Supporting the Gold Standard: AD Clinical Trials

Clinical trials, which compare a potential new treatment with a standard treatment or a placebo, are the only way to prove whether a drug or other type of treatment is effective. These complex, expensive studies can involve hundreds or even thousands of people and often are conducted over a long period of time. Some clinical trials focus on prevention strategies to help people reduce the risk of developing AD in the future. Others focus on AD treatment strategies to preserve cognitive function for as long as possible, to alleviate behavioral or psychiatric problems, or to slow disease progression.

For example, a recently funded clinical trial will use gene therapy to treat AD with nerve growth factor (NGF). NGF potently prevents the death and augments the function of cholinergic neurons (neurons that produce the neurotransmitter acetylcholine) in regions of the brain that are extensively damaged in AD. This trial builds on the results of an earlier clinical trial of NGF gene delivery in early-stage AD patients. That earlier trial demonstrated robust growth responses of cholinergic neurons to NGF in the AD brain, possible effects on cognition over 22 months, and a significant increase in cortical glucose uptake in participants who received the treatment.

The new 24-month, multi-center clinical trial of NGF gene delivery in AD will test whether this therapy slows the clinical progression of AD by preventing cell loss and augmenting neuronal function. Fifty people with mild to moderate AD will be randomly assigned to receive two injections of NGF in their brains or to have a control surgical procedure with no injections of NGF. University of California San Diego investigators will conduct cognitive, clinical, and safety assessments as well as PET scans. If the preliminary results are favorable, participants who received the control surgery will be offered active NGF treatment.

Federal and non-Federal agencies and organizations are currently supporting more than 50 AD-relevant clinical trials (see the table, which lists trials funded by NIA). A cornerstone of NIA's efforts in clinical-trials research is the Alzheimer's Disease Cooperative Study (ADCS), launched in 1991. This consortium of about 70 sites focuses on trials of compounds developed by individual investigators or small companies with limited resources for clinical trials. A recent focus has been on partnering with larger companies. In addition to testing new compounds, the ADCS is developing new methods for conducting dementia trials.

The most recent round of ADCS trials, funded in October 2006, explore a variety of topics:

• Docosahexaenoic acid (DHA). This ongoing trial is examining whether treatment with DHA, an omega-3 fatty acid found in fish, will slow cognitive decline in AD. Observational studies associate high fish consumption with reduced risk of AD in people, and studies in mouse models of AD show that dietary DHA reduces levels of beta-amyloid in the brain, oxidative damage associated with beta-amyloid, and neurotoxicity.
• Immune globulin intravenous (IGIV). Interest in passive AD immunization strategies is growing. IGIV, a blood product that is administered intravenously, contains naturally occurring antibodies against beta-amyloid. Preliminary studies have shown that it may improve cognition. Other research has demonstrated that IGIV increased levels of anti-beta-amyloid antibodies in plasma and promoted clearance of beta-amyloid from CSF. The new ADCS trial will study whether IGIV is useful clinically for treating AD.
• Lithium. The biological activity of lithium, shown in animal studies to block abnormal changes in tau, has created interest in this drug as a novel treatment for AD. ADCS investigators plan to undertake a pilot biomarker trial to see whether lithium can lower tau and beta-amyloid levels in CSF and be safely tolerated in older AD patients.
• Home-based assessment. In this ADCS trial, conducted in people age 75 and older, researchers at 26 sites will test three home-based methods to assess cognition, daily functioning, mood, and other factors. The first involves the use of a computer “kiosk” that combines a touch-screen monitor with a telephone handset to answer a series of questions. The second is an interactive voice-response system that prompts a person to answer questions out loud. The third involves filling out and mailing in paper forms and completing a validated cognitive assessment by telephone. Each of these methods will be compared with traditional in-person methods. The findings will provide information about the use of home-based assessments to reduce the cost and increase the feasibility of participation in long-term clinical trials.
• Resveratrol. Investigators conducting this trial will evaluate the impact of resveratrol treatment on AD biomarkers and clinical outcomes in people with mild to moderate AD. Resveratrol, a molecule that promotes neuronal survival, has been shown to prevent learning impairments in mouse models of neurodegenerative diseases. Participants in this trial will receive either resveratrol or a placebo in addition to existing FDA-approved AD medical management.

NOTE: For information about new and currently recruiting trials, visit www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials or www.ClinicalTrials.gov.

* As of October 2008.
**Alzheimer's Disease Cooperative Study trial.
† NIA co-funded trials: GEM (National Center for Complementary and Alternative Medicine, lead institute); AREDS2 (National Eye Institute, lead institute).
‡ NIA-funded add-on trials: PREADVISE (add-on to National Cancer Institute's SELECT trial); ACCORD-MIND (add-on to NHLBI's ACCORD trial); KEEPS-CA (add-on to Kronos Longevity Research Institute's KEEPS trial).

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