This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Blood levels of homocysteine are elevated in Alzheimer's disease (AD), and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Homocysteine levels can be reduced by administration of high dose supplements of folic acid and vitamins B6 and B12. We propose a multicenter, randomized, controlled clinical trial to determine whether reduction of homocysteine levels with high-dose folic acid/B6/B12 supplementation will slow the rate of cognitive decline in subjects with AD. This will be a parallel design study, including two groups of unequal size: 60% of subjects will receive daily high-dose supplements (folic acid 5mg, vitamin B6 25mg, vitamin B12 1 mg), and 40% will receive identical placebo; the duration of treatment will be 18 months. The primary outcome measure will be the longitudinal decline in the ADAScog. To power the trial to detect a 25% reduction in rate of ADAScog decline (80% power, alpha=0.05, drop-out estimate 20%, drop-in estimate 10%), we will enroll a total of 400 subjects.This trial was developed by Dr. Aisen, and is being directed by Dr. Aisen and his group at Georgetown. The pilot study of the treatment regimen was also led by Dr. Aisen, and conducted at the Georgetown GCRC plus three other sites. The present trial is funded by NIA through the Alzheimer's Disease Cooperative Study (ADCS, Leon Thal, Director, Paul Aisen, Associate Director), and utilizes the ADCS Data Center at UCSD, and ADCS sites around the U.S.
SPECIFIC AIMS :Primary:1. Determine whether reduction of homocysteine levels with high-dose folic acid/B6/B12 supplementation will slow the rate of cognitive decline in subjects with ADSecondary:2. Determine whether reduction of homocysteine levels with high-dose folic acid/B6/B12 supplementation will slow the rate of clinical decline, as measured by the time to reach clinically significant end-points, in subjects with AD3. Determine whether reduction of homocysteine levels with high-dose folic acid/B6/B12 supplementation will favorably influence measures of behavior, activities of daily living, global status, and quality of life in subjects with AD 4. Examine the influence of apolipoprotein E and methylenetetrahydrofolate reductase (MTHFR) genotype on homocysteine reduction in subjects with AD5. Determine the safety and tolerability of long-term treatment of AD subjects with high-dose supplements.Hypothesis: Blood levels of homocysteine are elevated in Alzheimer's disease (AD), and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Homocysteine levels can be reduced by administration of high dose supplements of folic acid and vitamins B6 and B12. We are conducting a multicenter, randomized, controlled clinical trial to determine whether reduction of homocysteine levels with high-dose folic acid/B6/B12 supplementation will slow the rate of cognitive decline in subjects with AD.
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