Human longevity and Alzheimer’s disease variants act via microglia and oligodendrocyte gene networks
Bibliographic record
Abstract
Ageing underlies functional decline of the brain and is the primary risk factor for several neurodegenerative conditions, including Alzheimer's disease (AD). However, the molecular mechanisms that cause functional decline of the brain during ageing, and how these contribute to AD pathogenesis, are not well understood. The objective of this study was to identify biological processes that are altered during ageing in the hippocampus and that modify Ad risk and lifespan, and then to identify putative gene drivers of these programmes. We integrated common human genetic variation associated with human lifespan or Ad from genome-wide association studies with co-expression transcriptome networks altered with age in the mouse and human hippocampus. Our work confirmed that genetic variation associated with Ad was enriched in gene networks expressed by microglia responding to ageing and revealed that they were also enriched in an oligodendrocytic gene network. Compellingly, longevity-associated genetic variation was enriched in a gene network expressed by homeostatic microglia whose expression declined with age. The genes driving this enrichment include CASP8 and STAT3, highlighting a potential role for these longevity-associated genes in the homeostatic functions of innate immune cells, and these genes might drive 'inflammageing'. Thus, we observed that gene variants contributing to ageing and AD balance different aspects of microglial and oligodendrocytic function. Furthermore, we also highlight putative Ad risk genes, such as LAPTM5, ITGAM and LILRB4, whose association with Ad falls below genome-wide significance but show strong co-expression with known Ad risk genes in these networks. Indeed, five of the putative risk genes highlighted by our analysis, ANKH, GRN, PLEKHA1, SNX1 and UNC5CL, have subsequently been identified as genome-wide significant risk genes in a subsequent genome-wide association study with larger sample size, validating our analysis. This work identifies new genes that influence ageing and AD pathogenesis, and highlights the importance of microglia and oligodendrocytes in the resilience of the brain against ageing and AD pathogenesis. Our findings have implications for developing markers indicating the physiological age of the brain and new targets for therapeutic intervention.
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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".