John Morris on Detecting Alzheimer's at the Preclinical Stage

Special Topic of Alzheimer's Disease Interview, October 2011

John Morris

Our Special Topics analysis on Alzheimer's Disease research over the past decade shows that the work of Dr. John C. Morris ranks at #10 by total paper and #13 by total cites, based on 203 papers cited a total of 9,323 times during the analysis period. Two of these papers are among the top 20 papers over the past decade and over the past two years.

In Essential Science IndicatorsSM from Thomson Reuters, Morris's record includes 375 papers, classified under Neuroscience & Behavior, Clinical Medicine, and Molecular Biology & Genetics, cited a total of 13,082 times between January 1, 2001 and June 30, 2011. Earlier this year, one of his papers was selected as a Fast-Breaking Paper in the field of Neuroscience & Behavior.

Morris is the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, Professor of Pathology and Immunology, Professor of Physical Therapy, and Professor of Occupational Therapy at Washington University in St. Louis, Missouri. He is also the Director and Principal Investigator of the Charles F. and Joanne Knight Alzheimer's Disease Research Center, Director of the Harvey A. and Dorismae Friedman Center for Aging, and Director of the Memory and Aging Project at Washington University School of Medicine.

Below, correspondent Gary Taubes talks with Morris about his highly cited Alzheimer's research.

SW: Alzheimer's disease research has gone from a small enterprise in the 1970s to an enormous industry today. How much of this do you attribute to the fact that the disease itself is increasing in prevalence or are there other factors as well?

Many factors are involved, such as the fact that we have much better criteria by which to diagnose the disorder now compared to the 1970s. Research in Alzheimer's disease was stimulated because it's a very interesting disease from a clinical perspective—why do people lose their memory and other cognitive abilities and develop behavioral abnormalities? Of course, it also is a devastating illness, not just for the patient but for the entire family. Both in terms of public health implications and the personal toll it exacts, it is a very costly illness and it's really important to try to understand it and develop effective therapies for that reason alone.

The main driver of the increased research efforts, however, is the rapidly aging population. The older adult population has increased greatly since the 1970s, not just in the US, but worldwide, and continues to grow. The "baby boomers" have just started turning 65 and are at the forefront of a tremendous demographic revolution that will result in the graying of America. The public health consequences will be enormous. Medicare already is strained and will be overwhelmed by the number of people in the next 10 to 15 years who reach the ages at which Alzheimer's disease is most prevalent. As they develop the illness, our capacity to care for them will be exceeded. There thus is a very strong imperative to devote all resources needed to conquer Alzheimer's.

SW: Do you consider the present level of funding to be commensurate with that imperative?

Funding for Alzheimer's disease research has increased compared to where it was in 1980s, which was minimal. Compared with other major diseases, however, it is woefully under-funded. For example, more people in the US die each year of Alzheimer's disease than do of breast cancer and prostate cancer combined, and yet the National Institutes of Health annually provides over $6 billion for cancer research while providing less that $500 million for Alzheimer's research. Such disparity is difficult to understand, especially in relation to the costs of Alzheimer's for our health care system.

The Alzheimer's Association recently released some sobering statistics. Of the top 10 causes of death in the United States, Alzheimer's disease is the only one for which we still lack any means to prevent or slow its progression or to cure it. Everybody with Alzheimer's dies. For every $100 the government spends on Alzheimer's research, it spends more than $25,000 caring for people with Alzheimer's disease. So it's extraordinarily under-funded for its costs.

All other leading causes of death in the US—stroke, prostate disease, breast cancer, heart disease, HIV—show a decreasing number of deaths each year for the last decade as risk factors are controlled and effective therapies are developed. The only major illness for which the number of deaths is steadily increasing each year is Alzheimer's, as truly effective treatments are lacking in the face of a population that is growing ever older.

SW: Twenty years of clinical trials; you've been doing them since the late 1980s, and still no drug to slow process?


SW: So all trials failed?

