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

(NIA)  The National Institute on Aging (NIA) is the primary Federal 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 clinical trials. Some trials focus on treatments for Alzheimer’s that may preserve cognitive function for as long as possible or 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.

How Clinical Trials Are Conducted

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

NIA supports nearly 40 clinical trials looking at new ways to prevent, detect, or treat Alzheimer’s disease and age-related cognitive decline. Researchers are conducting trials examining the benefits of experimental drugs, new ways to use existing drugs that treat other illnesses, and nondrug interventions such as exercise or mental stimulation. 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 then 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 safely and effectively modify symptoms or change 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 participants nor researchers know which treatment each participant receives), and placebo-controlled (an inactive substance is given to one group of participants, and the drug being tested is given to another group). Randomized, double-blind, placebo-controlled studies are considered the “gold standard” of clinical trials.

The Positive Side of Negative Trials

So far, clinical trials have resulted in a limited number of drugs that treat some of the symptoms of Alzheimer’s. No intervention currently alters the course of the disease, however. Even negative clinical trials—those that do not achieve the desired outcome of improving symptoms or changing the course of the disease—contribute to our understanding of this complex disorder. Clinical trials may be negative for a number of reasons. Sometimes, the intervention being tested is simply not effective. A number of other factors can influence negative results, such as insufficient dosage levels or frequency, or missing the opportune stage of disease for effective treatment.

While they can be frustrating, negative trials can be important stepping stones because they add to our insights about the underlying mechanisms involved in disease progression. They can also provide vital information about how studies and outcome measures should be designed for future trials. For example, in May 2013, researchers at Weill Cornell Medical College, New York City, announced negative results from a trial testing whether or not intravenous immune globulin (IVIg), a blood product, could clear amyloid from the brain. While deemed a failed trial, the results are adding to our understanding of anti-amyloid treatments.

A mixture of antibodies derived from the blood of healthy donors, IVIg has been used for 30 years to treat infection and inflammation. It contains naturally occurring antibodies against beta-amyloid. Earlier, preliminary studies in much smaller groups of participants had shown that IVIg might improve cognition, increase levels of anti-beta-amyloid antibodies in plasma, and promote clearance of beta-amyloid from cerebrospinal fluid (CSF).

Based on those results, researchers tested IVIg over 18 months via weekly infusions in 390 volunteers with mild to moderate Alzheimer’s across the United States and Canada. This Phase III double-blind, placebo-controlled trial was designed to examine the safety, effectiveness, and tolerability of IVIg. While the volunteers tolerated the drug well, it did not reduce cognitive decline or preserve functional abilities at a significant level.

Despite these disappointing initial results, further analysis of the data did produce some intriguing findings. The researchers found that some volunteers with moderate Alzheimer’s who carried the APOE ?4 gene, a known risk factor for Alzheimer’s, showed some cognitive improvement. The therapy had some impact on Alzheimer’s-related changes, such as brain volume. The investigators are now conducting further analyses of brain images of these volunteers to learn more about IVIg’s effects, if any, on brain atrophy and metabolism.

Targeted Interventions in Trials Large and Small

NIA currently supports 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 listed in Table 1, two are NIA-funded add-ons to large National Institutes of Health (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.

NIA-funded trials listed in Table 5 are investigating the psychiatric conditions and symptoms—agitation, apathy and depression—commonly associated with MCI or Alzheimer’s. Researchers are investigating ways to alleviate these distressing symptoms.

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.

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 after serious illness. In older people, it sometimes has a long-lasting, negative impact on cognition.

The Dilemma of Delirium in Older Patients

Ill and hospitalized older people sometimes experience episodes of delirium, a state of confusion and disorientation. Long considered a transient and reversible condition, delirium in older people is still viewed by many to be a normal consequence of surgery, chronic disease, or infections.

There is mounting evidence, however, that delirium may be associated with increased risk for dementia and may contribute to morbidity and death. One recent study found that in a group of 553 people age 85 and older, those with a history of delirium had an eightfold increase in risk for developing dementia (Davis et al., 2012). The researchers also found that among the participants with dementia, delirium was associated with an acceleration of dementia severity, loss of independent functioning, and higher mortality rates. More research is needed to fully determine whether delirium is a risk factor for or, possibly, a marker of the onset of dementia in previously symptom-free people.

