Alzheimer's disease (AD) is a progressive, currently irreversible brain disorder. People with AD gradually suffer memory loss and a decline in thinking abilities, as well as major personality changes. These losses in cognitive function are accompanied by pathologic changes in the brain, including the buildup of insoluble protein deposits called amyloid plaques and the development of neurofibrillary tangles, which are abnormal collections of twisted protein threads found inside nerve cells. Such changes result in death of brain cells and breakdown of the connections between them. AD advances gradually but inexorably, from early, mild forgetfulness to a severe loss of mental function called dementia. Eventually, people with AD become dependent on others for every aspect of their care. The risk of developing AD increases exponentially with age, but it is not a part of normal aging.
AD is the most common cause of dementia among people age 65 and older and is a major public health issue for the United States because of its enormous impact on individuals, families, the health care system, and society as a whole. Scientists estimate that as many as 4 million people currently suffer with the disease, and annual costs associated with AD are estimated to exceed $100 billion.5,6 As the population ages, the numbers of people with AD and costs associated with increased prevalence could rise significantly.
The following section on Alzheimer's disease and related neuroscience describes recent advances in seven areas of AD research: early diagnosis, normal age-related cognitive change, the role of environmental factors in the development of AD, new animal models that may provide insights into the etiology of AD, preclinical studies of new preventive and therapeutic agents, clinical trials to test new therapies that may delay or prevent development of the disease, and studies related to easing caregivers' burdens.
Early Diagnosis of AD
Early diagnosis of AD benefits affected individuals and their families, clinicians, and researchers. For patients and their families, a definitive early diagnosis provides an opportunity to plan and to pursue options for treatment and care while the patient can still take an active role in decisionmaking. For clinicians, accurate early diagnosis facilitates the selection of appropriate treatments, particularly as new interventions are developed to stop or slow progression of symptoms. And for researchers, earlier and more accurate diagnosis may simplify clinical studies of new therapies and preventive measures by allowing early intervention, when cognitive loss is less severe and, consequently, the response is more easily measured. Research suggests that the earliest AD pathology may begin to develop in the brain 10 to 20 years before clinical symptoms yield a diagnosis. Scientists have made tremendous progress looking for ways to diagnose AD in its pre-symptomatic or pre-clinical stages, including reliable, valid, and easily attainable biological markers that can identify cases very early in the course of disease when treatment may be more effective. Eventually, combinations of specific strategies to image the brain, along with genetic, clinical, and neuropsychological assessments may become the key to identifying people at very high risk of developing AD.
Identification of Risk Factor Genes for Late-Onset Alzheimer's Disease. Until 2001, just four of the approximately 30,000 genes in the human genome were conclusively known to affect the development of AD pathology. Three of these genes are associated with early onset AD, and only one is associated with the more common form of the disease, late-onset AD. Recent genetic studies suggest that as many as four additional and as yet unidentified genes may also be risk factors for late-onset AD. Finding new risk factor genes will help identify pathways affecting the development or progression of AD and may eventually lead to better predictors of the disease even before it is clinically apparent.
Imaging Small Regions of the Brain in Humans and Genetically Modified Mice. Functional imaging, or the visualization of processes within the body in "real time," is potentially a useful tool for detecting changes in the brain that may suggest early AD, or for identifying markers that may indicate the extent of the disease. However, barriers to its optimal use remain. Traditional functional magnetic resonance imaging (fMRI), a common method for visualizing brain structures, allows imaging of structures a few millimeters in size, but no smaller. This resolution is insufficient for evaluating smaller structures, such as subregions of the hippocampus that are important to learning and memory. In addition, it requires that the person being imaged respond to specific instructions, an impossibility for many with cognitive impairments. A "new" method of fMRI has been developed that permits evaluation of these minute areas of the brain. In addition, this method, which is dependent on oxygen use in the brain during rest, does not require the person being studied to perform a mental task, making it easier to use among cognitively-impaired people. Although fMRI is currently available only in a research setting, these techniques could eventually be used to identify persons with loss of neurons in very specific brain regions—for example, in identification of persons at risk for developing AD.
