Currently, under the FDA guidelines for clinical trials, drugs are tested on people who are already showing symptoms of Alzheimer's disease. Since the desired outcome of any AD drug is improved thinking and memory, researchers measure effectiveness primarily through cognitive testing. However, there is growing apprehension among some scientists regarding whether drugs are being tested on the right population. By the time memory problems emerge, the AD process is well established, so it is possible that a lack of response to a drug may be owing to an advanced disease process rather than an ineffective drug. The memory center of the brain, the hippocampal formation, may be so damaged that it is beyond repair by any drug. Dr. Reisa Sperling conveyed the level of concern many researchers now feel: "The thing that keeps me up at night, the thing that I'm most worried about, is that we're testing these drugs too late in the disease, that once a person already has mild dementia or is at a stage where they've already lost their hippocampal activation, the chances that we can rescue that brain even if we've got a terrific drug and prevent further decline are very small. I think we're going to have a better chance as we move back earlier in the disease to mild cognitive impairment and ultimately perhaps to normal people who have the earliest changes of Alzheimer's disease in their brain. But that's hard."
Dr. John Trojanowski concurred. "The nightmare is that we would eliminate from our arsenal of potential therapeutics drugs that failed in late- or middle-stage Alzheimer's disease—not because they are not potentially disease-modifying or preventative, but because the disease has already wreaked its havoc. It's killed so many cells that there's no therapy that would be efficacious. It would be a terrible loss if those compounds were written off as not being effective because they had shown no efficacy in middle- or late-stage disease. But if used as prevention, they might indeed shut down the disease before it even manifests any symptoms. I don't know the best way to get around that, except to invest more money in research on exactly that question."
Perhaps the most important development needed to expedite the development of preventative drugs is determining a way to accurately and reliably measure the impact of a treatment on the progression of Alzheimer's disease. The only measurements of effectiveness currently recognized by the FDA are clinical and neuropsychological testing, which are subject to great variability since they measure performance that can fluctuate daily. Quantitative measures of biological processes in the body, such as cholesterol levels, are called biomarkers. In the same way that testing a patient's cholesterol can indicate the presence of atherosclerosis or a brain MRI can point to an area where a stroke has occurred, measurements such as beta-amyloid levels in cerebrospinal fluid or PET scans with PiB may be able to identify early pathogenic changes and track the progression of AD. Researchers are at the threshold of determining relationships between biomarkers and AD progression. Once those have been established definitively, scientists will be able to correlate a treatment's effect on a biomarker and its clinical impact on memory or cognitive function as determined by neuropsychological testing. Further research in this area is imperative if any preventative drugs are to be tested on research volunteers determined by these measurements to possess pathology without yet showing symptoms. In order for the FDA to approve the use of any experimental drug in such an ideal test population, investigators will need a way to track the drug's efficacy at preventing the accumulation of pathology or delaying the onset of symptoms.
Dr. Russell Katz, director of the FDA's division of neuropharmacological drug products, described the potential role that biomarkers could play in research on preventative therapies for AD. "There's a lot of interest now in developing treatments for patients who are at risk for the disease, but who don't have any symptoms. Everybody's interested in finding a treatment that will prevent the disease or delay the onset of symptoms. That's a very important thing to do. The problem with that approach is that, because the patients don't have symptoms, it's very difficult to know what to measure in order to determine that the drug works. So the question is how you measure the effect of a treatment when you can't measure a patient's symptoms. This is where biomarkers might be useful as indicators that the drug is having an effect on the underlying processes that cause Alzheimer's disease."
Risk and side effects must also be considered. All drugs carry risks of side effects, and some of them can be very serious. As a society, we will need to decide what level of risk we are willing to accept to develop aggressive drugs. Speaking for the FDA, Dr. Katz said, "Alzheimer's is a devastating disease. Everybody recognizes that. It's fair to say that as an agency we would be willing to take some risk if we had a drug that really made a profound difference in those patients' lives, or, even better, prevented Alzheimer's disease altogether."
However, these challenges do not dilute the pervasive optimism in the field. As Dr. Sperling told us, "I believe that we've got a cure for Alzheimer's disease in someone's test tube. The question is: How fast can we get that into clinical trials? And do we have the right drugs in clinical trials?" The positive outlook of AD researchers in general, who feel that tremendous progress has been made, was captured by Dr. Aisen: "This is a tremendously exciting time, and we all feel a huge sense of responsibility to work together effectively and get there as fast as we can."
Previous: Drugs in Development
Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs, www.publicaffairsbooks.com.
In This Section
- Building Cognitive Reserve
- Brain Efficiency
- The Role of Education
- Brain Building
- Personality Factors and Social Networks
- Assessing the Potential Benefits of Exercise and Diet
- Exercise and the Brain
- Diet and the Brain
- Developing New Drug Treatments
- Drugs in Development
- Practical Challenges
Momentum in Science: The Supplementary Series
- Understanding and Attacking Alzheimer's 12 min
- How Far We Have Come in Alzheimer's Research 15 min
- Identifying Mild Cognitive Impairment 20 min
- The Role of Genetics in Alzheimer's 12 min
- Advances in Brain Imaging 11 min
- Looking Into the Future of Alzheimer's 6 min
- The Connection Between Insulin and Alzheimer's 21 min
- Inflammation, the Immune System, and Alzheimer's 29 min
- The Benefit of Diet and Exercise in Alzheimer's 16 min
- Cognitive Reserve: What the Religious Orders Study is Revealing about Alzheimer's 20 min
- Searching for an Alzheimer's Cure: The Story of Flurizan 30 min
- The Pulse of Drug Development 15 min
- The DeMoe Family: Early-Onset Alzheimer's Genetics 25 min
- The Nanney/Felts Family: Late-Onset Alzheimer's Genetics 20 min
- The Quest for Biomarkers 17 min
Video: Inside the Brain: Unraveling the Mystery of Alzheimer's Disease
This 4-minute captioned video shows the progression of Alzheimer's disease in the brain.
Inside the Brain: An Interactive Tour
The Brain Tour explains how the brain works and how Alzheimer's affects it.
Alzheimer's Disease: Unraveling the Mystery
This book explains what AD is, describes the main areas in which researchers are working, and highlights new approaches for helping families and friends care for people with AD.
- About The Scientists
Connect with Alzheimer's Research
Find out how you can participate in clinical trials or studies, find a research center, or get up-to-date information at 1-800-438-4380.
The Alzheimer's Association 24/7 Helpline provides reliable information and support to all those who need assistance. Call us toll-free anytime day or night at 1-800-272-3900.
- Create A Tribute
Honor someone you care about and share your stories by contributing to The Tribute Wall on Facebook.
The Alzheimer's Association message boards and chat rooms are your online communication forum. Share your thoughts and experiences, query your colleagues, and make new friends.
- Rapid advances in our knowledge about AD have led to the development of promising new drugs and treatment strategies. However, before these new strategies can be used in clinical practice, they must be shown to work in people. Advances in prevention and treatment are only possible thanks to volunteers who participate in clinical trials.
- Among those touched by Alzheimer's (excluding self), nearly one-third provide support as a friend or relative, another 3% provide support as a healthcare professional, and the remaining two-thirds provide no support to the person suffering from Alzheimer's. When support is provided, it most often entails emotional support, followed by care-giving support. While small in comparison, more than one person in ten is providing financial support. Read more.