Homocysteine-lowering vitamin therapy on dementia

In this randomized, double-blind, placebo controlled, 26-week trial of subjects with mild to moderate AD, the daily use of over-the-counter supplements containing folic acid, vitamin B12, and B6 caused plasma homocysteine concentrations to decrease by 3.02 μmole per liter in the vitamin group than in placebo group. However, there were no significant differences in the change of score of cognition and daily living function between these two groups, even after stratification by age and gender. There was no

significant cognitive improvement in each group and no significant association between the change of cognition score and the change of Hcy concentration in either treatment group.

As for the Hcy-lowering therapy, different dosage and combinations have been studied and recommended in several reports. B6, B12, and folic acid supplementation has been successfully used in selected settings to reduce moderate hyperhomocysteinemia in patients with normal or abnormal B12 concentration ^153-157. Among the three vitamins, however, only folic acid seems to have a universal potential for reducing fasting plasma levels of Hcy ¹⁵⁸. Daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B12 should be efficient ¹⁵⁹. Additional combination with 5 to 10 mg of vitamin B6 has been reported to be safe and tolerable in reducing Hcy concentration¹⁵⁹. In viewing the entire over-the-counter vitamin supplements in Taiwan, the combined use of Methycobal capsule (Eisai Co.), containing methyl based vitamin B12 0.5 mg, and a nutritional regimen registered for pregnant women named Pramet®FA (Abbott

Laboratories Services Corp.), containing folic acid 1 mg and pyridoxine HCl 5mg, may meet the requirement of Hcy-lowering vitamin regimens. These regimens were also accessible and affordable over-the-counter daily supplements.

Although observational studies suggest an inverse association between Hcy concentration and cognitive performance ^112-114, a Cochrane review of randomized controlled trials of folic acid with or without vitamin B12160, as well as another review for vitamin B6 supplement ¹⁶¹, concluded that there was no benefit for healthy but cognitively impaired people. The participants in those previous studies had cognitive impairment but were not all diagnosed to have Alzheimer’s dementia. Besides, some studies did not mention the subjects’ serum level of B6, folic acid, or vitamin B12, which could influence the results of vitamin therapy. Moreover, the intervention periods were

no more than 12 weeks. A two-year, controlled trial of homocysteine lowering therapy showed no improvement for healthy older people ¹⁶². B12 or folic acid deficiency can be reversible factors in cognition performance, but most of the aforementioned studies did not clarify the vitamin status in the included subjects ^153-155. A randomized controlled trial with homocysteine-lowering therapy in patients with mild to moderate AD and with normal B12 and folic acid status has never been reported before in reviewed

literatures. This study was specifically designed to address the diagnosis of Alzheimer’s dementia as an inclusion criterion. We not only assessed the cognition performance but also the daily living function, as well as the homocysteine concentration change after 6 months of intervention.

Our study showed significant effects on lowering of the homocysteine

concentration by these over-the-counter multi-vitamin supplements as compared to the placebo group. Though there were evidences that plasma Hcy is associated with cognition function and Alzheimer’s disease, the Hcy-lowering therapy had no

significant clinical beneficial effects on cognition and daily living function in these AD patients. These results were similar to other clinical trials on healthy elderly or patients with vascular disease ^{163, 164}. In terms of homocysteine association with atherosclerotic vascular disease 32, 165, 166, several randomized controlled trials also showed that the Hcy-lowering therapy had no consistent effects on the incidence of vascular events

167-172. The possible explanations for the lack of statistic significance of the

Hcy-lowering therapy for cognition function in this study are as follows: 1. although there was no significant effect in our study, there still showed trend of benefit favoring vitamin treatment (Fig IV-2). Our sample size may be too small for a significant statistic power. 2. The treatment duration may be too short to have significant effects. It might take a longer duration to improve the cognition function by Hcy-lowering therapy. 3.

The pathogeneses of Alzheimer’s dementia are complicated and are related to amyloid deposition in addition to vascular factor ¹⁷³. Controlling one risk factor such as Hcy may not be sufficient to obtain the clinical benefit. 4. Our study participants were in the mild or moderate stage of dementia. The clinical effects of vitamin therapy may be little or not obvious on such irreversible and significant damage of brain. Further study with selection of target participants with mild cognition impairment and very early stage of dementia may be indicated for further exploring the efficacy of Hcy-lowering therapy on Alzheimer’s dementia.

Our study had several limitations. The duration was relatively short and thus, longer cognitive benefits from Hcy-lowering in AD patients cannot be excluded. Some of the participants also suffered from symptoms of gastric upset, nausea, and vomiting, which were often related to AChEIs ¹⁷⁴. Some subjects who dropped out were possibly due to these adverse effects, causing a smaller-than-desired final sample size. Further large randomized controlled trials with longer periods are needed.