{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T16:47:52Z","timestamp":1785257272091,"version":"3.55.0"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Alzheimer\u2019s disease (AD) is a major healthcare challenge, with existing diagnostics being costly\/infeasible. This study explores retinal biomarkers from optical coherence tomography (OCT) and OCT angiography (OCTA) as a cost-effective and non-invasive solution to differentiate AD, mild cognitive impairment (MCI), and healthy controls (HCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Participants from the CALLIOPE Research Program were classified as \u201cDem\u201d (AD and early AD), \u201cMCI,\u201d and \u201cHCs\u201d using neuropsychological tests and clinical diagnosis by a neurologist. OCT\/OCTA examinations were conducted using the RTVue XR 100 Avanti SD-OCT system (VISIONIX), with retinal parameters extracted. Statistical analysis included normality and homogeneity of variance (HOV) tests to select ANOVA methods. Post-hoc analyses utilized Mann\u2013Whitney <jats:italic>U<\/jats:italic>, Dunnett, or Tukey-HSD tests based on parameters\u2019 normality and HOV. Correlations with age were assessed via Pearson or Spearman tests. A generalized linear model (GLM) using Tweedie regression modeled the relationship between OCT\/OCTA parameters and MMSE scores, correcting for age. Another ordinal logistic GLM (OL-GLM) modeled OCT\/OCTA parameters against classes, adjusting for multiple confounders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We analyzed 357 participants: 44 Dem, 139 MCI, and 174 HCs. Significant microvascular density (VD) reductions around the fovea were linked with MCI and Dem compared to HCs. Age-related analysis associated thickness parameters with HCs\u2019 old age. Our OL-GLM demonstrated significant thickness\/volume reductions in Inner_Retina and Full_Retina layers. Foveal avascular zone (FAZ) area and perimeter were initially not correlated with cognitive decline; however, OL-GLM significantly associated FAZ perimeter enlargement with Dem and MCI groups. Significant average and inferior peripapillary RNFL thinning were linked to Dem and MCI groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first study to examine VD changes in G grid sections among Dem, MCI, and HCs. We found a significant association between various VD parameters and cognitive decline. Most macular thickness\/volume changes did not correlate with cognitive decline initially; however, our OL-GLM succeeded, highlighting the importance of the confounders\u2019 corrections. Our analysis excluded individual retinal layer parameters due to limitations; however, the literature suggests their value. Our study confirmed existing biomarkers\u2019 efficacy and uncovered novel retinal parameters for cognitive decline, requiring further validation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2025.1477008","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T07:21:23Z","timestamp":1740727283000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Retinal microvascular density and inner thickness in Alzheimer\u2019s disease and mild cognitive impairment"],"prefix":"10.3389","volume":"17","author":[{"given":"Yehia","family":"Ibrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Macerollo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Sardone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaochun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"ref1","first-page":"1","article-title":"Tukey\u2019s honestly significant difference (HSD) test","volume-title":"Encyclopedia of research design","author":"Abdi","year":"2010"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/ceo.13680","article-title":"Clinical validation of the RTVue optical coherence tomography angiography image quality indicators","volume":"48","author":"Ali","year":"2020","journal-title":"Clin. 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