Large-scale seroepidemiology uncovers nephro-urological pathologies in people with tau autoimmunity

Intraneuronal aggregates of the microtubule-associated protein tau play a pivotal role in Alzheimer's disease and several other neurodegenerative syndromes. Anti-tau antibodies can reduce pathology in mouse models of neurodegeneration and are currently being tested in humans. Here, we performed a large-scale seroepidemiological search for anti-tau IgG autoantibodies (ατ) on 40,497 human plasma samples. High-titer ατ+ individuals were surprisingly prevalent, with hospital patients being three times more likely to be ατ+ (EC50 ≥ 26; a nominal dilution of >1/64) than healthy blood donors (4.8% versus 1.6%). The prevalence increased with age over 70 years-old (RR 1.26, 95% CI 1.11-1.43, P < 0.001) and was higher for women (RR 1.20, 95% CI 1.07-1.39, P = 0.002). The autoantibodies bound selectively to tau, inhibited tau aggregation in vitro, and interfered with tau detection in plasma samples. No association was found between ατ autoantibodies and neurological disorders. Instead, tau autoreactivity showed a significant association with kidney and urinary disorders (adjusted RR 1.27, 95% CI 1.10-1.45, P = 0.001 and 1.40, 95% CI 1.20-1.63, P < 0.001, respectively). These results suggest a previously unrecognized association between ατ autoimmunity and extraneural diseases.