Amyloid-beta 40 adversely influences large artery stiffness and cutaneous microvascular function in older adults with diverse cardiovascular risk

Objective: Amyloid-beta (Aβ) peptides are considered to play a prominent role in Alzheimer's disease, but emerging experimental and clinical observations link Aβ40 with adverse extracerebral vascular manifestations and cardiovascular disease events. However, it is unclear if Aβ40 adversely influences both large artery stiffness and cutaneous microvascular function in humans. We sought to determine whether Aβ40 was associated with large artery stiffness and cutaneous microvascular function in older adults with diverse cardiovascular risk. Design and method: This cross-sectional study analysed data from 610 older adults (65.7±8.7 yrs, 242F). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (CFPWV) using a SphygmoCor device, and cutaneous microvascular function was assessed by measuring acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) responses following iontophoresis. Plasma Aβ40 concentration was measured using a human Aβ40 assay kit (Simoa Human A β40). Results: One standard deviation increase in Aβ40 was significantly associated with 0.74 (0.52, 0.96) m/s greater CFPWV in an age- and sex-adjusted model (Model-1, p<0.001), which remained significant after further adjustments for conventional cardiovascular disease risk factors [Model-2, 0.46 (0.26, 0.66) m/s, p<0.001]. Additionally, one standard deviation increase in Aβ40 was significantly associated with lower cutaneous acetylcholine [-27.3 (-38.9, -15.7) au] and sodium nitroprusside [-27.0 (-38.1, -15.9) au] responses in Model-1 (both p<0.001). Further adjustments for conventional cardiovascular disease risk factors did not modify the inverse association [Model-2, acetylcholine response, -20.7 (-32.5, -8.8) au: sodium nitroprusside response, -21.1 (-32.3, -9.9) au: both p<0.001]. Subgroup analyses found an indication of interaction effect whereby female sex influenced more on the association between Aβ40 and CFPWV, and type 2 diabetes influenced more on the association between Aβ40 and cutaneous acetylcholine responses (both p<0.05). Conclusions: Aβ40 was associated with increased large artery stiffness and decreased cutaneous microvascular function in older adults with diverse cardiovascular risk. These findings suggest a potential mechanistic link between Aβ40 deposition in the systemic circulation and previously observed adverse cardiovascular disease outcomes.