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Abstract Background 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. Methods 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. Results 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

Abstract Background Compared to standard neuro-diagnostic techniques, retinal biomarkers provide a probable low-cost and non-invasive alternative for early Alzheimer’s disease (AD) risk screening. We have previously quantified the periarteriole and perivenule capillary free zones (mid-peripheral CFZs) in cognitively unimpaired (CU) young and older adults as novel metrics of retinal tissue oxygenation. There is a breakdown of the inner retinal blood barrier, pericyte loss, and capillary non-perfusion or dropout in AD leading to potential enlargement of the mid-peripheral CFZs. We hypothesized the mid-peripheral CFZs will be enlarged in CU older adults at high risk for AD compared to low-risk individuals. Methods 20 × 20° optical coherence tomography angiography images consisting of 512 b-scans, 512 A-scans per b-scan, 12-µm spacing between b-scans, and 5 frames averaged per each b-scan location of the central fovea and of paired major arterioles and venules with their surrounding capillaries inferior to the fovea of 57 eyes of 37 CU low-risk (mean age: 66 years) and 50 eyes of 38 CU high-risk older adults (mean age: 64 years; p = 0.24) were involved in this study. High-risk participants were defined as having at least one APOE e4 allele and a positive first-degree family history of AD while low-risk participants had neither of the two criteria. All participants had Montreal Cognitive Assessment scores ≥ 26. The mid-peripheral CFZs were computed in MATLAB and compared between the two groups. Results The periarteriole CFZ of the high-risk group (75.8 ± 9.19 µm) was significantly larger than that of the low-risk group (71.3 ± 7.07 µm), p = 0.005, Cohen’s d = 0.55. The perivenule CFZ of the high-risk group (60.4 ± 8.55 µm) was also significantly larger than that of the low-risk group (57.3 ± 6.40 µm), p = 0.034, Cohen’s d = 0.42. There were no significant differences in foveal avascular zone (FAZ) size, FAZ effective diameter, and vessel density between the two groups, all p > 0.05. Conclusions Our results show larger mid-peripheral CFZs in CU older adults at high risk for AD, with the potential for the periarteriole CFZ to serve as a novel retinal vascular biomarker for early AD risk detection.