Serum β2-Microglobulin and Stroke Risk and Outcomes: A Systematic Review and Meta-Analysis

Abstract Background and Objectives: Serum β2-microglobulin (β2M) is implicated in immune activation, renal dysfunction, and neuroinflammation; however, its role across the spectrum of stroke risk and outcomes has not been systematically synthesized. The study aims to evaluate associations between serum β2M and stroke incidence, mortality, functional outcome, recurrence, and post-stroke cognitive impairment (PSCI). Methods: MEDLINE, Embase, and Web of Science were searched from inception to January 31, 2025 [Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020; International Prospective Register of Systematic Reviews (PROSPERO: CRD42025642387)]. Observational studies reporting multivariable-adjusted associations between baseline serum β2M and stroke outcomes in adults (≥18 years) were included. Two reviewers independently performed study selection, data extraction, and quality assessment using the Newcastle-Ottawa Scale. Given heterogeneity in study design, exposure definitions, and outcomes, narrative synthesis was prioritized; quantitative pooling was conducted where feasible and interpreted as exploratory. Results: Fifteen studies (n = 13,180, with possible overlapping cohorts) were included. Methodological quality was moderate to high. Elevated β2M showed directionally consistent associations with adverse outcomes. Evidence for stroke incidence was limited and heterogeneous; exploratory pooling of two studies yielded a non-significant association [odds ratio (OR) 2.29; 95% confidence interval (CI): 0.96–5.47; I² = 73%] and should not be considered definitive. Two prospective cohorts reported consistent associations between higher β2M levels and poorer 3-month functional outcomes (pending external validation). Single-study findings suggested associations with stroke mortality, recurrence, and PSCI. Conclusions: Serum β2M demonstrated directionally consistent associations with stroke risk and outcomes. However, current evidence is limited, heterogeneous, and vulnerable to confounding, especially by renal function. Serum β2M remains a candidate prognostic biomarker requiring prospective multicentre validation with standardized assays, adjustment for renal function, and formal discrimination analyses.