Using SEA-AD snRNA-seq data (Gabitto, Travaglini et al. 2024, doi:10.1038/s41593-024-01774-5) and cross-cohort replication in ROSMAP (Mathys et al. 2023), we will: (1) perform pseudotime / RNA velocity trajectory inference on joint microglia+oligodendrocyte subsets across Braak I–VI donors; (2) test whether DAM/MGnD compositional abundance (scCODA Dirichlet regression) precedes Oligo-1 and OPC proportional decline when donors are ordered by Braak stage; (3) identify ligand-receptor pairs (CellChat or LIANA) linking SPP1/GPNMB microglia states to OPC survival or differentiation signals; (4) cross-reference Depp et al. 2023 (doi:10.1038/s41586-023-06120-6) myelin-dysfunction–amyloid axis and Kim et al. 2022 (doi:10.1186/s13024-022-00589-x) stage-specific microglia subtypes for mechanistic triangulation. Success criterion: microglia DAM/MGnD composition shows statistically significant Braak-stage association (Dirichlet q<0.05) with effect size preceding matched oligo/OPC depletion by at least one Braak tier in ≥2 independent cohorts.
Details
- disease
- alzheimer's disease
- target_ref
- SEA-AD:DLPFC:microglia+oligodendrocyte
- identification_strategy
- in_silico_KO
Raw fields (1)
- hypothesis
Expansion of SPP1/GPNMB-high disease-associated microglia (DAM/MGnD) precedes measurable oligodendrocyte and OPC depletion in human DLPFC across Braak stages I–VI, and the two processes are mechanistically coupled through myelin debris phagocytosis and complement-mediated pruning rather than representing independent parallel pathologies.