In this issue we have asked Dr. Steven Ferris and Dr. Hillel Grossman
to address the following question:

How close are we to disease-modifying treatments in Alzheimer disease?

	Steven H. Ferris, Ph.D. Director, NYU Alzheimer’s Disease Center	Steven H. Ferris, Ph.D., is the Friedman Professor of the Alzheimer Disease Center at New York University (NYU) School of Medicine, Executive Director of the Aging and Dementia Research Center of NYU’s Silberstein Institute and Principal Investigator of their NIA-supported Alzheimer Disease Center. He has been studying brain aging and Alzheimer disease for more than three decades and is a neuropsychologist, psychopharmacologist, and gerontologist.

In my opinion, we are fairly close to developing effective disease-modifying treatments for Alzheimer’s disease. I have been involved in Alzheimer’s disease clinical trials for almost 34 years and I must admit that for many years it was a very frustrating experience. Most of the drugs tested in the 1970’s and 1980’s failed to show any clinical benefits because the drugs studied had either unknown mechanisms of action or their mechanisms were not related to the primary pathology of AD. Happily this situation improved somewhat in the late 1980’s and 1990’s when several drugs finally showed sufficient benefits to gain FDA approval and they became widely used by Alzheimer’s disease patients. The drugs currently available include the cholinesterase inhibitors donepezil (Aricept), rivastigmine (Exelon) and galantamine (Razadyne) and the NMDA antagonist memantine (Namenda). These symptomatic drugs address certain biochemical losses caused by the pathology of Alzheimer’s disease. However, the benefits of these drugs are modest, and they have not been shown to slow the progression of disease. Thus they are viewed as “symptomatic” rather than “diseasemodifying” treatments.

So why am I now extremely optimistic about having disease-modifying treatments available to patients in the near future? The most exciting development in Alzheimer’s disease research in the past 10 years has been the transition from testing symptomatic drugs to the testing of an array of new compounds that appear to address the basic pathophysiology of the disease and therefore have the potential to slow its progression. In fact, there are currently a few dozen treatments in early, middle or late stage clinical trials that may slow disease progression. These include several types of anti-amyloid drugs, such as immunotherapies (“vaccines” and antibodies) that attack and remove amyloid plaques; anti-aggregation drugs that block the changes in amyloid from soluble to dense, more toxic forms; and secretase inhibitors and other strategies (such as statins, insulin sensitizers and certain anti-inflammatory drugs) that inhibit or reduce initial amyloid production. Current treatments under development also include a smaller but growing number of compounds that may inhibit the accumulation of neurofibrillary tangles, the other major component of Alzheimer pathology that impairs brain cells and causes the loss of connections (“synapses”) that relate most directly to loss of memory and other cognitive functions. In addition, other potentially “neuroprotective” drugs in clinical trials enhance certain neural growth factors that can also help protect brain cells from loss of connections or other damage.

How close are we to having an effective disease-slowing treatment actually available to patients? The first results from several large, late stage clinical trials, hopefully showing a slowing of clinical progression, will be available within the next 1-12 months. Results from other similar trials will be reported within the following 1-2 years. While many of these new treatments will certainly fail to prove effective, I fully expect that at least some of these trials will show positive results.Thus, I predict that within 1-month to 3-years from now, one or more of the new “disease-modifying” treatments will be approved or close to approval by the FDA. Since some of the drugs being tested in clinical trials are already approved and marketed for other conditions, the availability to patients could be even sooner.

	Hillel Grossman, M.D.	Hillel Grossman, M.D., is the Medical Director of the Clinical Core of the Alzheimer’s Disease Research Center and of the Memory and Aging Center, both at the Mount Sinai Medical Center.

If I answer this question with my heart, I would say ‘very, very close. Tommorow’! Unfortunately, no matter how much I want this to happen it is not as close as we want.

By disease-modifying treatments I mean very specifically, treatments that will interfere with a disease process that naturally is inexorable and progressive. At present all Alzheimer treatments are symptomatic, meaning they help with symptoms of the disease, memory failure primarily, but do not interfere while the underlying disease process, which is ongoing. Current attempts at disease-modifying treatments include attempts to interfere with the accumulation of amyloid and brain cell destruction. The most promising approaches based upon this hypothesis are the secretase inhibitors and the immunotherapies. The secretase inhibitors aim to diminish the activity of enzymes responsible for the generation of the toxic forms of Abeta or to enhance the activity of the enzyme that produces a benign form of Abeta. Efforts to identify such agents have been hampered by safety: the body is remarkably efficient and its enzymes have multiple functions. One cannot simply just shut down an enzyme without impacting some other vital bodily function. A safe means to manipulate the enzymes remains a future goal.

It is important to remember that the processes of amyloid build-up and brain cell destruction may not be the cause of the disease but rather repercussions of it. The point at which virtually all clinical trials are aimed today, patients with mild–to-moderate Alzheimer’s disease may be too late— it may be impossible to restore a brain that has already lost crucial brain cells through years of the ravages of a disease process. More likely the point of necessary intervention is years earlier; by the time a patient is symptomatic enough to see a doctor and receive a diagnosis of Alzheimer’s disease it is likely too late for the disease-modifying treatments to take effect. Of course the difficulty with interfering at this earlier, pre-symptomatic stage is that we have no way of knowing who will get Alzheimer’s until he or she starts showing memory problems. By then, it may be too late. The recent example of Elan AN-1792, the so-called “Alzheimer’s vaccine” is very informative. This 2002 study was terminated early due to the development of encephalitis in several participants. While the study, of course, demonstrated the risks inherent in human trials of immunotherapy, it also showed at least in the few people studied at autopsy that it may be possible to remove plaques. What was sobering however was the observation that there was no clinical improvement in the participants who did mount the expected immune response. In other words, the treatment worked but the patients were no better. This again emphasizes that the intervention in patients with fully established Alzheimer’s disease might be too late. The immunotherapy approach may hold much greater promise as a preventative intervention in people at risk for Alzheimer’s.

So success in eradicating Alzheimer’s will hinge on the ability to identify early means of detection of the disease, before symptoms are obvious. Success in clinical trials will depend upon success in biomarkers and early risk factor identification studies. Here we have some reassurance. The largest and most expensive study of biomarkers in Alzheimer’s is currently underway in this country. The Alzheimer’s Disease Neuroimaging Initiative has completed recruitment of several hundred volunteers who are being examined with common brain scan techniques and blood tests, but also with high field MRI imaging, PET scanning including amyloid imaging and more esoteric analysis of blood and cerebrospinal fluid. The goal of this massive study is nothing short of identifying these needed biomarkers for the disease. Once identified, they would become the targets of early identification and disease-modifying strategies. Similar large scale studies with the design and aims of the ADNI are underway or being planned in Europe, Japan and Australia.

While these are the dominant approaches to amyloid modification, there are many others. This is very reassuring in the long run: the means to change the course of the disease will be found. However, we cannot relax with the belief that it is simply around the corner—there is an incredible amount of work to be done. Hundreds if not thousands of compounds and interventions will need to be studied. We cannot lose sight of the reality that the average time to bring a compound from animal studies to safe human use is a decade. Ten years. That is a critically long time for any patient with Alzheimer’s. It means we have to work harder, much harder.

So the sad answer is that diseasemodifying treatment is not around the corner. But I am not discouraged or demoralized. Everyday I meet patients and caregivers who want to find the cure; who give of their time, their energy and of themselves to find better treatments. I am surrounded everyday at our Alzheimer’s Center by researchers and staff who have put their lives and careers into finding the cure.We cannot wait for a miracle but we can make it happen.

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