Loss of Neurons in a Particular Brain Region is Associated with Onset of Cognitive Decline in Older Individuals. Participants in a recent study had detailed clinical evaluations within 12 months of death and were categorized as having no cognitive impairment, mild cognitive impairment (MCI—often a precursor of AD), or mild to moderate AD. At autopsy, people with MCI all had significant losses of neurons in the entorhinal cortex (EC) of the brain relative to those with no cognitive impairment, and these losses were as extensive as those in the patients with full-blown AD. In a second study, autopsies were done on people whose cognitive status had been assessed shortly before their death. This study found extensive loss of neurons in the EC in people with very mild AD. In contrast, those with no loss of neurons in the EC, but with plaques and tangles in their brains (the hallmarks of AD), showed no cognitive decline. These findings indicate that elderly people with MCI and very mild AD already have dramatic decreases in the number of neurons in a particular region of the EC, and that it is the onset of neuronal loss, rather than the development of plaques and tangles alone, that is associated with the onset of AD-related memory loss. This suggests that the development of interventions that will prevent, delay, or slow the degeneration of these critical neurons may be extremely beneficial to people at risk of AD.
Normal Age-Related Cognitive Change
While most people remain alert and mentally able as they age, some age-related changes in memory, learning, and attention are normal. Improved characterization of normal cognitive function and underlying brain changes throughout life will help us distinguish normal from abnormal age-related cognitive changes. A better understanding of what is "normal" and what is not may aid the early diagnosis of AD; it could also alleviate the anxiety of people who observe modest but perceptible changes in cognitive function in themselves or a loved one and fear that such changes are the harbingers of a decline into dementia.
Some People with Mild Cognitive Impairment (MCI) Progress to Alzheimer's Disease and Some Don't: How To Tell. Researchers evaluated people with MCI and, based on clinical findings, categorized their MCI as representing probable AD-related dementia, "incipient" AD-related dementia, or "uncertain" AD-related dementia. These volunteers were reassessed annually for up to 9.5 years, and at that time all the volunteers whose clinical findings had indicated probable AD-related dementia had developed the clinical symptoms of AD. However, many in the less severe groups had not. In another study, investigators categorized people as having normal cognition or having MCI or probable AD, both at entry into the study and at a subsequent clinical evaluation 2-4 years later. Each participant had an MRI scan at baseline and at follow up. The size of the hippocampus decreased in all groups, most rapidly in AD patients, less rapidly in those with MCI, and least in the control group. Within the control and MCI groups, those who experienced decline in cognitive function over time had a significantly greater decrease in hippocampal size than those who remained clinically stable. Previous studies have shown that baseline hippocampal volume can provide predictive information about which patients with MCI will decline to AD versus which will remain stable; together with this baseline information, serial measurements of hippocampal size through non-invasive MRIs may be a useful tool in the future for identifying people with MCI who will and won't progress to AD.
Early Life/Environmental Factors and AD
Environment May Protect Against Cognitive Decline and Alzheimer's Disease. Investigators hypothesized that recreational activities would be an excellent measure of mental activity, as these are less strongly influenced by economic and social factors than other risk factors for AD, such as the number of years of formal education. They recorded the extent to which 500 AD patients and age-matched healthy people had participated in recreational activities over their adult life. Patients with AD were found to have been much less active than healthy people of similar background in terms of both diversity and intensity of recreational activities engaged in during early and middle adulthood. These differences were not related to differing educational or income levels, age, or gender. People who were relatively inactive in midlife had a two and a half fold increased risk of developing AD. In a separate study, the relationship of social ties and support to patterns of cognitive aging over a 7.5 year period was examined in 1200 high functioning, community-dwelling adults aged 70-79. The results showed that greater baseline emotional support was a significant predictor of better-maintained cognitive function at the 7.5-year follow-up, controlling for known socio-demographic, behavioral, psychological, and health status predictors of cognitive aging.
