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Moderately elevated plasma total homocysteine (tHcy) is a strong modifiable risk factor for vascular dementia and Alzheimer's disease. Prospectively, elevated tHcy is associated with cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles, and dementia. Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period. In contrast, trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process. Homocysteine may interact with both risk factors and protective factors, thereby identifying people at risk but also providing potential strategies for early intervention. Public health steps to slow cognitive decline should be promoted in individuals who are at risk of dementia, and more trials are needed to see if simple interventions with nutrients can prevent progression to dementia.
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Download all Supplemental Material as a single PDF, including additional text ("Does high folate status impair cognition?") and Supplemental Figures 1–6 (also reproduced below).
NOTE: Supplemental Material was revised on Oct. 10, 2016 to correct reference numbers in figure legends.
Supplemental Figure 1. Changes in episodic memory over time in relation to plasma total homocysteine (tHcy) and plasma folate. Associations between scores on an episodic memory test (Kendrick Objective Learning Test, KOLT) at follow-up and changes in plasma concentrations of tHcy (n = 1,670) and folate (n = 1,660) between baseline and follow-up over a 6 y period. The reference value for KOLT is the approximate value associated with no change over the 6 y period in tHcy or folate levels, respectively. Solid lines are the estimated concentration-response curves; dashed lines show the 95% confidence intervals. (Modified from reference 88).
Supplemental Figure 2. Meta-analysis of prospective studies on the association of tHcy with incident dementia. Modified from reference 7.
Supplemental Figure 3. Cognitive decline in Alzheimer’s disease. Expected course of CAMCOG scores (global cognition) in patients with AD aged 70 y according to baseline tHcy concentrations at the time of diagnosis. The plots were generated from a non-linear mixed model adjusted for several covariates from patients in OPTIMA. Redrawn from reference 93.
Supplemental Figure 4. Regulation of protein phosphatase-2A (PP2A) by methylation (from Sontag & Sontag (126) with permission. The formation of the PP2A/Bα holoenzyme, the primary Ser/Thr tau phosphatase in vivo, is believed to be controlled by Leu-309 methylation of PP2A catalytic subunit by LCMT1. This reaction requires the supply of SAM, the universal methyl donor, and is inhibited by SAH. The PP2A methylesterase, PME-1, can demethylate and inactivate PP2A through distinct mechanisms, and form a complex with inactive PP2A enzymes. Those inactive complexes could be reactivated via the action of the PP2A activator PTPA, allowing for subsequent methylation of PP2AC subunit. Many brain Ser/Thr protein kinases, including GSK3β, oppose the action of PP2A/Bα and promote tau phosphorylation. Inhibition and/or down-regulation of PP2A can enhance tau phosphorylation directly by preventing its dephosphorylation, or indirectly by up-regulating tau kinases.
Supplemental Figure 5. Brain atrophy in VITACOG trial in subjects with Mild Cognitive Impairment. Global brain atrophy rate in relation to baseline tHcy concentration. Subjects were treated for 2 y with B vitamins (folic acid, vitamins B6 and B12). Plotted from data in Table S2, reference 123.
Supplemental Figure 6. Effect of B vitamin treatment on MMSE and semantic memory. Subjects (n = 266) with Mild Cognitive Impairment in the VITACOG trial were treated with placebo or B vitamins (folic acid, vitamins B6 and B12) for 2 years. The graphs illustrate the longitudinal effect of treatment on the MMSE and semantic memory scores and its interaction with baseline tHcy level using generalized linear mixed effect models. 'Low' and 'High' baseline tHcy refer to values below and above the median (11.3 μmol/L), respectively. From Figure S2 of de Jager et al. (18).