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 toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.

Previous studies have demonstrated that cognitive impairment (CI) is not limited to the brain but also affects the retina. In this pilot study, we investigated the correlation between the retinal vascular complexity and neurodegenerative changes in patients with CI using a low-cost multimodal approach. Quantification of the retinal structure and function were conducted for every subject (n = 69) using advanced retinal imaging, full-field electroretinogram (ERG) and visual performance exams. The retinal vascular parameters were calculated using the Singapore Institute Vessel Assessment software. The Montreal Cognitive Assessment was used to measure CI. Pearson product moment correlation was performed between variables. Of the 69 participants, 32 had CI (46%). We found significantly altered microvascular network in individuals with CI (larger venular-asymmetry factor: 0.7 ± 0.2) compared with controls (0.6 ± 0.2). The vascular fractal dimension was lower in individuals with CI (capacity, information and correlation dimensions: D₀, D_1, and D₂ (mean ± SD): 1.57 ± 0.06; 1.56 ± 0.06; 1.55 ± 0.06; age 81 ± 6years) vs. controls (1.61 ± 0.03; 1.59 ± 0.03; 1.58 ± 0.03; age: 80 ± 7 years). Also, drusen-like regions in the peripheral retina along with pigment dispersion were noted in subjects with mild CI. Functional loss in color vision as well as smaller ERG amplitudes and larger peak times were observed in the subjects with CI. Pearson product moment correlation showed significant associations between the vascular parameters (artery-vein ratio, total length-diameter ratio, D₀, D₁, D₂ and the implicit time (IT) of the flicker response but these associations were not significant in the partial correlations. This study illustrates that there are multimodal retinal markers that may be sensitive to CI decline, and adds to the evidence that there is a statistical trend pointing to the correlation between retinal neuronal dysfunction and microvasculature changes suggesting that retinal geometric vascular and functional parameters might be associated with physiological changes in the retina due to CI. We suspect our analysis of combined structural-functional parameters, instead of individual biomarkers, may provide a useful clinical marker of CI that could also provide increased sensitivity and specificity for the differential diagnosis of CI. However, because of our study sample was small, the full extent of clinical applicability of our approach is provocative and still to be determined.

Purpose: To investigate distances from retinal capillaries to arterioles or venules noninvasively. Methods: An adaptive optics scanning laser ophthalmoscope (AOSLO) and optical coherence tomography angiography (OCTA) imager acquired detailed maps of retinal vasculature. Using OCTA, we quantified the distance from the edge of an arteriole or venule to the middle of the nearest capillaries (periarteriole or perivenule capillary-free zones, respectively) within the superficial vascular plexus of 20 young healthy subjects with normal axial lengths. These distances were compared to AOSLO images for three subjects. We tested the relation between the peripheral capillary-free zones and FAZ horizontal, vertical, effective diameters, and asymmetry indices in the deep vascular plexus. We examined enlargement with OCTA of capillary-free zones in a type 2 diabetic patient. Results: The periarteriole capillary-free zone (67.2 ± 25.3 μm) was readily visible and larger than the perivenule capillary-free zone (42.7 ± 14.4 μm), F_{(1, 998)} = 771, P < 0.0001. The distance from foveal center (P = 0.003) and diameter (P = 0.048) were predictive of perivenule capillary-free zone values. OCTA and AOSLO corresponded for arterioles. FAZ effective diameter was positively associated with asymmetry indices, r = 0.49, P = 0.028, but not peripheral capillary-free zones, although focal enlargements were found in a diabetic patient. Conclusions: For normal retinas, periarteriole and perivenule capillary-free zones are readily visible with OCTA and AOSLO. Periarteriole capillary-free zones were larger, consistent with arterioles carrying oxygen rich blood that diffuses to support the retina.

The potential diagnostic value of plasma amyloidogenic beta residue 42/40 ratio (Aβ42/Aβ40 ratio), neurofilament light (NfL), tau phosphorylated at threonine-181 (p-tau181), and threonine-217 (p-tau217) has been extensively discussed in the literature. We have also previously described the association between retinal biomarkers and preclinical Alzheimer’s disease (AD). The goal of this study was to evaluate the association, and a multimodal model of, retinal and plasma biomarkers for detection of preclinical AD. We included 82 cognitively unimpaired (CU) participants (141 eyes; mean age: 67 years; range: 56–80) from the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS). Blood samples were assessed for concentrations of Aβ42/Aβ40 ratio, NfL, p-tau181, and p-tau217 (ALZpath, Inc.) using Single molecule array (SIMOA) technology. The Spectralis II system (Heidelberg Engineering) was used to acquire macular centered Spectral Domain Optical Coherence Tomography (SD-OCT) images for evaluation of putative retinal gliosis surface area and macular retinal nerve fiber layer (mRNFL) thickness. For all participants, correlations (adjusted for age and correlation between eyes) were assessed between retinal and blood-based biomarkers. A subgroup cohort of 57 eyes from 32 participants with recent Aβ positron emission tomography (PET) results, comprising 18 preclinical patients (Aβ PET + ve, 32 eyes) and 14 controls (Aβ PET -ve, 25 eyes) with a mean age of 69 vs. 66, p = 0.06, was included for the assessment of a multimodal model to distinguish between the two groups. For this subgroup cohort, receiver operating characteristic (ROC) analysis was performed to compare the multimodal model of retinal and plasma biomarkers vs. each biomarker alone to distinguish between the two groups. Significant correlation was found between putative retinal gliosis and p-tau217 in the univariate mixed model (β = 0.48, p = 0.007) but not for the other plasma biomarkers (p > 0.05). This positive correlation was also retained in the multivariate mixed model (β = 0.43, p = 0.022). The multimodal ROC model based on retinal (gliosis area, inner inferior RNFL thickness, inner superior RNFL thickness, and inner nasal RNFL thickness) and plasma biomarkers (p-tau217 and Aβ42/Aβ40 ratio) had an excellent AUC of 0.97 (95% CI = 0.93–1.01; p < 0.001) compared to unimodal models of retinal and plasma biomarkers. Our analyses show the potential of integrating retinal and blood-based biomarkers for improved detection and screening of preclinical AD.

The aim of the study was to report postoperative corneal and surgically induced astigmatism (SIA) in patients with preoperative against-the-rule (ATR) astigmatism who underwent superior approach manual small incision cataract surgery (MSICS). 58 eyes of 58 cataract patients with preoperative ATR astigmatism were involved in this study. All patients had operable cataracts and underwent superior approach MSICS. Keratometric (K) readings were taken prior to surgery and at 12 weeks after surgery. Centroid values of SIA, preoperative astigmatism, and postoperative astigmatism were calculated using Cartesian coordinates based analysis. Wilcoxon signed rank test was used to compute statistical significance between mean preoperative and postoperative corneal astigmatism. Cohen’sdwas used as effect size measure. Centroid values of 1.42 D × 179, 2.48 D × 0, and 1.07 D × 1 were recorded, respectively, for preoperative astigmatism, postoperative astigmatism, and SIA. Wilcoxon signed rank test indicated that mean ± SD postoperative corneal astigmatism (2.80±1.40 D) was statistically significantly greater than preoperative corneal astigmatism (1.49±1.34 D),Z=-6.263,p<0.0001. A high Cohen’sdof 1.32 was found. Our results suggest statistical and clinically significant greater postoperative corneal astigmatism than preoperative corneal astigmatism for ATR astigmatism cataract patients who underwent superior approach MSICS.