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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.