Research for a New Age

In the beginning of this century, Dr. Alois Alzheimer, a psychiatrist, discovered two unusual things in the brain of a woman who had died with what he thought was a mental disorder. First, there were deposits of "senile plaques" of an unknown substance; second, some of the brain cells contained fibers that were twisted and tangled as if in a complex knot.

Neuritic plaques and neurofibrillary tangles, as they are now known, remain the hallmark of the disease that was named after Dr. Alzheimer, and today, they and other aspects of the disease are the focus of intense study. Much more is now known about Alzheimer's disease - some of its early signs, the brain regions and neurochemicals involved, and now even some of the genes that may be responsible. But much remains unknown; we do not yet have a viable treatment for, or know of a way to prevent, Alzheimer's disease. The most common cause of dementia among older people, Alzheimer's disease affects the parts of the brain that control thought, memory, and language. Early symptoms may be only mild forgetfulness and confusion, but eventually patients have difficulty carrying out routine, everyday tasks. In the later stages of the disease there may be behavioral changes, such as aimless wandering.

In the search for the causes of Alzheimer's disease, neuroscientists have delved into the chemical make-up of neuritic plaques (left) and neurofibrillary tangles (right).

What Causes Alzheimer's Disease ?
Since Dr. Alzheimer's discovery, plaques and tangles have been studied intensely in the search for the cause of Alzheimer's disease. Neuroscientists have found that plaques contain abnormal concentrations of a protein called beta amyloid, which begins as part of a larger protein, amyloid precursor protein or APP. One of the major questions facing Alzheimer's disease researchers now is why beta amyloid accumulates and how it affects cells in Alzheimer's disease.

Other abnormalities also seem to disrupt the brain's communication network. For instance, neurotransmitters, the chemicals that carry messages between nerve cells, are in reduced supply in the brains of Alzheimer's patients. Moreover, the connective points on nerve cells (synapses) decline in number and nerve cells themselves are lost. Why neurotransmitters and synapses decline and how nerve cells die are critical questions in Alzheimer's research.

More clues to Alzheimer's disease are emerging from studies of genes, the units of heredity located along chromosomes in all living things. On chromosome 21, NIA-supported investigators have pinpointed a gene that occurs in mutated forms in people with early-onset Alzheimer's disease. The gene carries the code for the APP and appears to be one link in the chain of events that leads to deposits of beta amyloid.

Recently a team of scientists from the University of Washington in Seattle and other institutions have found another defective gene in people with early-onset Alzheimer's in a region of chromosome 14. The early-onset forms of the disease, which appear in middle age, account for only a small percent of Alzheimer's cases. However, investigators can learn a great deal about the underlying mechanisms of Alzheimer's by studying its early-onset and late-onset forms, since the progress of early-onset and late-onset forms appears similar.

Some scientists believe that as many as half of all cases of Alzheimer's may have a genetic component. Supporting this hypothesis is the recent discovery of a gene on chromosome 19 that appears to be defective in many people with the more common, late - onset form of the disease. Researchers in North Carolina have found that one form of the apolipoprotein E4 (APOE4) gene is inherited at an increased rate in people who develop Alzheimer's disease late in life. Exactly how the gene contributes to development of the disease is not completely clear, but recent studies suggest that its product binds more quickly with other key proteins.

Non-genetic, environmental factors may also play a role in the disease. These include a range of suspects. One possibility is that an infectious agent, such as a virus, is involved. Another is that toxic environmental substances - metals or industrial chemicals, for instance - may play a role.

One study is searching for environmental causes by comparing a group of Alzheimer's patients in Nigeria to a group of African - Americans with Alzheimer's disease. If the study uncovers certain environmental factors common to both groups or if the prevalence of the disease correlates with the prevalence of specific risk factors in each group, researchers will have significant new leads.

Diagnosis
So far, a definitive diagnosis of Alzheimer's disease is possible only after death, when autopsies reveal the characteristic plaques and tangles. A probable diagnosis must be based on a patient's medical history, physical examination, and tests of mental ability. Important in diagnosis is ruling out a number of other conditions, some of which are treatable, which can also cause memory or other cognitive problems.