At NIA and throughout the geriatric research community, momentum is building to better understand the mechanisms involved in delirium and to improve ways to recognize and treat the condition. Currently, NIA supports six clinical trials (see Table 4) focused on finding effective drugs and protocols to prevent or reduce the impact of delirium in hospitalized older people, including those in intensive care. Supplements, pain medications, and sedatives that that may alleviate delirium in pre- and post-operative patients are all being tested.

At this stage, unfortunately, there are more questions than answers. In order to treat or prevent delirium, it will be important to determine why some older people are more susceptible to delirium during hospital stays or as a result of trauma or illness.

In addition to supporting the clinical trials, NIA, in collaboration with the American Geriatrics Society, is sponsoring a conference on delirium in early 2014. The meeting will cover a wide array of delirium-related research topics, including biomarkers, genetic risk factors, neuroimaging, inflammation, brain injuries, drug and nondrug interventions, and animal models. Recommendations from the meeting will inform research on this topic for years to come.

Clinical Trials Target Alzheimer’s in Symptom-Free Volunteers

Because we know that Alzheimer’s-related brain changes take place years, even decades, before symptoms appear, scientists have long wanted to test therapies early in the disease process. Now, thanks to advances in imaging and biomarkers that enable researchers to detect the earliest signs of Alzheimer’s-related brain changes, we are entering an exciting new era of testing interventions across the disease spectrum. Clinical trials are recruiting a broad range of volunteers, from people free of overt symptoms but at risk for the disease, to those diagnosed with varying levels of Alzheimer’s dementia.

Several recently funded trials looking at ways to prevent or delay the onset of Alzheimer’s are recruiting cognitively healthy, but at-risk, volunteers. These trials, described below, are testing promising drugs that target amyloid proteins that form plaques, a key feature of Alzheimer’s disease. While previous trials of anti-amyloid agents did not prove successful in people with mild to moderate Alzheimer’s dementia, these groundbreaking prevention trials will help determine if the interventions are effective if begun earlier in the disease process.

  • The A4 Trial (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) is testing an amyloid-clearing drug in 1,000 symptom-free older volunteers who have abnormal levels of amyloid detected by positron emission tomography (PET) brain scans. The goal is to test the hypothesis that decreasing amyloid burden during the symptom-free stage of Alzheimer’s will reduce damage to the brain and delay cognitive decline. Clinically normal volunteers age 65 and older will be screened with PET imaging. Those with amyloid loads that place them at risk will be treated for 3 years with solanezumab, an anti-amyloid drug, or a placebo. Researchers will determine if the drug allows volunteers to maintain their cognitive health and will track how it impacts structural and functional brain changes.
  • The Alzheimer’s Prevention Initiative (API) is evaluating promising experimental treatments in people who, based on their genetic background and age, are at high risk of developing Alzheimer’s in their 30s, 40s and 50s. Participants include members of the world’s largest extended family of early-onset Alzheimer’s mutation carriers in Colombia, as well as a smaller group in the United States. The first API trial is a 5-year study of crenezumab, an anti-amyloid treatment.
  • The Dominantly Inherited Alzheimer Network (DIAN) Trial is a Phase II trial of three anti-amyloid drugs in volunteers who carry a gene for a rare form of early-onset Alzheimer’s disease. The study plans to recruit 160 volunteers free of symptoms or with mild symptoms at several national and international sites. The trial will test three anti-amyloid drugs: gantenerumab, solanezumab, and a third, as-yet undetermined drug. The agent that performs best with regard to safety, tolerability, and biomarker efficacy will be selected to go on to a Phase III trial.
  • The newly funded API APOE4 Trial will be a multicenter, randomized, controlled clinical trial evaluating an investigational amyloid-beta modifying agent in 650 cognitively unimpaired 60- to 75-year-old individuals who have inherited two apolipoprotein E ε4 alleles. Scientists will use cognitive, brain imaging, and CSF measurements of preclinical Alzheimer’s disease.

