Testing Therapies to Treat, Delay, or Prevent Alzheimer's Disease


Well-designed clinical trials are the best way to test whether a potential intervention for Alzheimer’s disease is safe and effective in humans. During a clinical trial, the experimental treatment is compared to the standard treatment or a placebo (an inactive ingredient). In a Phase I trial, a research team gives the treatment to a small number of participants and examines its safety and action in the body. The main goals are to establish the highest dose of a new drug or practice that people can tolerate and to define the dose at which harmful side effects may begin. If the treatment appears to be safe, it will go on to be tested in Phase II clinical trials.

Phase II trials involve larger numbers of people. In these trials, the study team wants to know whether the treatment can is safely and effectively at modifying symptoms or changing the course of the disease. Phase II trials involve the use of a placebo. Results from Phase II trials give researchers an indication of the effective dose to use in Phase III trials.

Phase III trials are large studies that compare an experimental treatment with a placebo or standard treatment to determine safety and efficacy (whether the treatment has the power to produce an effect). Phase III trials are complex, expensive studies involving hundreds or even thousands of volunteers and are often conducted over a long period of time.

The most compelling scientific evidence comes from clinical trials that are randomized (participants are randomly assigned to receive either the treatment or placebo), double-blind (neither participant nor researchers know which treatment the participant receives), and placebo-controlled (an inactive substance is given to one group of participants, while the drug being tested is given to another group). Randomized, double-blind, placebo-controlled studies are considered the “gold standard” of clinical trials.

Within the National Institutes of Health (NIH), the National Institute on Aging (NIA) is the primary institute supporting and conducting clinical trials on Alzheimer’s disease, mild cognitive impairment (MCI), and age-related cognitive decline. NIA funds a wide array of investigator-initiated clinical trials. Some trials focus on treatments for Alzheimer’s that may preserve cognitive function for as long as possible and alleviate behavioral or psychiatric problems. Others involve efforts to slow disease progression, such as delaying MCI’s progression to Alzheimer’s dementia, a type of research called secondary prevention. Still others focus on primary prevention, or helping cognitively healthy people reduce their risk of developing Alzheimer’s disease in the future. (See Table 1).

View a brief video of NIA’s Dr. Laurie Ryan describing NIA’s clinical trials program:

NIA-Supported Clinical Trials

Previous sections of this report describe the infrastructure and initiatives that support basic studies aimed at developing more effective interventions for the treatment, prevention, and caregiving of people with Alzheimer’s disease. Two major NIA-funded programs support clinical trials:

Alzheimer’s Disease Cooperative Study (ADCS). A large clinical trials consortium with sites throughout the United States, this major research initiative is investigating both the cognitive and behavioral symptoms of Alzheimer’s disease. ADCS investigators are developing innovative clinical trial designs, tools, and interventions, including therapies that industry might not otherwise be developed by industry. (See Advancing the Future of Alzheimer's Research for more about the ADCS.)

The most recent round of ADCS studies focuses on a variety of promising areas:

  • Intravenous Immune Globulin (IVIg) Study. A blood product administered intravenously, IVIg contains naturally occurring antibodies against beta-amyloid. Preliminary studies have shown that it may improve cognition, increase levels of anti-beta-amyloid antibodies in plasma, and promote clearance of beta-amyloid from cerebrospinal fluid (CSF). Also referred to as the GAP study, this Phase III double-blind, placebo-controlled study is examining the safety, effectiveness, and tolerability of IVIg in people with mild to moderate Alzheimer’s disease. Results are expected to be announced in 2013.
  • Home-Based Assessment Study. This ongoing, fully enrolled study, conducted in people age 75 and older, is examining the development and use of home-based assessments in clinical trials. Assessment and data collection methods being studied include mailed-in forms, telephone interviews, and online assessments. Scientists will evaluate cognition, daily functioning, mood, and other factors using each of these methods, then compare them with traditional in-person methods. The findings will provide information about how home-based assessments might be used in prevention trials. Such methods could significantly reduce the cost and increase the feasibility of participation in long-term clinical trials.
  • Resveratrol in Alzheimer’s Disease Study. This Phase II double-blind, randomized, placebo-controlled trial began recruiting 120 volunteers at 26 sites across the United States in early 2012. It will evaluate the impact of resveratrol treatment on biomarkers and clinical outcomes in people with mild to moderate Alzheimer’s disease. Resveratrol is an antioxidant compound found in grapes and red wine. Observational studies have shown that moderate consumption of red wine is associated with a lower incidence of Alzheimer’s disease, and animal studies have demonstrated resveratrol’s neuroprotective properties.
  • Nerve Growth Factor Study. This Phase II clinical study of Ceregene's CERE-110, a gene therapy product designed to deliver nerve growth factor to the brain to treat Alzheimer's disease, is recruiting volunteers at 10 research sites throughout the United States. The double blind, placebo-controlled trial will test whether or not the intervention promotes survival of certain neurons that degenerate in Alzheimer’s disease.

