alzheimer-apoe4-microglia-ldam-r1

Direction d2 from the Alzheimer's-mechanism IDEATE run.

Do APOE4 homozygous and heterozygous carriers in existing human snRNA-seq atlases show a statistically significant shift away from disease-associated microglia (DAM) and toward lipid-droplet-accumulating microglia (LDAM), and does this LDAM/DAM ratio correlate with excess tau pathology burden beyond what is explained by Aβ accumulation alone?

APOE4 is the strongest genetic risk factor for AD; recent work converges on lipid metabolism and microglial dysfunction as its mechanistic core. TREM2-dependent DAM is the protective microglial state for plaque clearance; LDAM is a dysfunctional, proinflammatory state that fails at phagocytosis. This OmiCairn run re-analyses open human snRNA-seq by APOE genotype, computes DAM vs LDAM microglial composition, and tests whether the LDAM/DAM balance tracks tau burden (Braak / tangle count) independently of amyloid load.

Hypotheses (pre-registered, lifted from d2):

H1 (primary — genotype-driven LDAM/DAM marker shift): APOE4/4 carriers show significantly higher LDAM marker expression (LGALS3, CD9, GPNMB, NPC2) and lower DAM2 marker expression (TREM2, LPL, CST7) in microglia compared to APOE3/3 carriers at matched Braak stage, consistent with a lipid-driven microglial dysfunction. Decision rule: per-donor pseudobulk DE within the microglia compartment, APOE4/4 vs APOE3/3 stratified to matched Braak; report log2FC + Benjamini–Hochberg FDR + 95% bootstrap CI per gene. H1 passes if ≥2 of the 4 LDAM markers are up (FDR<0.05) AND ≥2 of the 3 DAM2 markers are down (FDR<0.05).

H2 (secondary — LDAM/DAM ratio vs tau beyond amyloid): The ratio of LDAM to DAM microglial cells correlates positively with neurofibrillary-tangle burden (not just Aβ plaque count), suggesting APOE4-driven microglial dysfunction accelerates tau pathology independently of amyloid load. Decision rule: per-donor LDAM/DAM ratio regressed on a tau index (Braak stage and/or tangle count) with Aβ load as a covariate; report the partial regression coefficient for tau + p-value + 95% CI. H2 passes if the tau coefficient is positive and significant (p<0.05, 95% CI excluding 0) after adjusting for Aβ.

IMPORTANT — covariate dependency: H1 requires APOE genotype metadata; H2 requires tau/Braak (and ideally Aβ) metadata in the same donors. EXECUTE MUST first verify these covariates are present in the fetched object. If APOE genotype is missing, H1 cannot be tested — report that honestly and fall back to a Braak-stratified DAM-vs-LDAM description without the genotype contrast. If tau/Aβ neuropathology is missing, H2 cannot be tested — say so and report the LDAM/DAM composition descriptively. Do NOT impute or fabricate genotype or neuropathology.

A negative or partial result is fully informative. If APOE4 does not shift the LDAM/DAM balance, or the shift does not track tau, that must be the headline rather than re-tuning cluster definitions until H1/H2 pass.

The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.