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."

Previous: Drugs in Development

Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs,

Alzheimer's Disease (AD)

A progressive degenerative disease of the brain that causes impairment of memory and other cognitive abilities.

Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene

A gene that codes for a protein that carries cholesterol to and within cells; different forms of the ApoE gene are associated with differing risks for late-onset Alzheimer's disease. This gene may be referred to as a risk factor gene or a "susceptibility gene" because one form of the gene, called APOE4, is associated with the risk of developing late onset AD.


Derived from the amyloid precursor protein and found in plaques, the insoluble deposits outside neurons. May also be called A-beta.

Beta-Amyloid Plaque

A largely insoluble deposit found in the space between nerve cells in the brain. The plaques in Alzheimer's disease are made of beta-amyloid and other molecules, surrounded by non-nerve cells (glia) and damaged axons and dendrites from nearby neurons.

Cognitive Reserve

The brain's ability to operate effectively even when some damage to cells or brain cell communications has occurred.


A broad term referring to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease is one form of dementia.

Functional MRI (fMRI)

An adaptation of an MRI (see magnetic resonance imaging) technique that measures brain activity during a mental task, such as one involving memory, language, or attention.

Hippocampal Formation

A structure in the brain that plays a major role in learning and memory and is involved in converting short-term to long-term memory. Also called the hippocampus.


The process by which the body responds to cellular injury by attempting to eliminate foreign matter and damaged tissue.

Insulin Resistance

A condition in which the pancreas makes enough insulin, but the cells do not respond properly to it; characterizes and precedes type 2 diabetes.

Magnetic Resonance Imaging (MRI)

A diagnostic and research technique that uses magnetic fields to generate a computer image of internal structures in the body.

Mild Cognitive Impairment (MCI)

A condition in which a person has cognitive problems greater than those expected for his or her age. Amnestic MCI includes memory problems, but not the personality or other cognitive problems that characterize AD.

Neurodegenerative Disease

A disease characterized by a progressive decline in the structure and function of brain tissue. These diseases include AD, Parkinson's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.


Clusters of a small number of beta-amyloid peptides.

Oxidative Damage

Damage that can occur to cells when they are exposed to too many free radicals.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.


The tiny gap between nerve cells across which neurotransmitters and nerve signals pass.


A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.


A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.


Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease



Disease-Modifying Drug

Transgenic Mice

An animal that has had a gene (such as the human APP gene) inserted into its chromosomes for the purpose of research. Mice carrying a mutated human APP gene often develop plaques in their brains as they age.



Insulin & Insulin Resistance

Susceptibility Gene

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Susceptibility Genes

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Genome-Wide Association Study

Vascular Disease



Normal Aging