A distinct tau oligomer strain defines the molecular and proteomic landscape of rapidly progressive Alzheimer's disease.

Rapidly progressive Alzheimer's disease (rpAD) is a rare subtype with rapid decline, but its molecular underpinnings remain poorly defined. Here, brain-derived tau oligomers (TauO) were systematically compared across nondemented controls, slowly progressive AD (spAD), and rpAD to test whether subtype-specific TauO signatures align with clinical aggressiveness. TauO were immunoprecipitated from frontal cortex using T22 antibody and characterized by Western blotting, transmission electron microscopy, label-free quantitative proteomics, and SH-SY5Y toxicity assays, complemented by longitudinal analysis of tau phosphorylation in inoculated 3xTg AD mice. T22-positive high-molecular-weight TauO were successfully enriched from all groups, where rpAD TauO exhibited compact, densely packed oligomers under TEM and the highest phosphorylation at pS396 and pS422, exceeding both spAD and controls (p ≤ 0.0327). In 3xTg mice, pS396 showed an early increase followed by a late decline, consistent with dynamic shifts in tau solubility during disease evolution. Brain-derived TauO from spAD and rpAD, but not recombinant tau monomers or control-derived TauO, significantly reduced SH-SY5Y cell viability. Proteomic profiling identified 2388 TauO-associated proteins, including a shared 556-protein core and a striking expansion of rpAD-unique interactors (n = 1101). In controls and spAD, the core TauO interactome was enriched for translation, proteostasis, mitochondrial respiration, and vesicle-trafficking pathways, whereas these modules were absent in rpAD. Instead, rpAD TauO showed selective enrichment of aldehyde detoxification, amino-acid and carbon metabolism, and actin-regulatory modules, alongside increased association of SERPINA1, ALDH9A1, MAPRE3, DPYSL2, DPYSL3, and NFASC and reduced coupling to mitochondrial (MRPL17) and complement (C9) components. These convergent structural, post-translational, toxic, and interactome changes indicate that rpAD is defined by a biochemically distinct TauO species embedded in a metabolic and cytoskeleton-focused network, providing a mechanistic framework for its aggressive clinical course and a basis for subtype-specific biomarker and therapeutic strategies.