Effects of Alzheimer’s disease genetic risk on brain morphometric development in three multiple‐ancestry pediatric datasets
Bibliographic record
Abstract
Abstract Background Few prior studies have investigated whether genetic risk for Alzheimer’s disease (AD) can manifest through altered neurodevelopment of AD‐vulnerable brain regions. This pre‐registered study tests the effects of AD polygenic risk on morphometric neurodevelopment across 3 large datasets totaling 8,364 youths aged 3‐22 (Table 1) Method Polygenic risk score (PRS) was calculated using PRS‐CS software, with summary scores from Kunkle et al. (2021) for African ancestry individuals (AA) and Jansen et al. (2019) for European ancestry individuals (EA). For EA only, PRS were calculated with (PRS‐APOE+) and without (PRS‐APOE‐) the APOE locus included. All individuals had T1‐weighted MRI processed with FreeSurfer that passed quality assessment checks. ComBAT was used to harmonize sites within‐cohort. Primary analyses investigated effects of PRS, age and their interaction on bilateral hippocampal volume and AD MetaROI cortical thickness using generalized additive models. Age interactions were not evaluated in ABCD due to limited age range. Exploratory analysis examined effects of age and PRS on cortical thickness, volume, surface area and subcortical volume across Desikan‐Killiany regions, adjusting for multiple comparisons (FDR). For exploratory analyses only, ABCD was split into training and test sets. All analyses were conducted for EA and AA separately; sex, total intracranial volume, image quality (Euler number) and ten genetic principal components were included as model covariates. Result Table 1 summarizes primary results. Hippocampal volume increased with age in 3/6 datasets, while MetaROI thickness decreased with age in all datasets. Surprisingly, increased PRS was associated with larger hippocampi in three datasets. In one dataset only, greater PRS was associated with increased metaROI thickness (Fig 1). 2/3 AA datasets showed age*PRS interactions on hippocampal volume, but in opposite directions. An age*PRS interaction on metaROI thickness was found in one dataset (Fig. 2A‐C). For exploratory analyses, no regions survived multiple comparisons for any contrast in 5/6 datasets; APOE only PRS was associated with larger supramarginal surface area in one dataset (Fig 2E). Effects were not correlated across studies (Fig 2D) Conclusion This large, pre‐registered study provides little evidence that AD genetic risk manifests during pediatric brain morphometric development.
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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 | 0.013 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".