"Anti-amyloid and other therapies may yet be effective if we use them to intervene in the Alzheimer's disease process at the right time."

The current FDA-approved therapies do modestly benefit the symptoms of Alzheimer's disease, although ultimately they are ineffective in slowing the course of the disease.

SW: If you had Alzheimer's disease, would you take them?

How did you know that I was developing Alzheimer's?! Well, I still prescribe these drugs to my patients, so if nothing else were available, probably I would take them also. However, I very clearly indicate to patients and families that any benefit will be modest and temporary. The drugs will not slow the course of the disease. We need better treatments.

SW: How do you think researchers have to approach Alzheimer's disease to make the most progress? And how has this philosophy driven your own research?

At the risk of being over-simplistic, here's what I think: the Alzheimer's disease process occurs over many years, perhaps decades. The earliest stages of the disease begin with dysregulation of the amyloid-beta protein, such that it is overproduced or undercleared (or both). These abnormalities eventually result in the cerebral deposition of amyloid plaques and ultimately are marked by a cascade of pathological events that culminate in neurodegeneration.

This process may take place over many years in the absence of any detectable symptoms. Ultimately the accumulating pathologies reach a threshold where the integrity of neurons is compromised, and you begin to get dysfunction and ultimately death. When there is sufficient dysfunction of synapses and neurons, then brain function is impaired and the symptoms of Alzheimer's disease gradually become apparent.

By the time we're able to make the diagnosis, based on those symptoms, the brain already has been badly damaged. Perhaps it's not so surprising that the currently available drugs are not very beneficial, because we're trying to treat an already-damaged brain. Similarly, the recent failed trials of newer, putatively "disease-modifying" agents may relate to the fact that they were administered to persons with symptomatic Alzheimer's disease, when it likely is too late in the disease process to intervene successfully.

Our effort has been to try to understand when these brain changes occur in cognitively healthy people, years before the onset of symptoms. Ultimately, of course, we'd like to be able to successfully treat or even cure people with the symptoms of Alzheimer's dementia, but perhaps we'll realize much better results if we can intervene prior to symptoms, when the brain damage is minimal, in an effort to prevent symptoms from ever occurring.

SW: So by years before onset of symptoms, do you mean even before the mild cognitive impairment stage?

Yes, because mild cognitive impairment is the initial symptomatic stage of what later is recognized as Alzheimer disease dementia, it's too late. Over the past two decades, my colleague Joseph Price and I have demonstrated that even at this early symptomatic stage, the entorhinal cortex and certain hippocampal areas already have sustained neuronal loss of about 50%.

SW: So when isn't too late and how do you identify that point in the clinic?

"Of the top 10 causes of death in the United States, Alzheimer's disease is the only one for which we still lack any means to prevent or slow its progression or to cure it."

Early identification of the disease is appropriately where the Alzheimer's field is going—trying to characterize individuals with these early brain changes before there any detectable symptoms. We term this stage "preclinical Alzheimer disease." It only can be detected at present with biomarkers—pathobiologic features of the disease process.

The development and validation of Alzheimer's biomarkers is the focus of much of our research at the Knight Alzheimer Disease Research Center (ADRC) at Washington University and is being conducted by David Holtzman, Anne Fagan, Alison Goate, Mark Mintun, and several other investigators. We are particularly interested in identifying Alzheimer biomarkers in cognitively normal individuals, to determine if we can predict who is at an increased risk of developing Alzheimer dementia.

SW: What do you consider the most promising biomarkers based on the state of the research today?

The two most promising current molecular biomarkers of Alzheimer's disease are the proteins, amyloid-beta and tau, in the cerebrospinal fluid (CSF) and Pittsburgh compound B imaging of amyloid-beta deposits in the brain. The CSF assays of amyloid-beta and tau provide an Alzheimer's "signature" (amyloid-beta is reduced, tau is elevated) and can be detected in cognitively healthy people who are just beginning to develop Alzheimer brain changes.

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