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Background: Phosphorylated tau (p-tau) accumulation, a hallmark of Alzheimer's disease (AD), can also be found in the retina. However, it is uncertain whether it is linked to AD or another tauopathy., Methods: Retinas from 164 individuals, with and without AD, were analyzed for p-tau accumulation and its relationship with age, dementia, and vision impairment., Results: Retinal p-tau pathology showed a consistent pattern with four stages and a molecular composition distinct from that of cerebral tauopathies. The stage of retinal p-tau pathology correlated with age (r = 0.176, P = 0.024) and was associated with AD (odds ratio [OR] 3.193; P = 0.001), and inflammation (OR = 2.605; P = 0.001). Vision impairment was associated with underlying eye diseases (β = 0.292; P = 0.001) and the stage of retinal p-tau pathology (β = 0.192; P = 0.030) in a linear regression model., Conclusions: The results show the presence of a primary retinal tauopathy that is distinct from cerebral tauopathies., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer's disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)