Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures - PubMed

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Clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease (LOAD) contributes to variable therapeutic outcomes.
Molecular subtyping through proteomic and transcriptomic profiling reveals distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles.
Study analyzed genome-wide DNA methylation (DNAm) data from three independent postmortem brain cohorts (N = 826) to identify epigenetic subtypes of LOAD.
Two distinct epigenomic subtypes of LOAD were identified, consistently observed across three cohorts, both showing significant yet distinct microglial methylation enrichment.
Subtype 1 was enriched for immune-related processes, while subtype 2 was characterized by neuronal and synaptic pathways.
Single-nucleus transcriptional profiling of microglia indicated that both subtypes share AD-associated innate-immune remodeling, with subtype differences emerging primarily as state-dependent transcriptional shifts.
Subtype 1 showed a relative weighting toward more inflammatory microglial programs, whereas subtype 2 showed stronger transcriptional remodeling in specific microglial states alongside relatively greater engagement of regulatory and clearance-associated features.
Findings reveal distinct epigenetic and functional microglial states underlying LOAD subtypes, advancing understanding of disease heterogeneity and laying groundwork for targeted therapeutic strategies.

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