The Alzheimer’s Disease Pilot Clinical Trials Initiative supports a number of preliminary clinical evaluations of interventions for MCI, Alzheimer’s, and age-related cognitive decline that industry might not otherwise be pursued by industry.

NIA Programs Support Clinical Trials

Overall, NIA currently supports more 38 active clinical trials, including pilot and large-scale trials, of a wide range of interventions to prevent, slow, or treat Alzheimer’s disease and/or MCI (see Table 1 and Table 2). Areas of investigation include the connection between Alzheimer’s and certain diseases, such as diabetes and cardiovascular disorders, as well as lifestyle factors that may influence disease onset and progress, such as exercise, stress, and hormones.

Of the primary prevention trials, two are NIA-funded add-ons to large NIH trials that address other primary outcomes. One add-on is part of the National Heart, Lung, and Blood Institute’s Systolic Blood Pressure Intervention Trial (SPRINT), which will evaluate the health effects of lowering systolic blood pressure from 140 mm Hg to 120 mm Hg. The add-on study, funded by NIA and the National Institute of Neurological Disorders and Stroke and called SPRINT-MIND, will assess the effect of lowering systolic blood pressure on cognitive decline and the development of MCI and Alzheimer’s disease. The study will also use brain imaging to measure treatment effects on brain structure, including white matter lesions typical of vascular disease.

Additionally, NIA currently supports clinical trials focused on understanding and treating age-related cognitive decline and investigating its relationship to Alzheimer’s disease and other dementias (see Table 3). These trials are testing a wide range of possible interventions that may help preserve or improve cognition in older people, including dietary supplements and vitamins, estrogen and testosterone hormones, exercise and cognitive training, and various drugs that may help promote brain health.

NIA-supported clinical trials investigating drugs and protocols to prevent and treat delirium in older people are listed in Table 4. Normally a transitory state of confusion, delirium may occur following surgery, as a result of trauma or serious illness. In older people, it sometimes has a long-lasting, negative impact on cognition.

This image of an older individual with Alzheimer’s shows in red an area of the brain with volume loss. This region is important to planning, self-control, and decision-making.
Courtesy of Paul M. Thompson, PhD, and Arthur W. Toga, PhD, Laboratory of Neuro Imaging, UCLA.

Reports from Recently Completed Clinical Trials

Researchers working on two early-phase studies of treatments for MCI and Alzheimer’s disease reported promising results in 2011 and early 2012. These findings and other incremental discoveries may soon lead to major clinical trials that result in effective treatments for Alzheimer’s disease. Even results from failed clinical trials ultimately prove useful, as they provide important insights into the disease and will inform future studies.

Nicotine Therapy

A small, preliminary trial showed that nicotine delivered via a skin patch alleviated some symptoms of MCI in nonsmoking older volunteers. The 6-month pilot study, led by researchers at the University of Vermont College of Medicine, Burlington, involved more than 70 participants; 39 received 15 mg of nicotine daily while 33 wore a placebo patch. Cognitive testing showed improvements in attention, memory, and mental processing in volunteers receiving nicotine compared to the placebo group (Newhouse et al., 2012). The nicotine patch was also shown to be safe. A larger study is needed to further examine this promising intervention.

Insulin Therapy

The hormone insulin has several important functions in the brain, including regulating how glucose (sugar) is used by neurons. Alzheimer’s disease disrupts insulin’s normal function in the brain, and basic studies continue to examine the relationship between glucose and Alzheimer’s. Scientists had enough evidence to see if regulating glucose might help treat Alzheimer’s. In a pilot clinical trial led by researchers at the Veterans Affairs Puget Sound Health Care System, Seattle, insulin was delivered via a nasal spray to more than 100 study volunteers with either MCI or mild to moderate Alzheimer’s disease (Craft et al., 2012).

The novel delivery system enabled the insulin to easily bypass the blood–brain barrier and enter the brain but did not have unwanted side effects elsewhere in the body. Researchers found that the lower of two tested doses improved memory, and that both the lower and higher doses staved off decline in general cognition and functional abilities after 4 months. In preliminary analyses, changes in memory and function were accompanied by changes in CSF levels of Alzheimer’s biomarkers.

Based on these promising results, in early 2012 as part of the President’s Alzheimer’s Disease initiative, NIH Director Francis Collins provided funds to jump-start further testing of the intranasal insulin therapy. To read more about this announcement, go to www.nia.nih.gov/newsroom/2012/02/we-cant-wait-administration-announces-new-steps-fight-alzheimers-disease.

Related Topics