P3–165: MRI traits are heritable among Alzheimer disease cases and their siblings in the MIRAGE Study
Bibliographic record
Abstract
Magnetic resonance imaging (MRI) traits can serve as more precise measures of degenerative or cerebrovascular brain injury than can be ascertained through history, risk factors, clinical signs or symptoms. Moreover, they are potentially useful intermediate phenotypes for genetic studies of Alzheimer disease (AD). Recent studies of quantitative white matter hyperintensity (WMH) have estimated heritability between 0.55–0.73 among cognitively normal family members. Persons with and without AD are expected to have substantially different MRI phenotypes distributions. Our objective was to determine whether of MRI traits in siblings discordant for AD are heritable. We measured WMH, a rating of cerebrovascular disease (CVR) that reflects the WMH rating plus the number, size and location of infarcts if present, and general atrophy (GA) via MRI in 402 participants from 205 families, of the MIRAGE Study. Traits were rated on a 0–100 scale, and log–transformed to reduce skewness. Linear regression was used separately in cases and unaffected siblings to adjust for gender, age at first symptoms, and time from onset to MRI scan (cases), and gender and age at MRI (controls). We estimated heritability for the adjusted traits correcting for ascertainment by conditioning on the AD proband in each sibship using the variance components approach of SOLAR. All three traits were significantly heritable. The heritability of CVR was 0.49 (SE=0.15, p=0.0004); WMH and GA had slightly lower heritability (h=0.32, 0.27, p=0.019, p=0.017). We used a measured genotype approach to test for differences in means of the adjusted transformed traits by the number of APOE ϵ4 alleles. The number of ϵ4 alleles was significantly associated with WMH (p=0.017, proportion of variance explained: 0.020). A trend toward association was observed also with CVR (p= 0.070, proportion of variance explained: 0.011), but no association was observed with GA. Heritability of all measures remained significant after accounting for APO genotype, suggesting that a substantial portion of the genetic variation in these MRI traits remains to be explained by additional genes. The degree of degenerative change associated with AD is under genetic control. Identification of the genes involved may provide insights about pathogenesis.
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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 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.003 | 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".