Peripheral Microvascular and Endothelial Dysfunction as Predictors of Cognitive Decline and Small Vessel Disease: A Systematic Review and Meta-Analysis

Background: Endothelial and microvascular dysfunction play a central role in the pathogenesis of both cardiovascular and neurodegenerative disorders. However, whether impaired peripheral endothelial function independently predicts cognitive decline, cerebral small-vessel disease (SVD) progression, or stroke remains uncertain. Methods: We conducted a systematic review and meta-analysis of prospective cohort studies assessing the prognostic value of non-invasive peripheral endothelial tests—flow-mediated dilation (FMD), peripheral arterial tonometry (PAT/EndoPAT), and sublingual microcirculatory imaging—for cognitive or cerebrovascular outcomes. Databases (PubMed, Embase, Scopus, Web of Science) were searched from inception through 30 September 2025. Study quality was appraised using the Newcastle–Ottawa Scale (NOS), and evidence certainty was graded via GRADE. Random-effects models (DerSimonian–Laird or REML) pooled hazard ratios (HRs) using inverse-variance weighting. PROSPERO-registered (CRD42025211876). Results: Fifteen prospective cohorts (n = 13,972 participants; median follow-up 4.3 years) met inclusion criteria. Across all modalities, impaired endothelial or microvascular function predicted cognitive decline, SVD progression, or cerebrovascular events (pooled HR = 1.72, 95% CI 1.38–2.14, p < 0.001; I2 = 57%). Subgroup analyses confirmed consistent associations for FMD (HR = 1.59, 95% CI 1.27–1.98) and PAT/EndoPAT (HR = 1.84, 95% CI 1.40–2.41). Evidence certainty was rated moderate-to-high according to GRADE. Conclusions: Peripheral endothelial dysfunction, measured by validated non-invasive techniques, independently predicts future cognitive and cerebrovascular events. These findings support the concept of a vascular–neural continuum, suggesting that endothelial health represents a modifiable biomarker for early neurovascular risk stratification. Routine assessment of endothelial function may help identify high-risk individuals and guide preventive interventions aimed at preserving brain and vascular health.