Lipoprotein(a) -Related Cognitive Vulnerability After Stroke Beyond High-Sensitivity C-Reactive Protein

Post-stroke cognitive impairment (PSCI) reflects vulnerability to cognitive decline beyond acute brain injury. Lipoprotein(a) (Lp(a)) is a genetically determined vascular risk factor with pro-inflammatory and pro-atherogenic properties, but the pathways linking Lp(a) to cognitive outcomes after stroke remain unclear. We examined whether systemic inflammation mediates or modifies Lp(a)-related cognitive risk after ischemic stroke. We analyzed data from a prespecified substudy of the Third China National Stroke Registry. Baseline serum Lp(a) and high-sensitivity C-reactive protein (hs-CRP) were measured. PSCI was defined as a Montreal Cognitive Assessment score ≤ 22 at 1 year. Multivariable logistic regression, interaction, joint exposure, and causal mediation analyses were performed to evaluate the role of systemic inflammation in the Lp(a)-PSCI association. Among 954 patients with acute ischemic stroke, higher baseline Lp(a) was associated with increased PSCI risk after adjustment for baseline cognitive performance and clinical covariates (highest vs. lowest tertile: OR, 1.479; 95% CI, 1.007-2.170). In contrast, hs-CRP was not independently associated with PSCI after multivariable adjustment. No significant multiplicative interaction between Lp(a) and hs-CRP was observed (P = 0.2026). Although joint exposure analyses showed the highest PSCI risk among patients with both elevated Lp(a) and hs-CRP, mediation analysis did not support hs-CRP as a meaningful mediator (proportion mediated = 1.46%). These findings suggest that the observed association between Lp(a) and PSCI was not substantially explained by hs-CRP-indexed peripheral systemic inflammation. Elevated Lp(a) was associated with PSCI independently of baseline cognitive performance, but this association was not mediated or significantly modified by hs-CRP. Lp(a)-related cognitive vulnerability after ischemic stroke may therefore reflect vascular susceptibility not captured by hs-CRP alone, with hs-CRP-defined systemic inflammation contributing to cumulative risk rather than serving as the primary mechanistic pathway.