The National Institutes of Health announced on 14 January 2013 that it will fund the Alzheimer’s Disease Cooperative Study (ADCS) to conduct four new clinical studies over the next five years. The awards reflect a trend in the field toward earlier interventions, with the largest share going to the A4 prevention study in people with preclinical AD. Another study will look at whether aerobic exercise can slow cognitive decline in people who have mild cognitive impairment (MCI). A third aims to speed drug development by providing information on the pharmacodynamics and effectiveness of new drug candidates. The only new trial in AD patients will test a drug to control agitation, one of the most disruptive and intractable behavioral symptoms of the disease. The four studies will receive $11 million this year, and as much as $55 million altogether, with the money coming from the current NIH budget. Today, A4 leaders announced that they will evaluate solanezumab, Eli Lilly's anti-amyloid-β antibody in their trial (see ARF related news story).

Scientists whom Alzforum contacted seemed pleased with the choice of studies. “I think they reflect careful selection criteria,” said Ron Petersen, director of the Mayo Clinic in Rochester, Minnesota. Although he leads an ADCS site, he was not involved in the selection process. “They look like interesting areas to pursue,” agreed Bruce Lamb at the Cleveland Clinic in Ohio. “We certainly need to consider the things that ADCS is looking at.” Lamb added, however, that the field needs to continue to advance other approaches as well, including studying the basic science of disease mechanisms and testing drugs that target later stages of the disease.

The ADCS is a National Institute on Aging (NIA) clinical initiative conducted at about 80 research sites in the U.S. and Canada. It runs clinical trials to assess potential treatments. Many of the ADCS centers also contribute data to the National Alzheimer’s Coordinating Center, which maintains a huge, publicly available database (see ARF related news story). The program has been funded by NIH since 1991, with the grant renewed every five years.

The selection of new studies to go into the grant renewal package took two years, and was decided by a Steering Committee of about 30 experts from participating sites, ADCS director Paul Aisen at the University of California, San Diego, told Alzforum. Early in the process, Aisen sought potential ideas from the community, leading an Alzforum Webinar on the topic. Studies were chosen based on their feasibility, readiness for human trials, and how well they reflected the mission of the ADCS to advance therapeutic research, Aisen said. “The four studies represent a broad range of interventions across the disease spectrum,” noted Laurie Ryan, ADCS project officer at the NIA.

The A4 trial, led by Reisa Sperling at Brigham and Women's Hospital, Boston, will receive the lion’s share of the funding, and seems to be generating the most excitement among researchers. Today at the 7th Annual Human Amyloid Imaging conference being held in Miami, Florida, Sperling announced that solanezumab will be the first therapeutic drug to be tested (see ARF related news story). “I am quite enthusiastic about [the A4 trial]. I think it’s very exciting, especially when combined with the other two preclinical studies,” said David Knopman at the Rochester Mayo Clinic. He participated in the Steering Committee. “In light of the failures of amyloid immunotherapies in symptomatic people, I think it is critically important to address the question of how soon is soon enough to attack amyloid," Knopman added. Petersen agreed, saying, "I think this is going to be a groundbreaking study."

The role of exercise in brain health has also caught the attention of AD researchers in recent years. Epidemiological studies consistently show a link between higher activity levels and a lower risk of AD (see ARF related news story; ARF news story; ARF news story; and ARF news story). In addition, small trials found that exercise can improve cognition, increase hippocampal volume, and curb amyloid deposition in older adults (see ARF related news story; ARF news story; and ARF news story). Nonetheless, researchers have yet to demonstrate in a randomized controlled trial showing that exercise can delay AD. To investigate this, researchers led by Laura Baker at Wake Forest School of Medicine, Winston-Salem, North Carolina, and Carl Cotman at the University of California, Irvine, plan to enroll 300 sedentary adults with MCI in an 18-month study. The control group will do stretching exercises, while the experimental group will engage in aerobic exercise four times per week for half an hour or more. Participants can choose among several types of exercise, but must reach 70 percent of their maximum heart rate, Baker noted. For comparison, people can attain this level of exertion during a brisk walk.

The primary outcome will be changes in cognitive function as measured by the ADAS-cog, as well as by a computerized battery of tests. The trial will employ some of the same tests as the A4 study in order to facilitate comparisons, Baker said. In addition, the researchers will look at cerebrospinal fluid (CSF) biomarkers, including Aβ, tau, markers of inflammation, and brain-derived neurotrophic factor (BDNF), which has been shown to ramp up in animals during exercise (see ARF related news story). Structural MRI will track changes in hippocampal volume, as well as whole brain volume and frontal lobe alterations. Baker said that they may do brain amyloid imaging in a subset of participants, but that amyloid burden is not a requirement for participating in the trial. Many people with MCI have cerebrovascular impairment instead of AD, and animal studies suggest that exercise will also improve cognition in this group, she added.

If exercise does delay AD, will the finding motivate people to hit the gym? People already know that exercise is good for them, but that does not always translate into a more active lifestyle. Baker hopes that a positive finding might lead to a rigorous effort to develop a specific exercise program for people with MCI that would include clear goals, social support, and feedback to healthcare professionals. Petersen noted that both the A4 trial and the exercise study have tremendous public health implications, adding that he plans to run both at his center.

For people who already have AD, a major unmet need is for a safe, effective medication to calm agitation, Ryan said. This behavioral symptom precipitates nursing home admissions because family members can no longer handle care at home. The antipsychotic drugs currently used to treat the condition seem ineffective (see ARF related news story) and have many side effects, including sedation, parkinsonism, slight risk of stroke, and even death. The last led to a black box warning by the FDA (see ARF related news story). Led by Elaine Peskind at the University of Washington, Seattle, a small pilot trial of 22 people with AD found that the α-adrenergic blocker prazosin quieted agitation better than did placebo (see Wang et al., 2009). This FDA-approved drug dampens the brain adrenaline system. It also relieves symptoms of post-traumatic stress disorder in veterans, Peskind noted (ARF related news story). Millions of middle-aged and elderly men take it to control enlarged prostates, and its side effects are typically mild, with the most common being nasal congestion.