Targeting Alzheimer’s-Related Psychiatric Syndromes

NIA-funded researchers and clinicians are testing interventions to alleviate psychiatric conditions and symptoms associated with Alzheimer’s disease, including apathy, agitation, and depression. These conditions and symptoms cause additional distress for individuals with Alzheimer’s and their caregivers, as they make caregiving more difficult, increase medical costs, and may also contribute to cognitive decline and nursing home placement. NIA supports several important clinical trials looking at the use of antidepressants and other interventions for these conditions. The investigators want to determine if such treatments, used singly or in combination, improve quality of life and cognition, or delay the onset of dementia in those with MCI.

For example, prazosin, a generic drug used to treat high blood pressure, is used to treat agitation, which is often a chronic problem in people with Alzheimer’s, particularly in the later stages, and can lead to long-term care outside the home. Currently available drugs used to treat agitation are not very effective and may even cause additional harm in older people, such as increased risk of stroke or excessive sedation. Researchers recruiting volunteers in the Seattle area are testing whether prazosin is effective in treating behavioral problems by reducing excess adrenalin effects in the brain.

NIA supported researchers have also tested a nondrug intervention for agitation—a program of tailored activities—in volunteers living at home. To learn more about these clinical trials and others, see Table 5, Neuropsychiatric Symptoms Clinical Trials.

Recent findings from completed trials are adding to our understanding of these syndromes and may one day lead to effective interventions:


People with dementia often experience agitation, a syndrome that includes anxious, disruptive, or aggressive physical behavior, such as pacing, hitting, repeating words or phrases, and yelling. Agitation is a major reason caregivers place loved ones with dementia in residential care.

A team led by researchers at Tel Aviv University, Israel, and Innovative Aging Research, Silver Spring, MD, developed a behavioral intervention for agitation called Treatment Routes for Exploring Agitation (TREA). TREA is an individually tailored intervention that identifies and seeks to address unmet patient needs, such as pain, loneliness, or boredom, which may cause agitation.

The researchers tested TREA in a clinical trial involving 125 older people with advanced dementia living in nine nursing homes in Maryland (Cohen-Mansfield et al., 2012). For each study participant, the researchers identified likely reasons for agitated behavior based on data collected from nursing home staff, family caregivers, and direct observation. They also identified the time of day when the residents showed the most agitation on average. They then presented the residents with different interventions and determined which were most effective in alleviating their distress.

For example, if the source of agitation seemed to be boredom, the researchers offered the resident different activities, like arts and crafts, walking outdoors, or games. Once the most beneficial interventions for each resident were identified, they were given for 4 hours per day during the periods when agitation was typical. Compared to control-group participants, those who received the TREA intervention for 2 weeks showed significantly reduced physical and verbal agitation. They also reported increased levels of pleasure and interest, suggesting improved quality of life.


An estimated 5 to 15 percent of people with dementia experience anxiety. A team led by investigators at the VA HSR&D Houston Center of Excellence developed the Peaceful Mind program as an intervention for anxiety in people with dementia. Peaceful Mind is based on cognitive-behavioral therapy—it teaches patients coping skills like deep breathing and reassuring “self-talk”—but is tailored to the needs of those with dementia, e.g., it involves simpler and shorter practice sessions.

The researchers studied 32 volunteers (average age, 79) with mild or moderate dementia, of whom half received at least 8 hours a week of Peaceful Mind therapy for 3 months, and half received usual care (Stanley et al., 2013). After 3 months, the participants who completed the Peaceful Mind program showed significantly greater reductions in anxiety, as judged by their physicians and caregivers, than did the control patients. By 6 months, however, the improvements had disappeared, suggesting a possible need for a longer treatment period.


