The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults.Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid, absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and towards validation of AD risk biomarkers that could potentially be used as a first step in a multi-step screening process for AD risk detection.

Introduction We conducted a 27-month longitudinal study of mid-life adults with preclinical Alzheimer's disease (AD), using spectral domain optical coherence tomography to compare changes in volume and thickness in all retinal neuronal layers to those of age-matched healthy control subjects. Methods Fifty-six older adults (mean age = 65.36 years) with multiple risk factors for AD completed spectral domain optical coherence tomography retinal imaging and cognitive testing at baseline. Twenty-seven months later, they completed the same examinations and an 18 F-florbetapir positron emission tomography imaging study. Results Compared to healthy control subjects, those in the preclinical stage of AD showed a significant decrease in macular retinal nerve fiber layer (mRNFL) volume, over a 27-month follow-up interval period, as well as a decrease in outer nuclear layer and inner plexiform layer volumes and thickness in the inferior quadrant. However, only the mRNFL volume was linearly related to neocortical positron emission tomography amyloid standardized uptake value ratio after controlling for any main effects of age ( R 2 = 0.103; ρ = 0.017). Furthermore, the magnitude of mRNFL volume reduction was significantly correlated with performance on a task of participants' abilities to efficiently integrate visual and auditory speech information (McGurk effect). Discussion We observed a decrease in mRNFL, outer nuclear layer, and inner plexiform layer volumes, in preclinical AD relative to controls. Moreover, the largely myelinated axonal loss in the RNFL is related to increased neocortical amyloid-β accumulation after controlling for age. Volume loss in the RNFL, during the preclinical stage, is not related to performance on measures of episodic memory or problem solving. However, this retinal change does appear to be modestly related to relative decrements in performance on a measure of audiovisual integration efficiency that has been recently advanced as a possible early cognitive marker of mild cognitive impairment.

Introduction We propose a minimum data set framework for the acquisition and analysis of retinal images for the development of retinal Alzheimer's disease (AD) biomarkers. Our goal is to describe methodology that will increase concordance across laboratories, so that the broader research community is able to cross‐validate findings in parallel, accumulate large databases with normative data across the cognitive aging spectrum, and progress the application of this technology from the discovery stage to the validation stage in the search for sensitive and specific retinal biomarkers in AD. Methods The proposed minimum data set framework is based on the Atlas of Retinal Imaging Study (ARIAS), an ongoing, longitudinal, multi‐site observational cohort study. However, the ARIAS protocol has been edited and refined with the expertise of all co‐authors, representing 16 institutions, and research groups from three countries, as a first step to address a pressing need identified by experts in neuroscience, neurology, optometry, and ophthalmology at the Retinal Imaging in Alzheimer's Disease (RIAD) conference, convened by the Alzheimer's Association and held in Washington, DC, in May 2019. Results Our framework delineates specific imaging protocols and methods of analysis for imaging structural changes in retinal neuronal layers, with optional add‐on procedures of fundus autofluorescence to examine beta‐amyloid accumulation and optical coherence tomography angiography to examine AD‐related changes in the retinal vasculature. Discussion This minimum data set represents a first step toward the standardization of retinal imaging data acquisition and analysis in cognitive aging and AD. A standardized approach is essential to move from discovery to validation, and to examine which retinal AD biomarkers may be more sensitive and specific for the different stages of the disease severity spectrum. This approach has worked for other biomarkers in the AD field, such as magnetic resonance imaging; amyloid positron emission tomography; and, more recently, blood proteomics. Potential context of use for retinal AD biomarkers is discussed.

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Background Episodic memory decline is one of the earliest cognitive indicators in Alzheimer’s disease (AD) with impairment in memory in older adults an important indicator of incipient AD. Optometry has potential for population based, point‐of‐care screening as retinal biomarkers can detect both symptomatic and preclinical AD. Here, we aimed to develop and optimize a test of episodic memory for use in clinical optometry/ophthalmology settings alongside retinal imaging methods to detect both preclinical and early symptomatic AD. Method 30 cognitively normal (CN) older adults (55‐81 years; 68.5±7) from the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) completed the Snellen Memory Test (SMT). Participants completed a a Snellen Eye Chart for three learning trials of 10 seconds exposures, followed by immediate free recall. After a 20‐minute delay, participants completed delayed free recall in which they were asked to recall as many of the letters as they had been shown. This was followed by a recognition test in which participants viewed a mock chart identifying the correct letters and if they were in the correct location as the original chart. Result An intraclass correlation coefficient was calculated to determine the inter‐rater reliability among three raters for 10 randomly selected administrations. Overall results indicated good reliability with a mean coefficient of 0.87 (95% CI: 0.71‐1.03). Convergent and divergent validity for the 30 participants was assessed by comparing SMT performance to RBANS indices and the Free and Cued Selective Reminding Test (FCSRT). The SMT significantly correlated with the RBANS Immediate Memory Index (r = 0.38‐0.52), Language Index (r = 0.39‐0.51), and Attention Index (r = 0.39‐0.46) as well as with selective reminding trial 1 and 2 (r = 0.45‐0.78), and free and cued recall for trial 3 (r = 0.45‐0.47). Conclusion The SMT has potential as an episodic memory test that could be used for point of care detection of preclinical AD. Future work will continue to validate the SMT against reference standard neuropsychological assessments of episodic memory and against AD retinal imaging biomarkers.