AbstractBackgroundPathogenic processes characteristic of neurodegenerative brain diseases, such as accumulation of phosphorylated Tau protein (pTau), can also be detected in the retina. Given the advanced state of retinal imaging technology and its potential to aid in the clinical diagnosis of Alzheimer’s disease (AD), it is imperative to investigate the part the retina plays in neurodegenerative diseases of the brain, as well as the associated eye‐specific degenerative processes.MethodsRetinas from 129 individuals who underwent eyeball resection/evisceration for severe ophthalmological conditions and from 35 post‐mortem donors with or without AD were analyzed. Paraffin‐embedded sections from cross‐sectioned retinas were stained with antibodies against different pTau species and Gallyas staining to detect neurofibrillary tangles. Retinal pTau accumulation, its distribution over the retinal layers, and molecular composition were determined neuropathologically and correlated with visual performance, age, and the presence of dementia.ResultsRetinal pTau pathology showed a consistent topographical expansion pattern that allowed distinguishing four stages: Stage 0: no pTau pathology; Stage 1: thread‐like pTau in the outer plexiform layer; Stage 2: additional cytoplasmic pTau in the inner nuclear layer; Stage 3: thread‐like pTau also in the inner plexiform layers. Antibodies against pTauS202/pT205 (AT8), pTauT231 (AT180), and anti‐MC‐1 Tau showed comparable results. Neurofibrillary tangles were not found. The stage of retinal tauopathy was correlated with age (r = 0.176, p = 0.024, n = 164), the underlying ophthalmologic diseases (p = 0.001; β = 0.292), and independently associated with vision impairment (p = 0.030; β = 0.192) in a linear regression model. Cases with a clinical diagnosis of dementia were associated with slightly higher stages of retinal tauopathy (binary logistic regression: p = 0.026; odds ratio (OR) = 1.685 [95% C.I.1.066‐2.664), although some demented cases were free of pTau pathology.ConclusionsThese results point towards the existence of a primary retinal tauopathy (PReT). It differs in its molecular composition from cerebral tauopathies by the lack of argyrophilic inclusions and the predominance of 3‐repeat Tau. However, PReT may be a prerequisite for developing AD pathology in the retina. Altogether, these findings support the presence of retinal neurodegenerative changes that may reflect changes in the brain.FundingSAO/FRA 2020/017