Genetic moderation on the relationship between brain white matter hyperintensities and amyloid‐beta
Bibliographic record
Abstract
BACKGROUND: Brain white matter hyperintensities (WMH) are vascular lesions commonly observed in Alzheimer's disease (AD). WMH were previously shown to be associated with greater brain amyloid, but the molecular pathways underlying their complex relation remain unclear. Here, we aim to identify single nucleotide polymorphisms (SNP) that modify the relationship between WMH and AD amyloid biomarkers. METHOD: We conducted a genome-wide interaction study in participants with AD, mild cognitive impairment, and normal cognition from the Alzheimer's Disease Neuroimaging Initiative (ADNI). WMH were measured from FLAIR MRI using an automated atlas-based segmentation. Amyloid-β 42 (Aβ42) in cerebrospinal fluid (CSF) were measured using immunoassays. Interactions between SNPs and WMH volumes on CSF-Aβ42 were assessed via a linear regression model adjusting for age, sex, diagnosis, MMSE, APOE-ε4 status, head-size, and 4 genetic principal components in PLINK2. The most influential SNP was identified via Sum of Single Effects (SuSiE) regression. Significant SNP-WMH interactions were validated in participants from the UK Biobank (UKB) with available plasma-Aβ42 data quantified by liquid chromatography-mass spectrometry. SNP-WMH interactions in relation to amyloid pathology (diffuse and neuritic plaque burden) was investigated in the Religious Orders Study/Rush Memory and Aging Project (ROSMAP). RESULT: >0.99%, n = 863) interacted with WMH to predict Aβ42 (nearest gene: U7 small nuclear RNA (snRNA) XR_007066478.1 [-111KB]). The effect of this SNP was also significant in the dominant and recessive genetic models (relative to the minor A-allele). This SNP-WMH interaction was replicated in UKB (n = 645) in both additive (B=0.91, p = 0.017) and dominant models (B=0.96, p = 0.024). In ROSMAP (n = 195), significant SNP-WMH interaction was observed on diffuse plaque burden in the additive (B=-0.46, p = 0.049) and dominant (B=-0.51, p = 0.046) models. The minor A-allele exhibited a protective effect by being associated with higher circulating Aβ42 (in ADNI and UKB) and lower diffuse plaque burden (in ROSMAP) in individuals with greater WMH. CONCLUSION: Genomic variants moderated the relationship between WMH and amyloid biomarkers, suggesting a novel regulatory role for snRNA. This genome-wide interaction study highlights the potential contributions of snRNA and related pathways to the relationship between vascular disease and amyloid biomarkers in AD.
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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 | 0.006 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".