Practical Challenges

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."

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Alzheimer's Disease (AD)


Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene




Beta-Amyloid Plaque


Cognitive Reserve




Functional MRI (fMRI)


Hippocampal Formation




Insulin Resistance


Magnetic Resonance Imaging (MRI)


Mild Cognitive Impairment (MCI)


Neurodegenerative Disease



Clusters of a small number of beta-amyloid peptides.

Oxidative Damage


Pittsburgh Compound B (PiB)


Pittsburgh Compound B (PiB)









Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease



Disease-Modifying Drug

Transgenic Mice




Insulin & Insulin Resistance

Susceptibility Gene


Susceptibility Genes


Genome-Wide Association Study

Vascular Disease



Normal Aging