Large-scale seroepidemiology uncovers nephro-urological pathologies in persons 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 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 + (EC 50 ≥ 2 6 ; a nominal dilution of > 1/64) than healthy blood donors (4.8% vs 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.