Alzheimer's Disease Begins Before Symptoms Appear

"This means that, to develop truly effective therapies, we must learn how to stop the brain lesions before they accumulate to the point where they interfere with mental function," says John C. Morris, M.D., the Harvey A. and Dorismae Hacker Friedman Professor of Neurology at Washington University School of Medicine in St. Louis.

Because the risk for developing Alzheimer's increases dramatically with age, such a goal could have a major impact on the quality of life and health-care costs of America's aging population. The U.S. Census Bureau projects that 79 million Americans will be 65 or older by 2050 (up from 35 million in 2000) and that almost 18 million Americans will be 85 or older (up from 4 million in 2000).

Morris and lead author Joseph L. Price, Ph.D., professor of anatomy and neurobiology, present their evidence for preclinical Alzheimer's disease in the March issue of Annals of Neurology.

Their study was possible because the medical school's Alzheimer's Disease Research Center, which Morris co-directs, has monitored both healthy individuals and people with Alzheimer's since 1984. The center also developed a sensitive diagnostic tool - the Clinical Dementia Rating (CDR) scale - that can distinguish healthy aging from even the very early stages of dementia. So through very careful clinical assessments, researchers had determined the mental status of each member of the current study. Then Price was able to examine brain tissue from the same people after death. "I don't think there's any other group in the world that has such a well-defined set of subjects," Price says.

Studying the tissue samples, Price focused on parts of the brain that Alzheimer's affects most, such as a seahorse-shaped structure called the hippocampus. Using both traditional silver staining methods and antibodies, he looked for two signs of brain disease: beta-amyloid plaques and neurofibrillary tangles. Beta-amyloid forms when a large brain protein is cut in the wrong place. A tangle is a nerve cell containing twisted and knotted filaments. These filaments contain an abnormal form of a protein called tau.

All of the healthy and demented subjects - a total of 62 - had at least a few tangles in the brain, especially in the hippocampus and related structures, and the number increased exponentially with age. "It seems to me that tangles are a normal part of aging," Price says. "And though the nerve cells that have them clearly are sick,tangle formation usually is slow and therefore affects a relatively small number of cells. So it probably causes few difficulties by itself."

When Price looked for amyloid plaques, he found no splotches of the abnormal protein in most of the healthy subjects. "We even had a woman who had reached age 88 without developing these lesions in the brain," Morris says. "This is further evidence that there is such a thing as truly healthy aging and that Alzheimer's disease is not inevitable - at least to the age limit we have studied."

Amyloid plaques were abundant in the brains of the people diagnosed with Alzheimer's disease, especially in eight very demented subjects who got the maximum score on the CDR. Price even found numerous plaques in the brains of the 15 people who had displayed only the mildest symptoms of dementia. "So at the earliest clinically detectable stage, the disease is fairly well advanced inside the brain," Price says. "Presumably, the brain has a fair amount of reserve capacity and can suffer a certain amount of insult."

The people with plaques also had many more tangles than those with no pathological signs of Alzheimer's, Price determined. "So people with plaques and tangles have Alzheimer's," Morris says, "whereas people with no plaques and few tangles do not."

The researchers' most important finding was that seven of the 39 subjects with no clinically detectable dementia had both plaques and an unhealthy dose of tangles. "Even with our very sensitive detection methods, we could find no evidence of dementia symptoms in these seven subjects," Morris says. "So we think they had preclinical Alzheimer's disease."

This finding parallels observations of Down syndrome, where plaques and tangles develop during the 20s and 30s and dementia inevitably follows within a couple of decades.

As well as providing the first evidence for preclinical Alzheimer's in seemingly normal people, the study may help quell a longstanding debate. Some researchers argue that plaques are key to Alzheimer's, whereas others favor tangles. But Price and Morris's study supports the idea that both types of lesion play a role. As plaques condense, any nerve cell "arms" that run through them swell up and become contorted. Using antibodies, Price showed that these abnormal structures contain filaments of tau. "So at the stage where you get a large number of plaques, you also see what appears to be an interaction between amyloid deposition and filament formation," he says.

Because the subjects with amyloid plaques had many more tangles than the healthy subjects but had them in the same parts of the brain, Price argues for cause-and-effect. "My interpretation is that beta-amyloid greatly accelerates tangle formation," he says. "The result is the devastating condition called Alzheimer's disease."

Price and Morris hope their work will spur drug developers to look for compounds that might prevent beta-amyloid from forming or from damaging nerve cells. They also hope radiologists will find ways to detect amyloid lesions at the preclinical stage, so such drugs could be taken early. "It might be possible to tag this abnormal protein with a marker that shows up with PET (positron emission tomography) or MRI (magnetic resonance imaging) Price says.

But what can people at risk for Alzheimer's do right now? Should they take vitamin E or gingko extract? "As long as there are no side effects and people can afford them, that may not be harmful," Morris says. "But whether those supplements are effective or not is unknown. We just don't have good information."

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Funding from the National Institute on Aging supported this research.

Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Annals of Neurology, vol. 45(3), March 1999.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.