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

Abstract

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 (OR_adj 1.30; 95% CI: 1.08-1.58, p = 0.007), vitamin B6 (OR_adj 1.37; 95% CI: 1.12-1.67, p = 0.002), riboflavin (OR_adj 1.73; 95% CI: 1.44-2.09, p < 0.001), and higher plasma homocysteine (OR_adj 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).

Keywords: Apolipoprotein E (ApoE ε4); Cognitive function; Folate; Homocysteine; One-carbon metabolism; Riboflavin; Trinity-Ulster-Department of Agriculture (TUDA); Vitamin B12; Vitamin B6.

Fig. 1

Flow diagram of study participants from the TUDA study. ¹ Participants were excluded as a diagnosis of dementia was made since recruitment as per the TUDA study exclusion criteria. ² The ε2/ε4 genotype was excluded from the analysis, as it contains both the protective ε2 allele and the risk ε4 allele [7]. Abbreviations: RBANS, Repeatable Battery for Neuropsychological Status; TUDA, Trinity-Ulster-Department of Agriculture

Fig. 2

Association of B-vitamin biomarker status with cognitive dysfunction. Data presented as adjusted odds ratios and 95% CIs from logistic regression of cognitive dysfunction (RBANS total score < 80). Biomarkers were categorised into quartiles, with the reference category set at high B-vitamin status. For homocysteine, the reference category equates with high B-vitamin status. Each B-vitamin biomarker was included in separate logistic regression models, adjusted for age, sex, obesity (waist circumference), education, socioeconomic deprivation, and ApoE ε4 status (ε3/ε4 and ε4/ε4). Additional adjustments for other covariates, including depressive symptoms, did not materially alter the results.* p < 0.05; ** p < 0.01; *** p < 0.001. Abbreviations: EGRac, erythrocyte glutathione reductase activation coefficient; HoloTC, holotranscobalamin; PLP, pyridoxal 5′-phosphate; RBANS, Repeatable Battery for Neuropsychological Status; RBC, red blood cell; ref, reference category