The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization
Bibliographic record
Abstract
ABSTRACT Importance Alzheimer’s disease is the leading cause of disability and healthy life years lost. However, to date, there are no proven causal and modifiable risk factors, or effective interventions. Objective We aimed to identify: a) factors modified by prodromal Alzheimer’s disease pathophysiology and b) causal risk factors for Alzheimer’s disease. We identified factors modified by Alzheimer’s disease using a phenome-wide association study (PheWAS) on the Alzheimer’s disease polygenic risk score (PRS) (p≤5×10 -8 ), stratified by age tertiles. We used two-sample bidirectional Mendelian randomization (MR) to estimate the causal effects of identified risk factors and correlates on liability for Alzheimer’s disease. Design, setting, and participants 334,968 participants of the UK Biobank aged 39 to 72 years old (111,656 in each tertile) met our eligibility criteria. Exposures Standardized weighted PRS for Alzheimer’s disease at p≤5×10 -8 . Main outcomes and measures All available phenotypes in UK Biobank, including data on health and lifestyle, as well as samples from urine, blood and saliva, at the time of analysis. Results Genetic liability for Alzheimer’s disease was associated with red blood cell indices and cognitive measures at all ages. In the middle and older age tertiles, ages 53 and above, higher genetic liability for Alzheimer’s disease was adversely associated with medical history (e.g. atherosclerosis, use of cholesterol-lowering medications), physical measures (e.g. body fat measures), blood cell indices (e.g. red blood cell distribution width), cognition (e.g. fluid intelligence score) and lifestyle (e.g. self-reported moderate activity). In follow-up analyses using MR, there was only evidence that education, fluid intelligence score, hip circumference, forced vital capacity, and self-reported moderate physical activity were likely to be causal risk factors for Alzheimer’s disease. Conclusion and relevance Genetic liability for Alzheimer’s disease is associated with over 160 phenotypes, some as early as age 39 years. However, findings from MR analyses imply that most of these associations are likely to be a consequence of prodromal disease or selection, rather than a cause of the disease.
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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 | 0.033 | 0.072 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".