BACKGROUND. Noninvasive detection of Alzheimer’s disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS. Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls ( n = 37). In a proof-of-concept retinal imaging trial ( n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS. Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ ₄₂ plaques (4.7-fold; P = 0.0063) and neuronal loss ( P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex ( P = 0.0097 to P = 0.0018; Pearson’s r = 0.84–0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls ( P = 0.0031). CONCLUSION. The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING. National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate—GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential mechanism of action (MOA) and outcomes of GA immunization in patients. Furthermore, results from these and animal studies suggest that GA has a direct immunomodulatory effect on adaptive and innate immune cell phenotypes and responses. These MOAs have been postulated to have a common neuroprotective impact in several neuroinflammatory and neurodegenerative diseases. Notably, several clinical studies report that the use of GA mitigated MS-associated cognitive decline. Its propensity to ameliorate neuro-proinflammatory and degenerative processes ignites increased interest in potential alternate uses such as in age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). Preclinical studies are exploring less frequent subcutaneous administration of GA, such as once weekly or monthly or a single dosing regimen. Indeed, cognitive functions were found to be either preserved, reversed, or improved after the less frequent treatment regimens with GA in animal models of AD. In this systematic review, we examine the potential novel uses of GA across clinical and pre-clinical studies, with evidence for its beneficial impact on cognition. Future investigation in large-size, double-blind clinical trials is warranted to establish the impact of GA immunomodulation on neuroprotection and cognitive preservation in various neurological conditions.

Background: Histological and in vivo imaging studies suggest a loss of retinal ganglion cells (RGCs) in Alzheimer's disease (AD) patients, potentially contributing to dysfunctions such as contrast sensitivity, color vision, and circadian rhythms. We previously reported elevated pathogenic‐tau isoforms, particularly hyperphosphorylated tau at serine 396 (pS396‐tau) and tau oligomers (oligo‐tau), in the retinas of patients with mild cognitive impairment (MCI, due‐to‐AD) and AD dementia compared to cognitively normal (CN) individuals. However, the presence of pathogenic‐tau isoforms in RGCs and their impact on RGC integrity in AD have not been studied. Method: Retinal cross‐sections from 25 patients with MCI or AD and 16 age‐ and sex‐matched CN controls were analyzed. Immunofluorescence and Nissl staining were conducted, using the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) in conjunction with pathogenic tau‐isoforms, and markers of apoptosis, granulovacuolar degeneration (GVD) bodies, and GVD‐associated necroptosis. Stereological quantifications and analyses of RGC size and distribution were performed. Findings were correlated with corresponding brain pathology and cognitive status. Result: We present the first evidence of tau inclusions, pS396‐tau and T22 ⁺ oligo‐tau, within RBPMS ⁺ RGCs, alongside a 46–56% reduction in RBPMS ⁺ ‐RGCs and Nissl ⁺ ‐neurons in the ganglion cell layer of MCI and AD retinas. RGC loss was accompanied by morphological and molecular alterations: soma hypertrophy (10‐50% enlargement), nuclear displacement, apoptosis (30‐50% increase), and prominent expression of CHPM2B ⁺ GVD bodies and pMLKL ⁺ GVD‐necroptotic markers. PS396‐tau ⁺ ‐RGC and oligo‐tau ⁺ ‐RGC counts were 2.1–3.5‐fold higher in MCI and AD retinas compared to CN. Tauopathy‐laden RGCs intercorrelated ( r = 0.85, p <0.0001), and were associated with RGC reduction ( r = ‐0.40–(‐0.64), p <0.05–0.01). Their abundance linked with advanced brain pathology (Braak stage V–VI) and cognitive decline (clinical dementia rating 3, mini mental state evaluation <26). Conclusion: Our findings suggest that abnormal tau‐isoforms accumulate within RBPMS ⁺ RGCs in MCI and AD patients, contributing to early and pronounced RGC loss and correlating with disease severity. This link involves apoptotic and GVD‐necroptotic cell death pathways. Future research should validate these results in larger cohorts and develop RGC‐tauopathy as a noninvasive biomarker for early AD detection and monitoring.

Background: This study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer’s disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post‐translational modifications, including hyperphosphorylation (p‐tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs). Previously, increased p‐tau and other abnormal forms were detected in postmortem retinas of AD patients; however, their presence and levels at earlier stages – in mild cognitively impaired (MCI due to AD) patients – and their association with brain pathology remain undefined.Method: In this study, we acquired 75 postmortem human eyes and 39 paired brains. Retinal cross‐sections in predefined geometric regions were prepared from 34 AD and 11 MCI patients, and 30 age‐ and sex‐matched cognitively normal controls. Histological analyses involved Bielschowsky silver staining and immunostaining of brains and retinas with antibodies for tau (pS396, AT8, AT100, CitR₂₀₉, T22, PHF‐1, and MC‐1). Stereological examination and quantification were conducted, and correlations were determined with brain pathology and cognition. P‐tau forms were also determined by NanoString GeoMx digital spatial profiling.Result: Our immunohistochemical examination revealed significant upregulation of immature hyper‐citrullinated (CitR₂₀₉) and p‐tau forms, propagating tau oligomers, as well as mature PHF‐tau and NFT forms in the retinas of patients with early‐AD (MCI due to AD) and AD‐dementia stages. Interestingly, retinal PHF‐tau accumulated only in the AD‐dementia stage. GeoMx spatial profiling analyses revealed site‐specific increases in various p‐tau epitopes in AD, particularly at the early MCI stage. Tau oligomers had the largest accumulations in MCI and, moreover, AD retinas, showing a strong correlation to Braak staging, representing the spread of tauopathy across brain regions during disease progression. Strong correlations were also found between retinal tauopathy and brain NFTs, ABC, and MMSE severity scores.Conclusion: Our data demonstrate that most forms of retinal tauopathy are increased in early AD and correlate with one or more AD neuropathology and cognitive parameters, encouraging the development of retinal tauopathy imaging for AD detection and monitoring disease progression.