Retinal microvascular density and inner thickness in Alzheimer’s disease and mild cognitive impairment

Background: Alzheimer’s 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). Methods: Participants from the CALLIOPE Research Program were classified as “Dem” (AD and early AD), “MCI,” and “HCs” 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–Whitney U, Dunnett, or Tukey-HSD tests based on parameters’ 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. Results: 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’ 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. Conclusion: 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’ corrections. Our analysis excluded individual retinal layer parameters due to limitations; however, the literature suggests their value. Our study confirmed existing biomarkers’ efficacy and uncovered novel retinal parameters for cognitive decline, requiring further validation.