Peskind will lead a six-month ADCS trial of prazosin in almost 200 participants, using the Neuropsychiatric Inventory Score as the primary outcome measure. One challenge in studying agitation is that the most severely impaired patients may be unable to participate in a placebo-controlled trial, rendering drug effects in the trial difficult to measure. To encourage their participation, the researchers will allow a “rescue strategy” in which participants can receive the sedative lorazepam on days when they are out of control, up to a total of 42 days during the study. Participants can also withdraw from the study if their agitation continues. The number of days on lorazepam and total time in the study will be secondary outcomes, Peskind noted.

Another problem that plagues the AD field is that the current drug pipeline for AD remains relatively small, Doug Galasko at the University of California, San Diego, told Alzforum. In an attempt to speed up drug development, he and Martin Farlow at Indiana University, Indianapolis, will investigate the pharmacodynamics of several agents in Phase 1 trials to aid investigators in making “go/no go” decisions. “One of the failures we’ve had at times is not knowing if the treatment is engaging the target,” Ryan pointed out. The investigators are considering applications from researchers with compounds of interest. Initially, they will focus on drugs that lower Aβ production, but they will consider agents with other mechanisms of action as well.

To measure drug effect, they will insert a catheter into the CSF of participants, give them a dose of the drug, then measure Aβ levels over the next 18-24 hours. For some agents, they may use the stable isotope-linked kinetics (SILK) methodology developed by Randall Bateman and David Holtzman at Washington University School of Medicine in St. Louis, Missouri (see ARF related news story). In this procedure, patients are given labeled leucine, which is then incorporated into newly made Aβ, allowing researchers to track production and clearance of the peptide. The method has been used by pharmaceutical companies, and played a crucial role in choosing drug amount and dosing frequency for Lilly’s discontinued γ-secretase inhibitor semagacestat and Merck’s current BACE1 inhibitor, for example (see ARF related news story). The researchers will also measure plasma Aβ levels to see if they reflect CSF changes and could be used as a biomarker for the given drug. Because they will do all studies in-house with the same protocols, the researchers will be able to directly compare different kinds of compounds. This might help investigators decide which drugs to take forward into expensive Phase 2 trials. “The CSF study is very interesting, and I think it will yield useful information,” Knopman said, although he noted it does not offer any immediate benefit to participants.––Madolyn Bowman Rogers.

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References

News Citations

  1. Solanezumab Selected for Alzheimer’s A4 Prevention Trial
  2. Pass the Bordeaux—Mediterranean Diet, Exercise Reduce AD Risk
  3. Research Brief: To Preserve Your Gray Matter, Take a Hike
  4. Exercise and the Brain: More Support for Protective Effects
  5. Research Brief: Total Activity, Not Just Exercise, Keeps Mind Sharp
  6. Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
  7. Get Moving—Walking Enlarges Hippocampus, Preserves Memory in Seniors
  8. On Your “Virtual” Bike! Exercise and Exergames Bring Benefits
  9. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis
  10. Rethinking Antipsychotics for Alzheimer Patients—Again
  11. More Trouble for Atypical Antipsychotics—Dementia Patients at Risk
  12. Stress and Trauma: Tackling Post-traumatic Stress Disorder
  13. Studies Reveal New Hope, Old Problems With AD Biomarkers
  14. Wave of New BACE Inhibitors Heading to Phase 2

Webinar Citations

  1. Treating Before Symptoms—ADCS Invites Ideas for Clinical Trials in Very Early AD

Paper Citations

  1. . Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry. 2009 Sep;17(9):744-51. PubMed.

Other Citations

  1. ARF related news story

External Citations

  1. Alzheimer’s Disease Cooperative Study
  2. research sites
  3. National Alzheimer’s Coordinating Center

Further Reading

News

  1. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis
  2. Pass the Bordeaux—Mediterranean Diet, Exercise Reduce AD Risk
  3. Research Brief: To Preserve Your Gray Matter, Take a Hike
  4. Stress and Trauma: Tackling Post-traumatic Stress Disorder
  5. Exercise and the Brain: More Support for Protective Effects
  6. DC: Ways to Slow Brain Aging: Exercise, Estrogen, and Sleep?
  7. On Your “Virtual” Bike! Exercise and Exergames Bring Benefits
  8. Q&A With Ryan Watts, Genentech Lead Scientist on API Trial
  9. DIAN Trial Picks Gantenerumab, Solanezumab, Maybe BACE Inhibitor
  10. Solanezumab Selected for Alzheimer’s A4 Prevention Trial
  11. More Trouble for Atypical Antipsychotics—Dementia Patients at Risk
  12. Rethinking Antipsychotics for Alzheimer Patients—Again
  13. Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
  14. Studies Reveal New Hope, Old Problems With AD Biomarkers
  15. Get Moving—Walking Enlarges Hippocampus, Preserves Memory in Seniors
  16. Could New Hormone Compete With the Treadmill?
  17. NACC News: Building a Frontotemporal Database, and More
  18. Wave of New BACE Inhibitors Heading to Phase 2
  19. Can Epigenetics Explain Variable Progranulin Expression?
  20. Research Brief: Total Activity, Not Just Exercise, Keeps Mind Sharp
  21. NIH Director Announces $100M Prevention Trial of Genentech Antibody

Webinars

  1. Treating Before Symptoms—ADCS Invites Ideas for Clinical Trials in Very Early AD