Animal Models of Neurodegenerative Disease
Animal models that mimic human disease are central to research for many reasons. Animals and humans share many genetic and physiologic features, so experimental results obtained in animals can frequently (although not always) be extrapolated to humans. It is much easier to create specific genetic mutations and observe their effects in animals than to search for them in humans, and because the lifespan of most animals is relatively short, it is easier to observe the effects of those mutations over several generations. Recently, scientists have created several new models for research on neurodegenerative diseases, including AD.
The TAPP Mouse: The First Link Between Plaque and Tangle Formation. The neurofibrillary tangles (NFTs) that characterize AD are composed primarily of a form of the protein called tau. In addition to NFTs, another key feature of AD is the deposition of beta-amyloid (Aß) in insoluble amyloid plaques outside brain cells. The fragment is formed by clipping it out of the much larger amyloid precursor protein (APP). Although many scientists believe that excess production of Aß is a root cause of AD, it is still unclear how this causes pathology. In particular, scientists do not understand whether excess production of Aß leads to development of NFTs.
Now, a new mouse model may help us answer this question. A number of transgenic mouse models of AD have been developed by inserting human mutated APP genes into mice. Amyloid plaques, but not NFTs, form in these mice. A model for pathology of the tau gene has also been developed, but the NFTs in these mice do not usually form in areas of the brain that are vulnerable to AD. Scientists recently crossbred the tau mutant mice with the APP mutant mice to produce a new model, the TAPP mouse. The TAPP mice produce amyloid plaques; they also produce NFTs in regions of the brain that are vulnerable to AD, suggesting that APP or Aß peptide can influence the regional formation of NFTs. This is the first animal model in which the elusive connection between amyloid pathology and tangle formation can be investigated.
This improved animal model for AD may also be critical for success in developing therapies against NFT formation and the death of neurons in AD brain.
Pesticide Creates a Rat Model of Parkinson's Disease. Parkinson's disease is a progressive neurodegenerative disorder characterized by selective death of neurons that make the neurotransmitter dopamine in a region of the brain called the substantia nigra. In an effort to develop a new model of Parkinson's disease, scientists exposed rats to rotenone, a common pesticide. Exposed rats showed pathological changes characteristic of Parkinson's disease, as well as motor behavior abnormalities, such as rigidity and decreased motor activity, that are frequently seen in Parkinson's disease patients. This new model of Parkinson's disease will be useful in designing and testing new therapeutic interventions, as well as further identifying environmental exposures that may be risk factors for developing the disease.
There are currently no effective, generally useful treatments for Alzheimer's disease; i.e., a treatment that works on large numbers of patients, that maintains its effectiveness for a long period, that works in both early and late stages of the disease, that improves functioning of patients in activities of daily living as well as on sensitive neuropsychological measurements, and that has no serious side effects. In addition, none of the treatments presently approved for AD alter the progressive underlying pathology of the disease. One way to treat the disease successfully may be to interfere with early pathological changes in the brain, including the development of amyloid deposits and the formation of neurofibrillary tangles. A number of promising approaches, many of them targeted at the reduction of amyloid plaques, are currently being developed and tested in various model systems. If these approaches prove safe and effective in animals, studies in humans could follow.
Promising Immune Treatment for AD. Using mice that were genetically engineered to produce Aß and develop AD-like pathology in the brain, investigators found that treatment with an antibody that recognizes Aß peptide results in clearance of Aß plaques from the brain. Based on these findings, the investigators hypothesize that treatment with antibodies may be a useful and important approach for the treatment and prevention of AD and other neurodegenerative diseases.
Phenserine Regulates Translation of $-Amyloid Peptide Message: A New Target for Alzheimer's Disease Drug Development. AD's tell-tale amyloid $-peptide (Ab) plaques are formed when a larger protein called amyloid precursor protein (APP) breaks down. Researchers are working to develop agents that reduce APP expression. In a recent study, investigators conducted laboratory tests of a drug called phenserine, originally developed to increase levels of the chemical messenger acetylcholine, which is depleted in the brains of people with AD. They discovered that phenserine inhibits APP formation in cells through a mechanism independent of acetylcholine. Current research is directed towards the design, synthesis, and development of agents that optimally and safely regulate APP and Aß levels with the aim of slowing or halting the molecular events that lead to AD.
