INTRODUCTION: Previous research identified a link between increased large artery stiffness and adverse brain health, supporting the concept that the penetration of excess pulsatility into cerebral circulation damages its small vessels and, when persisted, leads to cognitive decline. Although assessing cerebral microvasculature non-invasively at bedside poses a major challenge, systemic microvascular function such as that of skin can be utilised to investigate the link. We determined whether large artery stiffness and systemic microvascular function were associated with cognitive function in older adults, and also determined whether systemic microvascular function mediated an association between large artery stiffness and cognitive function. METHODS: Older adults with diverse cardiovascular risk (n=435, 162 females) participated in this study. Estimated pulse wave velocity (ePWV) as an indirect estimate of large artery stiffness was calculated from age and mean arterial pressure as described elsewhere.¹ Systemic microvascular function was assessed by responses to pharmacological stimulation of forearm skin blood vessels using a solid-state laser Doppler imager (LDI2, Moor Instruments, Axminster, UK) as previously described.² Endothelium-dependent (acetylcholine: ACh) and -independent (sodium nitroprusside: SNP) vasodilators were delivered trans-dermally via iontophoresis, and forearm skin perfusion was measured as the area under the response curve of each vasodilator (ACh_auc and SNP_auc, respectively) normalised to resting perfusion. Validated cognitive tasks [Addenbrooke’s Cognitive Examination Revised (ACE-R), Trail Making Test Part-A (TMT-A) and Part-B (TMT-B)] were administered to assess participants’ global cognitive function, speed of processing and executive function, respectively. A higher total score for ACE-R and a shorter completion time for TMT-A and TMT-B indicate better functions. All procedures accorded with current UK legislation. RESULTS: One standard deviation (SD) increase in ePWV was positively associated with TMT-A [β=0.339 (0.226, 0.467), p<0.001] and TMT-B [β=0.342 (0.232, 0.451), p<0.001] after accounting for conventional cardiovascular risk factors. Additionally, one SD increase in ACh_auc was inversely associated with TMT-B after adjusting for conventional cardiovascular risk factors [β=-0.113 (-0.201, -0.024), p=0.013]. A mediation analysis revealed that the association between ePWV and TMT-B was partially mediated by ACh_auc explaining about 3% of the total effect in the unadjusted model (p<0.05), but this did not persist in the adjusted model. CONCLUSIONS: Large artery stiffness and systemic microvascular function were associated with cognitive function in older adults, but these vascular measures may independently contribute to cognitive function without systemic microvascular function mediating the association between large artery stiffness and cognitive function in our cohort.