Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Cognitive Outcome after Stroke: A Systematic Review

Post-stroke cognitive impairment (PSCI) is a common and disabling consequence of stroke. Brain-derived neurotrophic factor (BDNF) plays important roles in neuroplasticity, and the BDNF Val66Met (rs6265) polymorphism may alter cognitive outcomes after stroke; however, evidence remains inconsistent. We searched PubMed, Scopus, and Web of Science. Observational studies involving adults with stroke that evaluated the association between BDNF Val66Met and post-stroke cognitive outcomes were included. Two reviewers independently screened studies; one reviewer extracted and another verified the data. Methodological quality was assessed using the Newcastle-Ottawa Scale. Findings were synthesized narratively because of substantial heterogeneity in study population, genotype classification, and cognitive measures. Seven studies involving 2,494 participants met the inclusion criteria. Five studies evaluated global cognitive outcomes. Four reported significant genotype-related associations or differences in global cognition, with three showing poorer cognitive outcomes among Met-allele carriers and one reporting the opposite direction. In the largest cohort, Met carriers had significantly lower 12-month telephone Montreal Cognitive Assessment scores after adjustment for covariates. Memory was the most consistently affected domain, with poorer performance among Met carriers. Evidence for language was inconsistent, while data on attention and executive function were limited. One cohort reported an opposite association, with Val-allele carriers demonstrating poorer global cognition and language performance. One study also identified poorer cognitive functional recovery among Met carriers. BDNF Val66Met may be associated with variability in post-stroke cognitive outcomes, particularly global cognition and memory. However, population-specific findings and methodological heterogeneity preclude definitive conclusions. Larger prospective multicenter studies using standardized cognitive assessments are warranted.