Statins May Reduce the Risk of AD. Evidence increasingly suggests that high levels of cholesterol may have a role in the development of AD. Two recent studies found that the use of statins, the most common type of cholesterol-lowering drugs, may lower the risk of developing AD. In a third study, transgenic mice fed a high cholesterol diet had much higher levels of blood cholesterol and the mean number of amyloid deposits in their brains (a hallmark of AD) was 65 percent higher than those on the normal diet. Taken together, these results suggest that statins—or dietary interventions—may be effective treatments or preventives for AD.
Imaging Clearance of Plaques by Immunotherapy in Living Mice. Researchers have developed a powerful new imaging technique, multiphoton microscopy, that enables them to view changes in the brain caused by AD and subsequent changes induced by treatment. Multiphoton microscopy provides a resolving power 100 times greater than that of other noninvasive imaging techniques, and allows sufficient resolution to view very small structures and lesions in the brain such as plaques. In a recent experiment, antibodies specific for amyloid and labeled with a fluorescent dye were placed directly onto the surface of brains of anesthetized mice who had developed AD-like plaques. Using the new imaging technique, scientists noted reversal of existing amyloid-$ deposits in the brain within 3 days of treatment with the antibodies. These findings demonstrate the potential effectiveness of antibody-mediated passive immunization for the removal of plaques from the brain.
BACE1 is the Major Beta-Secretase for Generation of Amyloid-beta Peptides in Mouse Brain. A major focus of study has been the process by which the amyloid precursor protein (APP) is clipped apart by enzymes to release Ab fragments, which are then deposited in the brain as AD's characteristic plaques. A recently discovered enzyme that helps clip Ab out of the APP protein was given the name b-secretase. In order to identify the enzyme that is responsible for production of Aß in the brain, scientists developed a mouse model in which the gene for the BACE1 enzyme, a candidate for the active b-secretase, was selectively eliminated to see whether removing it would interfere with the clipping of APP to produce amyloid. Indeed, Aß peptides were no longer produced in brain cell cultures made from the "knockout" mice, suggesting that BACE1 is responsible for the cleavage of APP into Aß in the mouse brain. These findings will help in design of drugs to inhibit b-secretase activity, in hope of slowing plaque production. Furthermore, because the mice in which the BACE1 gene has been eliminated seem to develop normally, it may be possible to develop BACE1 inhibitors that interfere with Aß deposition without negative effects on other metabolic pathways in brain or other tissues.
Today, the few FDA-approved drug treatments for AD maintain cognitive function in AD patients in only a subset of patients and for only a limited time. However, an estimated 50 to 60 compounds are presently or will soon be tested in human AD clinical trials. These studies are sponsored by a number of sources, including the NIA, other NIH institutes, and the private sector, primarily pharmaceutical companies. Compounds now under scrutiny focus on three major areas of treatment: short-term maintenance of cognitive function; slowing the progress of the disease, delaying AD's onset, or preventing the disease altogether; and managing behavioral problems associated with AD.
Interest is currently focusing on compounds that directly target disease-related pathologies. A rapidly evolving research focus lies in prevention trials, and a number are underway to test the effectiveness of therapies in people without symptoms or who have only slight memory problems. Recruitment is now complete for the first NIH AD prevention trial, which will take place at more than 70 sites across the U. S. This trial compares the effects of vitamin E and donepezil (brand name Aricept) in preventing the development of AD in people diagnosed with mild cognitive impairment, a population at high risk for developing AD. Further examination of estrogen and studies of various classes of anti-inflammatory drugs and antioxidants are also ongoing, and as scientists test these currently available medications, the next generation of drugs is being developed, targeting specific abnormal cellular pathways uncovered by recent discoveries, including plaque and tangle formation and death of brain cells. Prevention trials are among the most costly of research projects, but, if successful, the payoff in terms of reduced disease and disability will be significant.
