**Background:** Mild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population, with an annual conversion rate to dementia of 15–20% in specialty clinics. The COVID-19 pandemic has been linked to increased conversion from MCI to dementia in older adults, but the underlying mechanisms remain unclear. Emerging evidence suggests that SARS-CoV-2 infects endothelial cells, causing systemic and cerebrovascular endothelial dysfunction, which may impair neurovascular coupling (NVC)—the homeostatic mechanism that adjusts cerebral blood flow to meet neuronal metabolic demands. Preclinical studies show that impaired NVC is causally related to cognitive decline, and its restoration improves cognition. This study aims to establish a mechanistic link between COVID-19 and progression from MCI to dementia by assessing NVC, white matter hyperintensity (WMH) burden, and systemic endothelial function.
**Methods:** This is a prospective longitudinal study conducted at the University of Oklahoma Health Sciences Center (OUHSC) and Oklahoma City VA Medical Center. Up to 200 patients aged 55–85 years with a formal diagnosis of MCI and available baseline MRI will be enrolled. Patients with chronic uncontrolled conditions (e.g., diabetes, hypertension), prior cerebrovascular complications, neurodegenerative diseases, or eye pathologies contraindicated for dynamic retinal vessel analysis (DVA) are excluded. Participants are stratified by COVID-19 history (confirmed by PCR or serology). At baseline (Visit 1) and 18-month follow-up (Visit 2), participants undergo: (1) cognitive assessment using NIH Toolbox Cognitive Battery and n-back working memory paradigm; (2) NVC measurement via functional near-infrared spectroscopy (fNIRS) during n-back tasks and DVA of retinal arteriolar response to flickering light; (3) systemic endothelial function via flow-mediated dilation (FMD) of the brachial artery and laser speckle contrast imaging (LSCI) of skin microcirculation; (4) electroencephalography (EEG) during n-back; (5) blood draw for circulating pro-inflammatory cytokines (TNF-alpha, IL-1b, IL-6, IL-8, IL-10), endothelial biomarkers (MPO, MMP-9, E-selectin, VCAM-1, ICAM-1, PAI-1), and antioxidant capacity (HORAC assay). MRI scans (3T) are obtained at baseline and 18 months to assess WMH burden using the Fazekas scale (0–3 for periventricular and deep white matter). Progression to dementia is determined clinically by the neurology team through semi-annual evaluations and consensus conferences. Sample size estimation is based on prior data showing 55.6% conversion in COVID-19+ MCI patients vs. 23% in COVID-19− (p=0.011), with adjustments for dropout (≤10%), new COVID-19 infections in controls (5–15%), and mortality (2–5%).
**Key Results:** This is a protocol paper; no results are reported. The study is ongoing, with enrollment expected over 2 years and follow-up concluding in 2026. The primary analysis will use multiple logistic regression to determine whether COVID-19-related impairment in NVC (measured by fNIRS-derived beta coefficients) and increases in WMH burden contribute to progression to dementia. Secondary analyses will compare groups on endothelial function, cognitive performance, and circulating biomarkers using t-tests, Mann-Whitney U tests, chi-square tests, and 2-way ANOVA for longitudinal data. Multivariate models will adjust for demographic variables, COVID-19 variants, time since infection, and vaccination history.
**Clinical Implications:** If the hypothesis is confirmed, this study will identify NVC impairment and WMH burden as key mechanisms linking COVID-19 to accelerated cognitive decline in MCI. This could pave the way for therapeutic interventions targeting neurovascular uncoupling, such as NAD+ precursors (e.g., nicotinamide riboside) or antioxidant treatments, which have shown promise in preclinical models for restoring NVC and improving cognition. The findings may also inform risk stratification and monitoring strategies for MCI patients with a history of COVID-19. Limitations include potential loss to follow-up and confounding by comorbidities, which will be addressed through rigorous statistical adjustment.