Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer’s disease
Bibliographic record
Abstract
The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer’s disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [ 18 F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) phases GO/2 ( n =678). Near genome-wide significant interaction effect was observed for rs73069071 within the IAPP (amylin) and SLCO1A2 genes ( P =6.2 × 10 −8 ). Congruent results were found using data from participants followed up from ADNI-1 ( P one-tailed =0.028, n =165). Meta-analysis across ADNI-GO/2 and ADNI-1 revealed a genome-wide significant interaction effect ( P =1.1 × 10 −8 ). Our results were further supported by similar interaction effects on temporal lobe cortical thickness (whole-brain voxelwise analysis: familywise error corrected P =0.013) and longitudinal changes in ADAS-cog score and left middle temporal thickness and amygdalar volume ( P one-tailed =0.026, 0.019 and 0.003, respectively). Using postmortem beta-amyloid immunohistochemistry data from 243 AD participants in the Religious Orders Study and Memory and Aging Project, we also observed similar rs73069071-by-beta-amyloid deposition interaction effect on global cognitive function ( P one-tailed =0.005). Our findings provide insight into the complexity of the relationship between beta-amyloid burden and AD-related cognitive impairment. Although functional studies are required to elucidate the role of rs73069071 in AD pathophysiology, our results support the recently growing evidence on the role of amylin in AD.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".