This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer’s disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR₂₀₉-tau; 4.1-fold), and Oligo-tau (T22⁺, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR₂₀₉-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63–0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69–0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67–0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ₄₂ and arterial Aβ₄₀ forms (r = 0.76–0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

这项研究调查了早期和晚期阿尔茨海默病 (AD) 患者视网膜中的各种病理性 tau 亚型，探索它们与疾病状态的关系。将预先确定的颞上和下颞亚区域的视网膜横截面以及经神经病理学证实的临床诊断为轻度认知障碍 (MCI) 或痴呆 ( n = 45) 的 AD 患者的相应大脑与年龄和性别的视网膜进行比较- 具有正常认知能力 ( n = 30) 和非 AD 痴呆症 ( n = 4) 的匹配个体。对视网膜 tau 亚型，包括 tau 缠结、tau 配对螺旋丝 (PHF-tau)、寡聚 tau (Oligo-tau)、高度磷酸化 tau (p-tau) 和瓜氨酸 tau (Cit-tau) 进行体视学分析通过免疫组织化学和 Nanostring GeoMx 数字空间分析，并与临床和神经病理学结果相关。我们的数据表明各种 AD 相关的 pretangle tau 亚型显着增加，特别是 p-tau（AT8，2.9 倍，pS396-tau，2.6 倍）、精氨酸残基 209 处的 Cit-tau（CitR ₂₀₉ -tau；4.1 倍） ）和 Oligo-tau（T22 ⁺ ，9.2 倍），以及预缠结和成熟 tau 缠结形式，如 MC-1 阳性（1.8 倍）和 PHF-tau（2.3 倍），与对照相比，AD 中视网膜。 MCI 视网膜还表现出 Oligo-tau（5.2 倍）、CitR ₂₀₉ -tau（3.5 倍）和 pS396-tau（2.2 倍）的显着增加。 Nanostring GeoMx 分析证实视网膜 p-tau 表位升高：Ser214（2.3 倍）、Ser396（2.6 倍）、Ser404（2.4 倍）和 Thr231（1.8 倍），特别是在 MCI 患者中。 视网膜 tau 亚型与脑病理学和认知状态之间存在很强的相关性：a) 视网膜 Oligo-tau 与 Braak 阶段、神经原纤维缠结 (NFT) 和 CDR 认知评分 ( ρ = 0.63–0.71)，b) 视网膜 PHF-tau与神经纤维丝 (NT) 和 ABC 评分 ( ρ = 0.69–0.71)，以及 c) 视网膜 pS396-tau 与 NT、NFT 和 ABC 评分 ( ρ = 0.67–0.74)。值得注意的是，视网膜 Oligo-tau 与视网膜 Aβ ₄₂和动脉 Aβ ₄₀形式密切相关 ( r = 0.76–0.86)。总体而言，这项研究识别并量化了 MCI 和 AD 患者中不同的视网膜 tau 亚型，强调了它们与大脑病理学和认知的联系。这些发现提倡进一步探索视网膜tau蛋白病生物标志物，以促进通过无创视网膜成像检测和监测AD。