Tau seeds are widespread in the brain at the earliest stages of Alzheimer's disease-related changes.

Abstract

Alzheimer's disease (AD) is pathologically characterized by the systematic spread of 3R/4R tau species with progressing disease. Current imaging and CSF in-vivo assessments of tau are thought to reflect more mature tangle neuropathology. However, earlier oligomeric tau species are indicated to have greater neurotoxicity than mature forms and it is largely unknown how tau seeds correlate with histological indicators of AD. Furthermore, tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease (LBD); yet reliable measurements of tau seeds in such diseases remains an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to directly measure bioactive tau seeds in brain samples across a spectrum of neurodegenerative diseases to determine tau seeding activities at different stages of AD related changes. Tau RT-QuIC exploits the seeded polymerization growth mechanism of tau filaments, with sensitivities in the low fM range, allowing quantitation of disease-associated aggregates with unprecedented sensitivity and selectivity. Tau RT-QuIC assays were used to quantitate tau seeds in mid-frontal lobe brain tissue from 64 cases including subjects with neuropathologically confirmed AD (n=15), Parkinson's disease (n=7), multiple system atrophy (n=6), LBD (n=14), frontotemporal lobar degeneration (n=4), progressive supranuclear palsy (n=6), corticobasal degeneration (n=2), early Alzheimer's changes (Braak I-III) (n=7), and controls (n=3). All cases had Braak tau staging and frontal lobes were immunohistochemically stained for tau with NFT1. 3R/4R tau seeding activity is typically 100-1000-fold higher in cases with a primary AD diagnosis compared to controls, 4R tauopathies, and synucleinopathies, consistent with our prior observations. Seeding activity positively correlated with Braak tau stage, a histological measure of tau accumulation, with increased tau seeding activities at higher Braak stages. Tau seeds are detectable in the frontal lobe even at Braak I, a stage at which frontal lobe lacks histologically visible tau deposits. Ultrasensitive RT-QuIC assays detect tau seeds at the earliest stages of disease processes, prior to histopathological evidence of more mature tau accumulations and can indicate co-occurrence of tau pathology in non-AD cases. Tau seeding activity correlates with overall Braak tau stage, raising the possibility of quantitative value of tau RT-QuIC assays.