Although the early and accurate diagnosis of Alzheimer's disease is difficult, it is possible to get a reliable diagnosis in many specialized centers with 80-to-90-percent accuracy (when compared with autopsy findings). In addition, researchers have begun an intensive search for early signs of Alzheimer's to aid in diagnosis.

Some investigators, for example, are using brain imaging - positron emission tomography (PET) and magnetic resonance imaging (MRI) - to search for markers of Alzheimer's disease. Their goals include early diagnosis as well as understanding more about the patho-physiology and mechanisms of the disease. One study at NIA has found that a special method of analyzing PET data - called discriminant analysis - helped distinguish Alzheimer's patients from people of the same age who did not have the disease. The diagnosis in this study was made when the patient still had a normal PET scan as assessed by traditional analytic methods. This and other studies are making early detection and definitive diagnoses more and more feasible.

In another major effort, NIA-supported centers around the country - the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) - are working to establish uniform standards for more accurate, timely diagnoses.

Educating people about Alzheimer's disease is another major initiative at NIA. The Alzheimer's Disease Education and Referral Center (ADEAR) answers thousands of calls each year at its toll-free number (1-800-438-4380). In addition, training materials have been developed by nine Alzheimer Disease Centers and distributed by ADEAR. Videotapes and other materials are available for health professionals and caregivers, including professional home care providers, family members, and the clergy. Spanish language videotapes for the general public have also been developed.

Research on Alzheimer's disease is the Institute's highest priority. While the ultimate goal is to eliminate the disease, a short-term objective is to delay the onset of debilitating symptoms by 5 years. This alone could dramatically reduce the human suffering and financial burden imposed by Alzheimer's disease.

The Search for Treatments
Studies exploring possible treatments for Alzheimer's disease can be divided into two broad categories. One involves the search for new drugs. The other, a behavioral approach, is looking for ways to fend off the onset of disability in Alzheimer's patients through adjustments in daily activities and interactions.

Researchers around the country and at NIA laboratories in Bethesda are working with a variety of possible drugs; some may prevent cell atrophy and death, others may modify neurotransmitter levels or block the formation of beta amyloid. Vitamin E and a drug called deprenyl may help prevent oxidative damage to nerve cells (see "How Does Biochemistry Affect Aging"). One study is assessing their ability, alone and in combination, to delay the progression of the disease.

The vitamin E-deprenyl investigation is the first study in a special drug discovery and testing program developed by NIA. Launched in 1991, six Drug Discovery Groups around the country are developing innovative new drugs while a 32 site consortium will be testing these and other compounds in an effort to speed the movement of new medications from the laboratory to the patient.

The second way of looking at treatment for Alzheimer's disease - the low-tech, behavioral approach - focuses as much on family members as on the patients themselves. The rationale is this: Disability is partly a function of the interaction between caregivers and patients; if the people who care for Alzheimer's patients know how to cope with symptoms of the disease, they can reduce the degree of disability associated with it.

Alzheimer's patients, for example, can often perform everyday tasks, such as getting dressed, when the motions are demonstrated to them. They may not understand verbal directions though. If a caregiver knows this, he or she can routinely demonstrate activities and avoid the frustration and futility of verbally asking the patient to do something.

Research has shown that such coping strategies can help patients maintain their independence, reduce the burdens of caregiving, and delay institutionalization by up to 2 years.

Pilot studies at various sites in 1991 and 1992 began looking at a wide range of new and innovative methods for managing the behavioral symptoms associated with Alzheimer's disease. Symptoms such as feeding and dressing difficulties, wandering, and aggression are the focus of these studies, which emphasize non-drug approaches, especially those that will enhance a patient's ability to perform everyday activities. Large-scale clinical trials are expected to follow.

