This is an "incredibly exciting time" for research in Alzheimer's disease (AD), stated Marcelle Morrison-Bogorad, associate director of the National Institute on Aging (NIA) Neuroscience and Neuropsychology of Aging Program. She said that after a decade of research advances, for example, the first wave of clinical trials aimed at preventing and halting the progression of the disease are about to begin.

The new trials, she explained, can "point to where the disease actually starts in particular people." She added, "In just a couple years, any one of these studies could have a tremendous impact." Promising new areas of research involve such diverse elements as vitamin e, estrogen replacement therapy, transgenic "designer" mice and the role of enhanced brain capacity.

The Alzheimer's Association, based in Chicago, estimates that the average lifetime cost of care per Alzheimer's patient is $174,000, making the affliction the third most expensive in the United States, following heart disease and cancer.

The NIA's new "Progress Report on Alzheimer's Disease: 1998" states that the annual economic toll of the illness in this country "in terms of healthcare expenses and lost wages of both patients and their caregivers is estimated at $80 to $100 billion." The U.S. Census Bureau estimates that people with AD will more than double to about 8.5 million by 2030.

The ailment commonly begins with puzzling behavior: A person may easily forget events that just occurred or become disoriented in familiar places. As the disease progresses, the person grows increasingly frustrated, often developing compulsive or ritualistic behavior. In the late stages, the patient is unable to comprehend simple sentences, doesn't recognize family or friends and cannot read or write. By the end, Alzheimer's patients are usually mute, bedridden and incontinent.

AD can take anywhere from two to 20 years to progress, with most patients living about eight years following onset. While some patients' cognitive skills degenerate steadily over time, others may reach a plateau for several years and then continue to decline slowly.

Scientists have identified two distinct forms of the illness: Familial or early-onset Alzheimer's strikes people in their 40s and 50s, is often linked to inherited genes, is more severe and tends to progress faster towards death than late-onset AD. The late-developing version accounts for more than 90% of the four million Americans estimated to have the disease, according to Zaven Khachaturian, research director of the Alzheimer's Association.

In 1998, the federal government is spending $349 million on research to identify risk factors, accurately diagnose the disease, treat AD and eventually prevent it. According to Bruce Reed, associate director of the University of California­Davis Alzheimer's Disease Center in Martinez, Calif., the chief risk factor is age. The prevalence of Alzheimer's increases sharply past age 60, when about 2% of people are diagnosed, and doubles every five years, he said. The rate at age 85 is 32%.

The NIA's latest "Progress Report" states that Alzheimer's "is caused by a complex cascade of events that take place inside the brain." Genetic factors are important, but there "is no single cause" for AD.

One "important new development" in 1998 cited by the report is a finding by researchers at Columbia University in New York City "that some unknown genetic or environmental factors are increasing the risk for AD among African Americans and at least some Hispanics." Part of the study looked at New Yorkers not carrying a variant gene called the apolipoprotein eepsilon4 (apoe e4) allele that is often associated with late-onset Alzheimer's. African Americans without this gene were four times more likely than whites to develop the illness by age 90; the risk for Hispanics was double that of whites. The NIA reports that research on various ethnic, racial and social groups may reveal risk factors suggesting "new theories about mechanisms involved in setting up and/or triggering the disease process."

In another development, scientists are designing transgenically engineered mice to study the complex relationships between genetic aberrations found in humans and the symptoms of AD. Since 1996, researchers have been creating these designer mice by surgically inserting in their brains human genes containing mutations of amyloid precursor protein, a substance found in deposits called "plaques" that develop in the brains of Alzheimer's patients. These animal models are being used to examine numerous mysteries associated with the disease, such as the roles of the apoe e4gene variant, what causes inflammation in AD brains and the reasons why particular plaques are deposited in these brains.

The hunt for genes associated with Alzheimer's is also convoluted. The Aug. 19, 1998, issue of the Journal of the American Medical Association revealed contradictory findings about the link of late-onset Alzheimer's to clusters of genes on chromosome 12. For the disease's early-onset version, there is a known association with defective genes found on chromosomes 1, 14 and 21. New evidence indicates a connection to defective genes on chromosome 19.

NIA's Morrison-Bogorad noted, though, that "identifying the genetic risk factors may be the easiest part of the puzzle. It's incredibly complicated for us to figure out what a gene does. One outcome in identifying the genes is that we will have the ability to predict with a degree of certainty who might get the disease and when. This will make it easier for us to study the disease in the earlier stages. Even though it's interesting to analyze the genes, our main goal is to prevent Alzheimer's altogether."

Despite all the advances in studying Alzheimer's, the only definitive diagnosis comes upon autopsy, when pathologists examine the brain for the presence of destructive plaques and tangles. However, efforts to develop accurate diagnostic methods have progressed considerably in the last decade. Although no blood test or simple diagnostic tool is currently available, Bruce Reed of UC Davis said skilled clinicians at specialized Alzheimer's centers can typically diagnosis Alzheimer's with 90% or greater accuracy through physical exams, memory and psychological tests and evaluation of family history.

The accuracy rate is somewhat lower for individual physicians. Morrison-Bogorad commented, "Our challenge is to educate the family practitioner to make them aware of when they should be concerned about possible dementia. There are still some clinicians who believe that forgetfulness and other signs are part of normal aging."

Also important, Morrison-Bogorad said, is identifying those with mild cognitive impairment, a group far more likely to develop AD within a few years than people without such problems. She added, "Alzheimer's probably starts 10 to 20 years before the onset of any clinical symptoms."

Among the treatments being studied for protection against AD are estrogen replacement therapy; anti-inflammatory agents like ibuprofen; and antioxidants, such as Gingko biloba, vitamin E and selegiline. All of these substances show signs of reducing the incidence of the illness. Aricept and Cognex, two drugs released in recent years, do not retard the progression of Alzheimer's but can maintain patients at a particular level for up to a year, according to Morrison-Bogorad.

Recent progress in identifying those with mild cognitive impairment is making it possible to treat them with drugs that may halt the advancement of AD before the onset of clinical symptoms, she said. The first studies comparing the effectiveness of vitamin eand Aricept for people with mild cognitive impairment will begin at the end of 1998, Morrison-Bogorad said. "This could do just what we want it to do, which is to retard the progression of Alzheimer's."

Other studies are evaluating how lifestyle changes may protect people from Alzheimer's by increasing the reserve capacity of the brain. Bruce Reed said he was not a proponent of the "use it or lose it" theory until recently. "Studies suggest that people in certain intellectually demanding occupations seem to have a lower risk of getting Alzheimer's. This is epidemiological evidence, and it's still not clear what the scientific mechanism is, but it does raise the possibility that those who have continuous mental demands may have some protection."

Morrison-Bogorad noted several studies examining the role of education, nutrition and physical exercise in increasing the number of connections between brain cells: "It's quite possible that when Alzheimer's strikes a person, if there are a lot of healthy brain connections, then there are more brain reserves. It could be that the disease develops without the patient suffering the consequences of Alzheimer's."

Reed observed, "The important thing to realize about Alzheimer's is that it is a multifactorial disease. As we learn more about the genetic factors, we will begin to understand the environmental and lifestyle factors better. Alzheimer's may prove to be like coronary artery disease, where there are clear genetic factors and also environmental and lifestyle factors that make a difference."

The National Institute on Aging's "Progress Report on Alzheimer's Disease: 1998," is available at www.alzheimers.org/adear.

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