Pre-stroke physical activity and Val66Met (rs6265) genotype of BDNF gene correlate with the post-stroke cognitive outcome: a prospective cohort study

Pre-stroke physical activity may protect against post-stroke cognitive impairment (PSCI) via neuroplastic mechanisms including BDNF signalling. However, evidence in stroke survivors and the modifying role of the BDNF Val66Met polymorphism remain limited. In this prospective single-centre cohort, 97 patients with ischaemic stroke underwent detailed neuropsychological assessment during index hospitalisation and at 6 month follow-up. Pre-stroke activity was quantified as weekly MET-minutes (IPAQ scale). Serum BDNF and Val66Met genotype were measured. Associations between METs and cognitive outcomes (baseline, follow-up) were assessed with Spearman correlations and adjusted multivariable linear regression. Higher pre-stroke METs correlated with superior baseline performance across global cognition (MoCA), verbal learning/recall (CVLT indices), attention and executive measures. After adjustment, CVLT long-delay free recall (LDFR) and TMTA remained significant (β for CVLT LDFR = 0.000087; β for TMTA = - 0.000336 per MET-min/week, p < 0.05). At 6 months several correlations indicated better performance with higher METs (VFT letter K, CVLT LDFR-sten, VFT fruits and vegetables, CVLT SDCR-sten, TMTA, TMTB), but did not remain statistically significant after FDR correction. The follow-up METs were associated with CVLT SDCR in adjusted models (β = 0.00011, p < 0.05). Mean serum BDNF did not correlate with METs (mean 27,261 ± 7967 pg/mL) and did not differ from controls. Val/Val (GG) carriers of Val66Met genotype of BDNF gene performed better cognitively than Met allele carriers, but the genotype did not correlate with serum BDNF level. No evidence of mediation, modification, or direct BDNF association was found in the tested cognition models. Greater pre-stroke physical activity is associated with better early cognitive outcomes, whereas 6 month findings remain exploratory. The BDNF Val66Met polymorphism also correlates with distinct cognitive domains. However, neither factor enhances peripheral BDNF levels suggesting the polymorphism affects BDNF activity rather than quantity. Evaluating these factors together highlights how modifiable lifestyle and non-modifiable genetics independently shape different facets of post-stroke cognitive reserve.