MGnD expansion and oligodendrocyte loss are coupled and sequentially ordered in…

In SEA-AD cortex, the transition from homeostatic microglia (P2RY12-high, TMEM119-high, CX3CR1-high) to MGnD/DAM states (APOE-high, TREM2-high, SPP1-high, LPL-high, GPNMB-high) is hypothesized to precede, and potentially drive, the loss of mature oligodendrocytes (MOL) across Braak stages III–VI. The causal ordering hypothesis predicts: (1) MGnD fraction rises significantly at Braak III–IV before MOL depletion reaches significance; (2) MERFISH spatial data shows MGnD cells co-localizing with demyelinated foci and amyloid plaques prior to MOL loss in the same layer; (3) trajectory inference (Palantir or PAGA) on joint microglia+OPC+MOL subsets recovers a temporal arc consistent with MGnD-driven phagocytosis of myelin, supported by elevated TREM2 and LPL in the MGnD cluster. Competing hypothesis: MOL stress signals (e.g. upregulated CXCL10, downregulated MBP) are upstream and recruit MGnD; testable by cross-lagged regression of subtype fractions against Braak stage in SEA-AD (n≈84 donors) and ROSMAP (n≈400 donors). A finding that either ordering is consistent across both cohorts would be a significant advance; inconsistency would implicate cohort-specific confounders (age, sex, APOE genotype) requiring stratified re-analysis.