Distinct neuronal vulnerability and metabolic dysfunctions are characteristic features of fast-progressing...

Tau protein accumulation is linked to dementia progression in Alzheimer's disease (AD), with potential co-pathologies contributing to it. The progression of dementia in patients with AD varies between individuals, and the association between co-pathology and heterogeneity in dementia progression rate remains unclear. We used longitudinal cohort data, postmortem brain tissues, and biochemical methods such as immunoassays and proteomic profiling to investigate the molecular components associated with progression rate. We report that AD with comorbidities, such as dementia with Lewy bodies (DLB) and TDP-43 pathology, progress faster than AD alone. Patients with AD-DLB had higher levels of soluble oligomeric tau proteins and lower levels of insoluble tau proteins compared to those with AD alone. Our data suggest that α-synuclein fibrils may enhance tau aggregation through cross-seeding. The prefrontal cortex is more vulnerable to Lewy body pathology than the temporal cortex, and Tau and α-synuclein aggregate in distinct neuronal populations, indicating selective neuronal and regional vulnerability to their respective pathologies. Dysfunctional metabolic pathways were more strongly associated with patients having fast-progressing AD-DLB. Our study suggests that comorbidities, such as α-synuclein aggregation and metabolic dysfunctions, are associated with rapidly progressing AD patients, highlighting the importance of patient subgrouping for clinical trials.