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Associations of one-carbon metabolism, related B-vitamins and ApoE genotype with cognitive function in older adults: identification of a novel gene-nutrient interaction.

  • 2025-07-28
  • BMC medicine 23(1)
    • Shane Gordon
    • Leane Hoey
    • Helene McNulty
    • Jordan Keenan
    • Faith Pangilinan
    • Lawrence C Brody
    • Mary Ward
    • J J Strain
    • Liadhan McAnena
    • Adrian McCann
    • Anne M Molloy
    • Conal Cunningham
    • Kevin McCarroll
    • Catherine F Hughes

Study Design

Type
Observational
Sample size
n = 3,348
Population
Community-dwelling older adults (≥ 60 years) from the Trinity-Ulster-Department of Agriculture (TUDA) study, stratified as ApoE ε4 carriers (n=1205) or non-ε4 carriers (n=3348)
Methods
Logistic regression models evaluating association between cognitive dysfunction and biomarkers of folate, vitamins B12, B6, and riboflavin status, plasma homocysteine levels, and ApoE ε4 genotype
Funding
Unclear

Background

The role of one-carbon metabolism and related B-vitamins in cognitive function in ageing is well-documented, particularly for folate and vitamin B12, with vitamin B6 and riboflavin receiving much less attention. ApoE is a well-established genetic risk factor for Alzheimer's disease, but the role of B-vitamins in modifying this risk remains largely unexplored. We examined associations between folate, B12, B6, riboflavin, and cognitive function in older adults, including interactions with the ApoE ε4 genotype.

Methods

Community-dwelling older adults (≥ 60 years) from the Trinity-Ulster-Department of Agriculture (TUDA) study were stratified as ApoE ε4 carriers (ε3/ε4 and ε4/ε4 genotypes; n = 1205) or non-ε4 carriers (n = 3348). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), the Frontal Assessment Battery, and the Mini-Mental State Examination. Logistic regression models were used to evaluate the association between cognitive dysfunction (defined as RBANS score < 80) and a range of variables, including biomarkers of folate, vitamins B12, B6, and riboflavin status, plasma homocysteine levels, and ApoE ε4 genotype.

Results

Lower status of vitamin B12 (holotranscobalamin; adjusted odds ratio (ORadj 1.30; 95% CI: 1.08-1.58, p = 0.007), vitamin B6 (ORadj 1.37; 95% CI: 1.12-1.67, p = 0.002), riboflavin (ORadj 1.73; 95% CI: 1.44-2.09, p < 0.001), and higher plasma homocysteine (ORadj 1.50; 95% CI: 1.22-1.83, p < 0.001) were each associated with higher risk of cognitive dysfunction. The ApoE ε4 genotype interacted adversely with low B12 status (p = 0.030) and elevated homocysteine (p = 0.008) in relation to cognitive outcomes.

Conclusions

Low status of vitamin B12, B6, riboflavin, and/or elevated homocysteine were each associated with a greater risk of cognitive dysfunction. A novel interaction between ApoE ε4 and low B12 or higher homocysteine was associated with an increased risk of cognitive dysfunction. Improving B-vitamin status may have important public health benefits for dementia prevention. Further investigation, ideally in the form of randomised trials, is however required to demonstrate a causative relationship and confirm whether intervention with B-vitamins can confer a beneficial effect in maintaining better cognitive health in at-risk older people.

Trial registration

TUDA study: ClinicalTrials.gov no. NCT02664584 (27/01/2016).

Research Insights

  • Vitamin B2→Reduced Cognitive Function

    The abstract reports associations for lower status of vitamin B12, B6, riboflavin, and higher homocysteine, but does not report a significant independent association for folate with cognitive dysfunction in the logistic regression models; folate is mentioned as a B-vitamin in the background but no significant OR is presented for folate in the results.

    Effect
    Neutral
    Effect size
    Small
  • Vitamin B6→Reduced Cognitive Function

    The abstract reports associations for lower status of vitamin B12, B6, riboflavin, and higher homocysteine, but does not report a significant independent association for folate with cognitive dysfunction in the logistic regression models; folate is mentioned as a B-vitamin in the background but no significant OR is presented for folate in the results.

    Effect
    Neutral
    Effect size
    Small
  • Vitamin B9→Reduced Cognitive Function

    The abstract reports associations for lower status of vitamin B12, B6, riboflavin, and higher homocysteine, but does not report a significant independent association for folate with cognitive dysfunction in the logistic regression models; folate is mentioned as a B-vitamin in the background but no significant OR is presented for folate in the results.

    Effect
    Neutral
    Effect size
    Small
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