A Framework for Finding Answers Alzheimer's disease has been a paramount research issue at NIA since the Institute came into existence. To conquer the disease and to bring urgently needed support to patients, families, and researchers, NIA has built a nation-wide framework for research and assistance. The structure includes : Alzheimer's Disease Centers (ADCs).Located at major medical institutions around the country, the 28 ADCs are systematically collecting and studying longitudinal data on the disease; working to translate research advances into clinical services; and educating and training professionals. Satellite centers are recruiting minority participants to the Centers program. Drug Discovery Groups. Located at six research centers, these groups are designing, developing, and testing new drugs aimed at delaying, halting, or reversing the progress of Alzheimer's disease. These groups focus on drugs at the pre-clinical stage, before they are ready to be tested in people. Cooperative Study Units. These 32 research sites are conducting cooperative clinical studies on drugs to treat Alzheimer's disease. Alzheimer's Disease Education and Referral Center (ADEAR). This clearing house is a central source of information on all aspects of the disease (call 1-800-438-4380). Consortium to Establish a Registry for Alzheimer's Disease (CERAD). These centers are working to establish uniform standards for diagnosis to facilitate early and accurate detection of the disease and support research. National Cell Repository. This growing repository of blood samples from Alzheimer's disease patients facilitates the study of genetic defects associated with the disease.

PET scans from an NIA laboratory show the difference between a normal brain (left) and the brain of a person with Alzheimer's disease (right). Neuroscientists are learning how to use brain imaging techniques to obtain accurate and timely diagnoses of this form of dementia.

Caregiving
The people who care for Alzheimer's patients (usually wives, husbands, and children) are as much victims of the disease as those they care for. Caregivers watch their parents or spouses lose their memories, mental abilities, and eventually their sense of self - their very identities. As caregivers for loved ones, they must cope simultaneously with the pain of separation and the needs of the patient. The burdens of care, emotional and physical, are acute and have been well documented. Much research on Alzheimer's disease therefore focuses on the experiences and strategies of caregiving. What happens to caregivers over time? How do they cope with the problems that inevitably come with caregiving? Why are some more vulnerable than others to the stresses of caregiving?

What is known is that caregivers often suffer mental and physical disorders, family strains, career disruption, and financial hardships. One of the key factors in dealing with these problems is support from relatives and friends. Studies show that people who have a sense of social support are better able to cope with the stress of caring for someone with Alzheimer's disease.

Knowing this, researchers have started looking for ways to provide various kinds of social support. A study in Cleveland, for example, has tested a computer network that linked a small group of caregivers with each other and with professionals who could answer day-to-day questions about caregiving. For the caregivers the network became a support group without walls, one that they used at all hours. It helped them confront and resolve problems and gave them more confidence in their decisions. Research like this, although still in the early stages, promises to lighten the burdens of the people who devote their time to Alzheimer's patients.

Special Care Units During the 1980s many long-term care institutions began placing residents with dementia in separate sections called "special care units," where staff could focus specifically on their needs. The idea behind special care units is that people with dementia may benefit from specially designed programs and environments. Traditional nursing home settings and activities are not usually designed to deal with cognitive problems or the wandering and behavioral symptoms accompanying Alzheimer's disease. A national survey conducted for NIA in 1990-1991 found that there are now almost 1,500 dementia special care units in licensed nursing homes that have 30 beds or more. Approximately 10 percent of nursing homes now have at least one SCU, and this figure is expected to rise rapidly in the next few years. One of the major decisions facing people seeking nursing home care is whether or not to select a special care unit. Until recently, however, there were few facts on which to base this decision; the effectiveness of these units was unknown. Now, ten cooperative NIA projects nationwide are studying these special arrangements to learn whether and how they make a difference for people with Alzheimer's disease and their caregivers.

Alzheimer's disease affects about 4 million people in the United States. Now costing the country an estimated $90 billion annually in medical care, social services, and lost productivity, the disease will consume more and more resources unless it can be prevented or treated.

These ten cooperative studies, the first comprehensive look at SCUs nationwide, are also examining what defines a special care unit. Early findings from one of the studies show that SCUs are not the same but can be divided into three categories. Those with "minimal" special care provide no more than one modification to the environment of the program offered by a traditional nursing home. Those considered "enhanced" offer two or more additional features, such as family support and staff training. "Maximal" SCUs include a range of modifications, including admission criteria for patients. More information on the impact of SCUs on both patient care and caregivers is expected by the mid-1990s.