Tandem Tau and α-Synuclein Seed Amplification Assays Reveal α-Synuclein Copathology Potentiates Tau Seeding in Alzheimer’s Disease

Accumulating evidence highlights the frequent co-occurrence of tau and α-synuclein (αSyn) pathology across neurodegenerative diseases, including Alzheimer’s disease (AD) and synucleinopathies. Whether the co-deposition of these proteinopathic aggregates influences their respective seeding capacities remains unknown. Seed amplification assays (SAAs) enable sensitive and specific detection of pathological seeding activity in brain tissue and cerebrospinal fluid (CSF) and have been widely used to assess tau or αSyn seeding independently; however, their tandem application in the same individuals has not been thoroughly investigated. Here we apply Tau- and αSyn-SAA in parallel on a well-characterized postmortem cohort of matched brain tissue and CSF spanning AD, synucleinopathies, other neurological diseases, and neuropathologically defined controls. We demonstrate that tau seeding activity in both brain and CSF closely reflects underlying neuropathological burden, increasing stepwise with the grade of AD neuropathological change (ADNC) and neurofibrillary tangle (NFT) stage, with strong within-donor concordance between matrices (r = 0.79, p < 0.001). Tau-SAA measured in postmortem CSF robustly discriminated AD-related neuropathology from other groups, supporting its potential as a neuropathologically informed biomarker. αSyn-SAA identified all synucleinopathy donors as positive and revealed that 44% of AD donors harbor concomitant αSyn seeding activity. Leveraging this tandem dataset, we find that αSyn-SAA positive AD donors exhibit significantly enhanced tau seeding activity in both brain and CSF, independent of NFT stage, age, and sex (p = 0.014). In synucleinopathy donors, tau seeding did not alter αSyn seeding capacity (p = 0.606). Together, these results suggest a potentially unidirectional relationship between tau and αSyn seeding in human disease, wherein αSyn copathology acts as a catalyst of tau seeding in AD. Our findings carry implications for understanding how mixed proteinopathies shape disease burden and trajectory and may represent the beginning of a new direction in the field moving towards precision medicine to identify all types of pathology concomitantly affecting the brain, which will have a profound impact on patient prognosis and treatment.