Association of low vitamin B12 status with incident dementia and stroke: an EHR database study

Epidemiological evidence linking low vitamin B12 status to dementia risk remains inconsistent, partly reflecting differences in exposure definitions, study designs, and analytical approaches. This study evaluated the association between low vitamin B12 status and long-term risks of incident dementia, related neurocognitive, and cerebrovascular outcomes.

This propensity score-matched retrospective cohort study used de-identified electronic health record data from the TriNetX Global Collaborative Network. Adults aged ≥50 years with two vitamin B12 measurements <300 pg./mL within a 2-year window were matched 1:1 with patients who had two vitamin B12 measurements of 300-900 pg./mL using the same framework. A 1-year landmark period was applied, with outcome follow-up beginning on day 366 after the index date. The primary outcome was incident all-cause dementia over 10 years. Secondary outcomes included Alzheimer's disease, vascular dementia, other dementia subtypes, mild cognitive impairment, stroke, and all-cause mortality. An exposure-gradient analysis was performed among patients with vitamin B12 deficiency, defined as two measurements <200 pg./mL.

After matching, 129,159 patients remained in each group. Low vitamin B12 status was associated with a higher risk of all-cause dementia (Hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.27-1.39, p < 0.001). Associations were also observed for Alzheimer's disease, vascular dementia, and other dementia subtypes (HRs 1.31-1.34), mild cognitive impairment (HR 1.33), stroke (HR 1.31), and all-cause mortality (HR 1.23; all p < 0.001). Among patients with vitamin B12 deficiency, the association with all-cause dementia was stronger (HR 1.64, p < 0.001). Results were consistent across six prespecified sensitivity analyses and sex-stratified subgroup analyses.

Low vitamin B12 status was associated with an increased long-term risk of incident all-cause dementia, with a numerically stronger association among patients with vitamin B12 deficiency. Given the observational design and potential residual bias, these findings should be interpreted as hypothesis-generating rather than causal. Further prospective studies with serial biomarker monitoring and interventional studies of vitamin B12 correction are needed to clarify this association.