Associations of Folate/Folic Acid Supplementation Alone and in Combination With Other B Vitamins on Dementia Risk and Brain Structure: Evidence From 466 224 UK Biobank Participants

Abstract

Previous researchers have tried to explore the association between folate/folic acid intake and dementia incidence, but the results remain controversial. We evaluated the associations of folate/folic acid supplementation alone and in combination with other B vitamins on dementia risk and brain structure. A total of 466 224 UK Biobank participants were investigated. Cox proportional hazards models were used to assess the associations between folate/folic acid supplementation status and the risk of Alzheimer's disease (AD) and vascular dementia (VD). Multivariable linear regression models were employed to evaluate the association between folate/folic acid supplementation status and brain structure. In the final model, folate/folic acid supplementation alone was significantly associated with a higher risk of AD (hazard ratio [HR] = 1.34, 95% confidence interval [CI] = 1.06-1.69, p = .015) and VD (HR = 1.61, 95% CI = 1.21-2.13, p = .001). Folate/folic acid supplementation alone was associated with a reduction in the hippocampus (β = -95.25 mm3, 95% CI = -165.31 to -25.19 mm3, p = .014) and amygdala (β = -51.85 mm3, 95% CI = -88.02 to -15.68 mm3, p = .012). The risk of AD and VD, as well as brain structure, in the group with combined folate/folic acid supplementation and other B vitamins did not show a statistically significant difference compared to the reference group (all p > .05). Folate/folic acid supplementation alone is significantly associated with a higher risk of AD and VD, as well as adverse alterations in brain structure. However, when combined with other B vitamins, these detrimental effects can be counteracted.

Keywords: Alzheimer’s disease; Brain structure; Folate; Folic acid; Vascular dementia.

Figure 1.

Association of folate/folic acid supplementation status and AD-GRS for AD risk. The multivariable model was adjusted for age, sex, BMI, TDI, education, ethnicity, assessment center, healthy diet, iron supplementation, smoking, alcohol, history of hypertension, cardiovascular disease, diabetes, stroke, and the levels of TG, HDL-C, LDL-C, and CRP. The vertical line indicates a reference value of 1. AD = Alzheimer’s disease; AD-GRS = AD genetic risk score; BMI = body mass index; CI = confidence interval; CRP = C-reactive protein; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; LDL-C = low-density lipoprotein cholesterol; TDI = Townsend deprivation index; TG = triglycerides.

Figure 2.

Folate/folic acid supplementation status and VD risk among different subgroups. Associations of folate/folic acid supplementation status and VD risk were grouped by sex, age, BMI, TDI, education, ethnicity, healthy diet, iron supplementation, smoking, and alcohol. The multivariable model was adjusted for age, sex, BMI, TDI, education, ethnicity, assessment center, healthy diet, iron supplementation, smoking, alcohol, history of hypertension, cardiovascular disease, diabetes, stroke, and the levels of TG, HDL-C, LDL-C, and CRP. The vertical line indicates a reference value of 1. BMI = body mass index; CI = confidence interval; CRP = C-reactive protein; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; LDL-C = low-density lipoprotein cholesterol; TDI = Townsend deprivation index; TG = triglycerides; VD = vascular dementia.