Plasma biomarkers of endothelial dysfunction and cognition: an IPD meta-analysis of cross- sectional data from 9,344 individuals from seven Dutch cohorts

Abstract

Introduction: Endothelial dysfunction has various detrimental effects on the brain that may lead to cognitive decline. However, data on the direct association between endothelial dysfunction and cognitive performance in humans are scarce. The aim of the present study was to assess the cross-sectional association between plasma biomarkers of endothelial dysfunction and cognitive performance. Methods: Data from 9,344 individuals without dementia from seven Dutch cohorts participating in the Netherlands Consortium of Dementia Cohorts (NCDC) were included: Doetinchem Cohort Study, Rotterdam Study, The Maastricht Study, Leiden Longevity Study, the EMIF-AD 90+ cohort, Longitudinal Aging Study Amsterdam, and SMART-MR Study (mean age range: 57-93 years, 18-58% women). Plasma biomarkers of endothelial dysfunction included intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin), which were measured in EDTA plasma samples with commercially available ELISA kits (MSD and R&D Systems Europe), or the Olink Cardiometabolic 96-plex panels. Subsequently, a standardized endothelial dysfunction composite score was calculated. Cognitive performance was measured on six domains: executive function, processing speed, immediate and delayed memory, attention, and language. A two-step individual participant data (IPD) meta-analysis was performed: linear regressions were run in the individual cohorts. Resulting standardized regression coefficients were subsequently pooled using random-effects models. Results: Pooled analyses showed an association between a higher endothelial dysfunction composite score and worse executive function (β = -0.04; 95% CI -0.06, -0.02), slower processing speed (β = -0.03; 95% CI -0.05, -0.01), worse immediate memory (β = -0.03; 95% CI -0.04, -0.01), worse delayed memory (β = -0.03; 95% CI -0.05, -0.00), and lower attention scores (β = -0.02; 95% CI -0.04, -0.00) (Figure 1). These associations were consistent across cohorts and independent of demographics, lifestyle and cardiovascular risk factors. No association was found between endothelial dysfunction and language (β = -0.02; 95% CI -0.05, 0.01). Discussion: Endothelial dysfunction was consistently associated with worse cognitive functioning across all domains, except for language. These findings support the hypothesis that endothelial dysfunction may contribute to cognitive impairment and may identify a new prevention target.Future research is needed to assess any longitudinal association between endothelial dysfunction and cognitive decline.