Vitamins Associated with Brain Aging, Mild Cognitive Impairment, and Alzheimer Disease: Biomarkers, Epidemiological and Experimental Evidence, Plausible Mechanisms, and Knowledge Gaps

Abstract

The key to preventing brain aging, mild cognitive impairment (MCI), and Alzheimer disease (AD) via vitamin intake is first to understand molecular mechanisms, then to deduce relevant biomarkers, and subsequently to test the level of evidence for the impact of vitamins in the relevant pathways and their modulation of dementia risk. This narrative review infers information on mechanisms from gene and metabolic defects associated with MCI and AD, and assesses the role of vitamins using recent results from animal and human studies. Current evidence suggests that all known vitamins and some "quasi-vitamins" are involved as cofactors or influence ≥1 of the 6 key sets of pathways or pathologies associated with MCI or AD, relating to 1) 1-carbon metabolism, 2) DNA damage and repair, 3) mitochondrial function and glucose metabolism, 4) lipid and phospholipid metabolism and myelination, 5) neurotransmitter synthesis and synaptogenesis, and 6) amyloidosis and Tau protein phosphorylation. The contemporary level of evidence for each of the vitamins varies considerably, but it is notable that B vitamins are involved as cofactors in all of the core pathways or pathologies and, together with vitamins C and E, are consistently associated with a protective role against dementia. Outcomes from recent studies indicate that the efficacy and safety of supplementation with vitamins to prevent MCI and the early stages of AD will most likely depend on 1) which pathways are defective, 2) which vitamins are deficient and could correct the relevant metabolic defects, and 3) the modulating impact of nutrient-nutrient and nutrient-genotype interaction. More focus on a precision nutrition approach is required to realize the full potential of vitamin therapy in preventing dementia and to avoid causing harm.

Keywords: Alzheimer; aging; biomarkers; brain; epidemiology; interventions; knowledge gaps; mechanisms; vitamins.

FIGURE 1

High blood folate concentration in combination with low serum vitamin B-12 concentration is associated with a higher risk for cognitive impairment. The graphs show results from a study performed in Australia (109) (A) and a study performed in the United States (110) (B). Data were adapted from references and with permission.

FIGURE 2

Results of a meta-analysis of 43 prospective cohort studies showing dietary factors associated with a reduced RR for dementia (119). The numbers in brackets in the figure are the 95% CIs. Data were adapted from reference with permission.

FIGURE 3

Results of a meta-analysis of 106 investigations showing statistically significant reductions in the concentration of 6 key vitamins in plasma of patients with AD relative to healthy controls (120). The meta-analysis only included studies that used established criteria for identifying AD cases and cognitively intact controls. Data were adapted from reference with permission. AD, Alzheimer disease.

FIGURE 4

The 6 metabolic pathways or pathologies associated with Alzheimer disease risk and the various vitamins that are required as cofactors in these pathways or that influence the severity of brain pathology (black cells). HCY, homocysteine; MMA, methylmalonic acid.

FIGURE 5

An overview of the current level of evidence of the association of low dietary intake or low blood concentration of various vitamins with risk for AD or cognitive dysfunction, brain pathology (e.g., brain atrophy, low glucose metabolism, and amyloid plaques), and DNA damage. Dark gray shading indicates substantial evidence, light gray shading indicates limited evidence, and no shading indicates insufficient or no evidence. AD, Alzheimer disease; Cog, cognitive function; conc., concentration.