BACKGROUND: Recent evidence suggests that Alzheimer's amyloid-beta (1-40) (Αβ1-40), an emerging biomarker of cardiovascular disease, may be involved in the heart-brain-renal axis. We aimed to comprehensively explore the association between circulating Aβ1-40 levels and renal function and its clinical relevance. METHODS: Consecutively recruited subjects in the Athens Angiometabolic Registry with measured Aβ1-40 plasma levels (n = 811) were analysed. Αβ1-40 was measured by enzyme-linked immunosorbent assay and glomerular filtration rate (GFR) was calculated using the abbreviated four-variable Modification of Diet in Renal Disease (MDRD) formula. All-cause mortality was the main clinical endpoint across a median follow-up of 47 months. RESULTS: Cross-sectionally, a bidirectional association between Αβ1-40 [adjusted odds ratio (adjOR) = 3.67 for highest tertile of Αβ1-40 and chronic kidney disease (CKD) stage ≥3, p <
.001] and CKD stage ≥3 (adjOR = 3.52 for association with highest Aβ1-40 tertile, p <
.001) was observed. Longitudinally, increased Αβ1-40 at baseline was associated with decline in renal function at follow-up (adjOR for CKD stage ≥3 = 2.26, p = .033). Similarly, longitudinal changes in Aβ1-40 were inversely associated with changes in GFR (OR = .77 per 1 SD increase in Aβ1-40, p = .006). Aβ1-40 was associated with all-cause mortality, independently of traditional risk factors (hazard ratio = 1.20 per 1 SD increase in Aβ1-40, p = .016). An indirect effect of GFR on the association between Aβ1-40 and mortality (p <
.05) with an estimated indirect-to-total effect ratio of .334, but not of Αβ1-40 on GFR with mortality, was observed. CONCLUSIONS: In a population with a wide range of GFR, we found a bidirectional association between Αβ1-40 levels and renal function. The association of Αβ1-40 with all-cause mortality was partly mediated by lower GFR.