Caregiving of AD Patients
Most of the approximately 4 million Americans with Alzheimer's today are cared for outside the institutional setting by an adult child or in-law, a spouse, another relative, or a friend. Caregivers frequently experience significant emotional stress, physical strain, and financial burdens, yet they often do not receive adequate support. Several recent studies have explored the problems faced by caregivers of AD patients, as well as possible interventions to reduce their burdens.
Depression and Agitation in Alzheimer's Disease: Effects on Caregivers. Previous research has examined the factors contributing to stress and depression in caregivers of an AD family member. A recent study found that the greater the level of depression in the patient, the greater the level of depression in the caregiver. Wives of AD patients and caregivers in poor health themselves were at particular risk for depression. This study demonstrates that the well-being of the caregiver and care recipient are closely related. The findings also support interventions for caregivers early in the family member's illness.
Women Caring for a Family Member with Dementia Can Benefit from an Exercise or Nutrition Program. A one-year study involved 100 women age 49 to 82 years who were sedentary, free of cardiovascular disease, and caring for a relative with dementia. Participants received either a home-based, telephone-supervised moderate-intensity exercise training or nutrition education program. Exercise consisted of brisk walking for four 30-to 40-minute sessions per week. Compared with the nutrition education group, caregivers who exercised showed significant improvements in physical activity levels, stress-induced blood pressure reactions, and sleep quality. The nutrition group reported significant reductions in percentages of total calories from fats compared to exercisers. Both groups reported significant improvements in psychological distress, including depressive symptoms and self-rated stress level.
Selected Future Research Directions in AD and the Neuroscience of Aging
National Cell Repository Expansion. To facilitate the identification of AD risk factor genes, NIA is planning the expansion of its National Cell Repository. A national resource for research on AD, the Repository was created to collect DNA, cells, and information from families with multiple affected individuals with AD. Its activities include the production of a catalog of cell lines and DNA samples that are available for qualified scientists to study. Because most researchers rely on extended families, sibling pairs, or case-control studies to look for genes, the goal of the expanded Repository will be to develop cell lines and collect data from persons identified through the Alzheimer's Centers who fall within one of the three categories. While previous research has emphasized the identification of genes associated with the familial form of the disease, this expansion will allow us to more rapidly identify the underlying genetic mechanisms of the more common late-onset form of AD.
Alzheimer's Disease Cooperative Study. NIA's major AD clinical trials effort is the Alzheimer's Disease Cooperative Study (ADCS), a consortium of 83 medical research centers in the U. S. and Canada. Established in 1991, the ADCS conducts clinical trials on compounds in which large pharmaceutical companies are generally not interested, including drugs that were patented and marketed for another use but might be useful for treatment of AD, or novel compounds from investigators with inadequate resources for clinical trials. During its first decade, the ADCS established a research infrastructure to carry out clinical trials for promising new therapies for AD, developed new and more reliable ways to evaluate patients enrolled in these and other studies, and initiated a number of clinical trials. The latest 5-year award will allow that work to continue and will move AD treatment research in new directions, including the study of a cholesterol-lowering statin drug, an antioxidant, and a high-dose vitamin regimen. Studies of interventions to combat behavioral and other manifestations of AD, including agitation and sleep disturbances, are also ongoing. In addition, the ADCS will develop and refine evaluation tools and methodologies for AD prevention research.
Extending Caregiving Research to Clinical Practice. NIA will expand the research scope and objectives of its Resources for Enhancing Alzheimer's Caregiver Health (REACH) program to extend promising caregiver interventions to the clinical setting. The REACH program is a large-scale, coordinated study to examine the effectiveness of social, behavioral, environmental and technological interventions for reducing caregiving burdens of caring for persons with dementia. In the first phase of the program (1995-2001), investigators at six sites tested a series of interventions. Now, in Phase II, the outcomes of these exploratory interventions will be analyzed and used to develop intervention strategies for further evaluation across multiple sites. Of particular importance is the program's emphasis on evaluating these interventions in diverse racial and ethnic populations.
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