Amyloid-beta (Aβ) and tau co-pathology synergistically accelerates neurodegeneration in Alzheimer's disease (AD), yet the cellular substrate bridging these converging pathological hallmarks remains unidentified. Using single-nucleus RNA sequencing of postmortem entorhinal cortex tissue from the Pitt ADRC discovery cohort (n = 26) and the ROSMAP independent validation cohort (n = 62), we applied integrative non-negative matrix factorization and a cross-compartmental analytical framework to test whether oligodendrocyte (OL) subtype abundance coordinately tracks multi-domain AD pathology. Across six independently resolved OL subtypes in ADRC and fourteen in ROSMAP, one subtype in each cohort selectively coordinated with Aβ burden, tau accumulation, cerebrovascular integrity, cholesterol metabolism, myelin lipid synthesis, and autophagy-lysosomal function exclusively in A+ donors, while all others did not. This disease-coordinating subtype showed upregulation of TLR/NF-κB and interferon-mediated signaling alongside suppression of myelination and maturation programs. The coordination pattern was absent in amyloid-negative donors with comparable tau burden, positioning Aβ as a necessary contextual factor. Histological examination of late-severe AD tissue confirmed that AT8+/SOX10+ oligodendrocytes associate with demyelination and cerebrovascular disruption. These findings reframe oligodendrocytes as active participants in the convergent neuropathological landscape of AD, opening avenues for OL-centered biomarker and therapeutic investigation.