Apathy, a loss of interest and motivation in daily activities in the absence of depression, is associated with poor quality of life, greater cognitive decline, and higher costs of care for people with Alzheimer’s disease. Researchers at the Medical University of South Carolina, Charleston, led an international team examining the use of methylphenidate, a drug that enhances dopamine transmission in the brain, to alleviate apathy (Rosenberg, et al, 2013). Dopamine is a neurotransmitter that plays a critical role in the brain’s complex system of motivation and reward.

During a 6-week, randomized, double-blind trial, 60 older people with mild to moderate dementia were treated with methylphenidate or a placebo. The researchers found marked improvement in apathy, as well as improved cognition, in the volunteers who received the drug. While the study size was small, the findings indicate that apathy is a distinct behavioral syndrome in people with Alzheimer’s (as opposed to depression) and that methylphenidate may be an effective treatment.

Evaluating Nondrug Approaches

Cognitive Training

NIA is funding studies looking at ways to improve cognitive function in older people. One area of interest is cognitive training. The goal of cognitive training is to improve specific skills, such as memory and decisionmaking, thought to be important in allowing older people to maintain independent living. Additionally, it is thought that cognitive training may help preserve brain function and play a role in delaying age-related cognitive decline. While research results have been mixed, a recent large study showed that cognitive training may not be effective in preventing dementia.

University of Indiana, Indianapolis, researchers reported results from an Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial that showed no beneficial effect of cognitive training on the risk of developing dementia (Unverszagt et al., 2012). The study involved 2,800 older participants (average age, 74) living in six metropolitan areas. The intervention consisted of 10 training sessions (each 60 to 75 minutes long) in specific cognitive domains—memory, reasoning, and mental processing speed—during 5 to 6 weeks.

During 5 years of follow-up, the dementia incidence among those who received the training was not significantly lower than among those who did not. It remains to be learned if a longer or differently designed cognitive training program would prove beneficial.

In a small clinical study, researchers at the University of Illinois at Urbana-Champaign found that cognitive training improved logical reasoning in cognitively normal older adults (Payne et al., 2012). The study involved 105 community-dwelling volunteers (average age, 73) assigned to either a training group or a control group. The training group completed a 16-week program of instruction in problem solving and did 10 hours per week of homework involving logic puzzles.

The training group showed significantly greater improvement in their reasoning-test performance, compared to the control group. Moreover, participants who indicated greater “memory self-efficacy”—or confidence in their own memory—at the start of the trial benefited the most from the training. Further analysis indicated that those with higher memory self-efficacy scores also spent more time working on their training materials at home.

This study suggests that people’s beliefs in their own cognitive abilities may influence their capacity to learn new skills in adulthood. Given that many older adults lose confidence in their memory performance, and the widespread negative stereotypes about aging and memory, interventions aimed at improving memory self-efficacy could enhance the benefits of training in multiple areas of cognitive function.


Although exercise is widely recommended to maintain physical function and reduce risk of a number of age-related medical conditions such as cardiovascular disease and diabetes, it has not been shown to improve cognition or alter the hallmarks of Alzheimer’s disease in the brain. The Exercise MCI Trial was recently funded as part of the Alzheimer’s Disease Cooperative Study (ADCS) renewal. This randomized, controlled trial will test whether supervised aerobic exercise can influence cognitive decline, slow brain atrophy, or delay Alzheimer’s in older adults with MCI, a condition that often leads to Alzheimer’s disease.

The trial will recruit sedentary older adults with MCI to participate in a year-long program in which one group will do high-intensity aerobic exercise and the other will do stretching. Cognitive testing, CSF biomarkers, and MRI results will provide critical data on the efficacy of aerobic exercise on improving cognition and Alzheimer’s-related pathology.

Deep Brain Stimulation

Deep brain stimulation (DBS) is a neurosurgical treatment in which electrodes are implanted within specific brain circuits to correct under- or over-activity in those circuits caused by disease. The electrodes are connected to an implanted pulse generator that is programmed to deliver continuous stimulation, much like a cardiac pacemaker. DBS implants can last for years. They are now widely used to treat Parkinson’s disease and have been used or tested for a number of other neurological and psychiatric disorders, including epilepsy, dystonia, and depression.

