Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

Background: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins.Objective: To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159).Methods and Findings: Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B₆ and B₁₂ in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B₁₂ (0.5 mg/d) and vitamin B₆ (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.Results: A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P=0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine &gt; 13μmol/L was 53% lower in the active treatment group (P=0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.Conclusions and significance: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease.</p

Alzheimer's Amyloidopathy: An Alternative Aspect.

From PubMed via Jisc Publications RouterPublication status: aheadofprintThe 'amyloid hypothesis' dominates Alzheimer's disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP) and presenilin-1 (PSEN1) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12. These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials