer protection from Alzheimer’s disease (AD) may be particularly critical in developing therapeutics. To target protective variant identification, we performed genetic association testing among selected individuals with whole genome sequencing (WGS) that remained alive and dementia‐free beyond age 85 (“Wellderly”). Methods We selected 1,873 White and Black Wellderly individuals with documented normal cognition beyond age 85 as determined by direct, in‐person assessment with WGS from the NHLBI TOPMed project. We used two sets of comparison groups: (i) general controls, non‐Wellderly individuals including persons without and with dementia [n = 8,502] and (ii) individuals who developed dementia before age 85 [n = 810]. We performed generalized mixed model regression for each variant with a minor allele frequency (MAF) > 1%, as well as analysis of aggregation of rare (MAF ≤ 1%) coding and non‐coding variants via a modified STAAR approach, with and without adjusting for APOE status. Results We observed a reduced likelihood of Wellderly status compared to general controls at the APOE locus (rs429358, MAF = 14%, odds ratio [OR] = 0.69, p = 1.6 × 10‐10), consistent with the known association of the APOE locus with dementia. We also observed 7 coding gene‐based tests associated with Wellderly status at an alpha of 5 × 10‐8 (Figure). For the aggregation of non‐coding variants, we observed Wellderly status associated with PRB4 (p = 4.7 × 10‐10) and suggestively (p<1 × 10‐6) associated with 3 additional genes. None of the variant aggregates showed significant association with Wellderly status when compared to the diseased controls. IKBKB encodes an inhibitor of nuclear factor kappa B kinase subunit beta, and deficiency of IKBKB protein in myeloid cells was reported to have improved cognitive functions in the AD mice. KCNK4, the potassium channel subfamily K member 4, plays an important role in controlling the cell potassium flux and dysregulated KCNK4 function can cause neurodevelopmental abnormalities. Conclusion Although only variants in the APOE locus have a reduced likelihood of Wellderly status in the single variant analysis, our aggregated tests suggest genes aside from APOE that are associated with Wellderly status with biological plausibility. We are pursuing replication using the Alzheimer’s disease Sequencing Project (ADSP) WGS data.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".