Retinal Microvascular Density and Inner Thickness in Alzheimer's Disease and Mild Cognitive Impairment

Yehia Ibrahim ¹ Antonella Macerollo ^2,3 Rodolfo Sardone ^1,4 Yaochun Shen ⁵ Vito Romano ^1,6 Yalin Zheng ^1,7*

• ¹ Department of Eye and Vision Sciences, University of Liverpool, Liverpool, United Kingdom
• ² Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, L69 7BE, Liverpool, United Kingdom
• ³ Department of Neurology, The Walton Centre NHS Foundation Trust, L9 7LJ, Liverpool, United Kingdom
• ⁴ Statistics and Epidemiology Unit, Local Healthcare Authority of Taranto, Taranto, Italy
• ⁵ Department of Electrical Engineering and Electronics, University of Liverpool, Liverpool, United Kingdom
• ⁶ Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
• ⁷ Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

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 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 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 modelled OCT/OCTA parameters and MMSE scores’ relationship, correcting for age. Another ordinal logistic GLM (OL-GLM) modelled 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 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 confounders corrections importance. Our analysis excluded individual retinal layers parameters due to limitations; however, literature suggests their value. Our study confirmed existing biomarkers' efficacy and uncovered novel retinal parameters for cognitive decline, requiring further validation.