DBS is now being tested as a treatment for Alzheimer’s disease, in which specific brain circuits break down. A preliminary small study led by researchers at the Johns Hopkins University, Baltimore, and the University of Toronto evaluated the effects of DBS in six patients with mild symptoms of Alzheimer’s disease (Smith et al., 2012). Electrodes were implanted in the fornix, a large bundle of nerve fibers that connects the hippocampus to other brain areas. Degeneration of the fornix is associated with memory problems in both animals and humans, and DBS of the fornix has been shown to improve memory deficits in rodent models.

After 1 year of treatment, the participants showed increased glucose metabolism and functional connectivity in two brain networks that typically degenerate in Alzheimer’s. These increases correlated with improvements in global cognition, memory, and quality of life.

This small, unblinded study paved the way for a larger study currently underway at multiple sites. The same investigators are conducting a double-blind, randomized controlled trial of DBS of the fornix (DBS-f) called the ADvance study. This public-private trial, supported by the NIA and Functional Neuromodulation Ltd., is designed to determine if DBS-f is safe and has potential clinical benefit for patients with mild Alzheimer’s.

NIA Supports Innovative Research Led by the Alzheimer’s Disease Cooperative Study

NIA’s support of the ADCS enables researchers to develop intriguing findings from basic studies into promising treatments that are tested in clinical trials. The ADCS is a large clinical trials consortium with sites throughout the United States that investigates both the cognitive and behavioral symptoms of Alzheimer’s disease. ADCS investigators develop innovative clinical trial designs, tools, and interventions, including therapies that might not otherwise be developed by industry. These efforts are critical to accomplishing the research goals set forth in the National Plan to Address Alzheimer’s Disease, including the primary research goal of preventing and effectively treating Alzheimer’s by 2025.

The most recent round of ADCS studies focuses on a variety of promising areas. Beyond the A4 Trial and MCI Exercise Trial described above, ADCS trials also include:

  • Study of Nasal Insulin to Fight Forgetfulness (SNIFF). This trial is evaluating whether a type of insulin, when administered as a nasal spray, improves memory in adults with mild memory impairment or Alzheimer’s disease. This double-blind, placebo-controlled, Phase II/III study is evaluating growing evidence that insulin carries out multiple functions in the brain and that poor regulation of glucose may contribute to the development of Alzheimer’s disease. Participants will use a nasal spray device with either insulin or a placebo for 12 months, followed by 6 months in which all will receive insulin. Recruitment is now underway for 250 volunteers diagnosed with amnestic MCI or early Alzheimer’s at about 30 research clinics nationwide.
  • Home-Based Assessment Study. This study is examining the use of home-based assessments, including mailed-in forms, telephone interviews, and online assessments, in clinical trials. Scientists evaluated cognition, daily functioning, mood, and other factors in volunteers aged 75 and older using each of these methods. They then compared the findings with data collected by traditional in-person methods. The study results, which are now being analyzed, will provide information about how home-based assessments might be used in future prevention trials. If the results are positive, such methods could significantly reduce the cost and increase the feasibility of participation in long-term clinical trials.
  • Resveratrol in Alzheimer’s Disease Study. 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 that resveratrol—an antioxidant compound found in grapes and red wine—may protect the health of neurons. This Phase II, double-blind, randomized, placebo-controlled trial recruited 120 volunteers at 26 sites across the United States in early 2012 to evaluate the impact of resveratrol treatment. It is looking at its effect on biomarkers and clinical outcomes in people with mild to moderate Alzheimer’s disease.
  • Nerve Growth Factor Study. This Phase II clinical study of 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.
  • CSF Pharmacodynamic Trial. When testing potential new drug therapies, specifically those targeting key Alzheimer’s disease pathways, scientists use CSF and blood plasma biomarkers to see if the compound crossed the blood-brain barrier and engaged the relevant target. To increase the efficacy and speed of drug development, the ADCS is developing advanced methods that sample CSF and plasma levels over time. These methods will enable researchers to track levels of several Alzheimer’s-related proteins to better understand how a drug influences Alzheimer’s disease and to help guide decisions on whether a drug warrants further clinical testing.