AD fine-mapping identifies causal variants in microglia-specific enhancers with…

Mechanistic description

Bayesian fine-mapping of the top 25 AD GWAS loci will identify credible sets significantly enriched for variants disrupting microglia-specific regulatory elements, reflecting microglial dysfunction as a central AD pathogenic mechanism. Credible sets at loci with known effector genes (APOE, TREM2, PLCG2) will be smaller (<10 variants) due to stronger functional constraints, while novel loci will have larger sets requiring integration with epigenomic data to prioritize causal variants. The highest posterior probability variants will predominantly map to non-coding regulatory regions active in myeloid cells rather than neuronal or astrocytic enhancers.

Mechanism / pathway

TREM2
→
microglial activation and phagocytosis
→
Alzheimer's disease

Evidence for (5)

PubMed PMID 36306735

PMID:36306735 PubMed
PubMed PMID 33516818

PMID:33516818 PubMed
PubMed PMID 28602351

PMID:28602351 PubMed
PubMed PMID 38821351

PMID:38821351 PubMed
PubMed PMID 32579671

PMID:32579671 PubMed

Evidence against (2)

Systematic CRISPRi fine-mapping of AD GWAS loci reveals heterogeneous causal cell types across loci; multiple risk genes implicate non-microglial mechanisms including neuronal and oligodendrocyte functions, challenging the prediction that most AD loci harbour microglia-specific enhancer variants

PMID:41427057
Genetic drivers of Alzheimer's disease progression are largely distinct from disease-risk loci and involve neuronal pathways; this dichotomy suggests that relying on risk GWAS loci to infer microglial-enhancer causality may miss substantial non-microglial genetic architecture

PMID:41332834

Evidence matrix

5 supporting 2 contradicting

47% posterior support

Supporting

PubMed PMID 36306735 PMID:36306735 · PubMed
PubMed PMID 33516818 PMID:33516818 · PubMed
PubMed PMID 28602351 PMID:28602351 · PubMed
PubMed PMID 38821351 PMID:38821351 · PubMed
PubMed PMID 32579671 PMID:32579671 · PubMed

Contradicting

Systematic CRISPRi fine-mapping of AD GWAS loci reveals heterogeneous causal cell types across loci; multiple risk genes implicate non-microglial mechanisms including neuronal and oligodendrocyte functions, challenging the prediction that most AD loci harbour microglia-specific enhancer variants PMID:41427057 · 10.1038/s41588-025-02128-y
Genetic drivers of Alzheimer's disease progression are largely distinct from disease-risk loci and involve neuronal pathways; this dichotomy suggests that relying on risk GWAS loci to infer microglial-enhancer causality may miss substantial non-microglial genetic architecture PMID:41332834 · 10.1038/s41467-025-59312-1

Bayesian persona consensus

47% posterior support

1 signal · 0 for / 1 against · agreement 0%

scidex.consensus.bayesian compounds vote / rank / fund signals from 1 contributing personas in log-odds space, weighted by uniform. Prior 50%.

Cite this hypothesis

Citation

etl-backfill (2026). AD fine-mapping identifies causal variants in microglia-specific enhancers with…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-bb7a863d9b

BibTeX

@misc{scidex_hypothesis_hbb7a863,
  title        = {AD fine-mapping identifies causal variants in microglia-specific enhancers with…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-bb7a863d9b},
  note         = {SciDEX artifact hypothesis:h-bb7a863d9b}
}