Abstract Body: Background: While B-vitamins have long been hypothesized to hold promise for primary stroke prevention, there is a lack of systematic and comprehensive assessment of the impact of the full range of folate intake and status, as well as other B-vitamins.
Methods: We examined roles of B-vitamins (dietary intake and supplements) in the Women's Health Initiative (WHI, 154,718 postmenopausal women) and circulating biomarkers in the United States (US) All of Us Research Program (AoU, 99,667 adults) for incident stroke, adjusting for known risk factors using multivariable Cox models. Mendelian randomization (MR), B-vitamin interactions, homocysteine mediation, and subgroup analyses by risk factors were evaluated.
Results: In WHI (7,577 incident strokes over median 19.2-year follow-up), higher baseline intakes of thiamin (highest vs. lowest quintile medians: 4.6 vs. 0.9 mg/d), riboflavin (5.9 vs. 1.3 mg/d), niacin (54.6 vs. 11.8 mg/d), pyridoxine (6.2 vs. 1.1 mg/d), and folate (913.6 vs. 253.9 mcg/d) were associated with lower stroke risk (HRs for highest vs. lowest quintile: 0.85-0.90). In AoU (5,163 incident strokes over median 5.7-year follow-up), higher plasma folate (24 vs. 7 nmol/L) and pyridoxine (234 vs. 18 nmol/L) linked to lower overall stroke risk (HRs: 0.82 and 0.60). Inverse relations for intakes and levels persisted for ischemic stroke, except plasma pyridoxine with hemorrhagic stroke. Significant interactions seen for thiamin-folate, riboflavin-niacin, and niacin-folate pairs. Inverse associations for thiamin, pyridoxine, and folate intakes were stronger in younger participants; thiamin, niacin, pyridoxine, folate, and cobalamin in lipid-lowering drug users. Higher plasma folate strongly associated with reduced risk in college-educated or smokers. Homocysteine mediated 12% of plasma folate-stroke link. MR supported pyridoxine and folate effects on small vessel stroke (OR per standard deviation: 0.96 and 0.52).
Conclusions: Higher folate and pyridoxine exposures consistently linked to lower stroke risk, largely independent of homocysteine. Higher thiamin, riboflavin, and niacin intakes also associated with lower risk, varying by participant characteristics. Findings support considering these vitamins in stroke prevention guidelines for subgroups like younger adults, smokers, and lipid-lowering drug users.