Abstract
Carotid intima-media thickness (cIMT), a noninvasive marker of subclinical atherosclerosis beginning in childhood, has been linked to cognitive decline in adulthood. However, the nature and shape of this association remain unclear. We investigated linear and nonlinear associations between cIMT and cognitive function using observational and Mendelian randomization (MR) analyses. Observational and one-sample MR analyses were conducted in UK Biobank participants (n = 19,588). Two-sample MR used summary data from the CHARGE/UCLEB Consortia (n = 71,128) for cIMT and from a meta-analysis of UK Biobank and COGENT (n = 257,828) for cognitive function. Mediation MR evaluated the role of cerebrovascular disease. Observational analysis showed higher cIMT was associated with lower cognitive function (β = -0.17, 95% CI = -0.27 to -0.08, p = 3.24 × 10-4), with no nonlinearity (pnonlinearity = 0.49). One-sample MR supported a causal effect of higher genetically predicted cIMT on lower cognitive function (β = -1.18, 95% CI = -2.33 to -0.03, p = 4.51 × 10-2), with no evidence of nonlinearity (Pquadratic test = 0.88; PCochran Q test = 0.90). This was confirmed in two-sample MR (β = -0.83, 95% CI = -1.39 to -0.26, p = 4.03 × 10-3). Mediation analysis indicated that 9.9% of this association was mediated by small vessel stroke. Reverse MR showed no causal effect of cognitive function on cIMT. Our findings demonstrate a linear-no-threshold relationship between cIMT and cognitive function, underscoring the importance of early-life vascular health.