By John Gever, Staff Writer, MedPage Today
Published: October 14, 2008
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
High-dose vitamin B supplements reduced homocysteine levels but did not slow Alzheimer's disease progression, researchers here found in a large placebo-controlled trial.After 18 months of treatment, patients taking high doses of vitamins B6 and B12 as well as folic acid showed the same degree of cognitive decline compared with baseline as those assigned to placebo, reported Paul Aisen, M.D., of the University of California San Diego, and colleagues in the Oct. 15 issue of the Journal of the American Medical Association.
Participants in the vitamin group also showed a significantly higher frequency of depressive symptoms, seen in 27.9% compared with 17.8% of the placebo group (P=0.02). Blurred vision and hyperhidrosis also appeared more common with vitamin supplements, but the differences missed statistical significance (P=0.7 and 0.53, respectively).
- Explain to interested patients that vitamin B supplements lowered blood levels of homocysteine, which was suspected of playing a role in the Alzheimer's disease process.
- Explain that the study found no benefit from the vitamin supplements, although they did reduce homocysteine levels. Explain, too, that it also found some evidence that the supplements were harmful at the doses used.
"Our study does not support the treatment of individuals with mild to moderate Alzheimer's disease and normal vitamin levels with B vitamin supplements," Dr. Aisen and colleagues concluded.
The study was prompted by earlier findings that blood homocysteine levels are elevated in patients with Alzheimer's disease and that B vitamin supplements can lower homocysteine levels.
Moreover, numerous studies had linked homocysteine to the major pathologies of Alzheimer's -- amyloid and glutamate neurotoxicity as well as neurovascular ischemia. In mouse models of cerebral amyloidosis, increased homocysteine led to neuron death, Dr. Aisen and colleagues said.
Earlier small clinical trials of vitamin B supplements gave conflicting results, they said.
In the current multicenter study, 409 patients with mild to moderate Alzheimer's were randomized in a 3:2 ratio to vitamin B supplements or placebo. Patients were evaluated at baseline and periodically during treatment with several standard assessments of cognition: the Alzheimer Disease Assessment Scale cognitive subscale, the Mini-Mental State Exam, the Clinical Dementia Rating, and the Alzheimer Disease Cooperative Study subscale on daily living activities.
Patients with vitamin B or folate deficiency were excluded. Patients were allowed to receive cholinesterase inhibitors and memantine, but those taking a variety of other drugs within two months of enrollment were excluded.
From a mean of about 9.1 micromol/L at baseline, mean homocysteine levels in the vitamin group declined to 7.0 micromol/L at six months and stayed in that range for the remainder of the 18-month study. Homocysteine levels in the placebo group fell slightly to about 8.7 micromol/L, which did not differ significantly from baseline.
But there was not even a hint that vitamin supplements slowed participants' cognitive decline by any measure used in the study:
- Alzheimer Disease Assessment Scale cognition scores increased 6.54 points (SD 8.17) in the placebo group after 18 months, compared with 7.38 points (SD 9.72) in the vitamin supplement group.
- Mini-Mental State Exam scores decreased 3.08 points (SD 4.46) in the placebo group versus 2.65 points (SD 4.56) with supplements.
- Clinical Dementia Rating scores increased 2.51 points (SD 2.57) with placebo compared with 2.58 points (SD 2.45) in the supplement group.
- Activities of daily living scores on the Alzheimer Disease Cooperative Study index decreased 10.00 points (SD 11.09) with placebo versus 10.96 points (SD 12.36) with supplements.
There was also no correlation between changes in cognition scores and baseline homocysteine levels. No subgroups were identified that showed significant differences between treatments.
Discontinuation rates were similar, at 18% in the placebo group and 15% among participants receiving the supplements. Most were because of caregiver decisions to withdraw.
Dr. Aisen and colleagues stopped short of ruling out any benefit from vitamin B supplements for anyone.
"Randomized studies in individuals without dementia have yielded conflicting results; supplementation may be useful in older individuals with relatively high homocysteine levels," they wrote. "The identification of groups that may benefit from such treatment remains an important goal."
They added that, in populations where homocysteine levels are generally higher and hence the opportunity to reduce them is greater, supplements may be helpful. In the U.S., where most grain products contain folic acid supplements, homocysteine levels are lower than elsewhere.
In an accompanying commentary, Robert J. Clarke, M.D., and Derrick A. Bennett, Ph.D., both of the University of Oxford, said the findings "provide further support for the conclusion that B vitamins are not effective in slowing cognitive decline in individuals with normal folate and vitamin B12 levels in societies with folate-enriched foods."
They said it was possible that supplements might be more effective if begun while cognition is still intact. "Individuals with established cognitive impairment may be refractory to treatment," Drs. Clarke and Bennett suggested.
But until future research identifies populations or circumstances in which supplements are beneficial, "there is insufficient evidence to justify routine use of homocysteine-lowering vitamin supplements for the prevention of Alzheimer disease and cognitive decline among individuals with normal vitamin status," they said.