Abstract

AbstractBackgroundClinical trials have been one size fits all, despite evidence that dementia ensues from a combination of pathologies with effects from environment, sex/gender, race/ethnicity and other factors influencing disease course. Cardiovascular diseases and cancer have measures (imaging and molecular biomarkers) that aid in capturing targetable biology. These biomarkers are used for risk stratification, precise diagnostic classification, in addition to inclusion as outcomes in trials. Clinical trials for brain degenerative disorders would benefit from a similar precision approaches.MethodWe performed proteomics analyses on banked plasma samples from longitudinal observational studies of vascular cognitive impairment and dementia (VCID) and a clinical trial (SPRINT‐MIND) targeting hypertension, a major VCID risk factor. Using multi‐modal analytical approaches we combined molecular measures with imaging and clinical outcomes to identify promising molecular markers for risk stratification for VCID clinical trials and maximizing benefit of interventions for VCID.ResultProteins related to angiogenesis as well as innate immune activation were found to be dysregulated in cases versus controls. With multivariate analyses, components with high loading from proteins involved in these multi‐cellular phenotypes were associated with cognitive outcomes. Using network analyses, key molecular nodes were validated via orthogonal methods.ConclusionA simple molecular panel with key proteins involved in dysregulated molecular networks mediating the effect of vascular disease on cognition could be developed and used for risk stratification in clinical trials of VCID. Greater precision in clinical trials would ensure higher benefit at lower cost, at all levels.

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