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Alzheimer's Disease and the Neuroscience of Aging

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 change. These losses in cognitive function are accompanied by pathologic changes in the brain, includingthe build up of amyloid plaques and tau-containing neurofibrillary tangles, which result in death of brain cells and breakdown of the connections between them. AD advances by stages, from early, mild forgetfulness to a severe loss of mental function called dementia. Eventually, all reasoning ability is lost and 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.

The most common cause of dementia among people age 65 and older, AD is a major 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,5 and annual costs associated with AD are estimated to exceed $100 billion.6

As the population ages, it is projected that the numbers of people with AD and costs associated with increased prevalence could rise significantly.

The following section on Alzheimer's disease and neuroscience describes recent research advances in 5 areas of AD research—improvements in early diagnosis, defining normal age-related cognitive change, the role of environmental factors in development of AD, pre-clinical research on animal models to better characterize what may be happening in the brain during the course of AD, and clinical trials to test new therapies that may delay or even prevent development of the disease. The discussion on AD begins with a Story of Discovery on exciting developments leading to potential new therapies to attack the formation of amyloid plaques in the brain, including a possible vaccine. It concludes with a look at future directions for research, outlining the NIA's AD Prevention Initiative and studies seeking to find how to maintain the health of the brain with age.

Story of Discovery: Alzheimer's Disease Amyloid—Discovery of Molecular Processes Leads to New Therapeutic Approaches

Alois Alzheimer first described the plaques and tangles found in the brains of dementia patients in 1906. He had a patient who became demented in her 50s and died at age 55. Upon her death, Dr. Alzheimer performed an autopsy and found plaques and tangles in her brain tissue. For the next 60 years, scientists and clinicians thought that this form of early-onset dementia was very different from the dementia of old age. Indeed, dementia in older people was considered an almost inevitable part of aging. Then, in the 1970s, scientists discovered that older people with dementia often had exactly the same plaques and tangles in their brains as those described so clearly by Dr. Alzheimer.

Two abnormal structures in the brain are hallmarks of AD: amyloid plaques and neurofibrillary tangles. Plaques are dense deposits of protein and cellular material outside and around the brain's nerve cells. Tangles are twisted fibers that build up inside the nerve cells. Though scientists have known about plaques and tangles since Dr. Alzheimer's time, the intensive research efforts of the last two decades have revealed much about their composition, how they form, and their possible roles in the development of AD. The deposition of amyloid in the form of plaques is thought by many to trigger the cascade of events leading to AD pathology. Amyloid now is believed to be a critical target for eventual treatment. In both the public and the private sector, important efforts are underway to expand understanding of the amyloid deposition process while, at the same time, developing potential therapies based on current knowledge.

The unfolding story of amyloid, from hypothesis to potential breakthroughs in treatment, illustrates the dynamics of AD research and the synergy of public and private efforts to challenge this dreaded disease. In the 1980s, amyloid from the brain tissue of an AD patient was found to consist of a short protein fragment (a peptide). The likely DNA sequence coding for this amyloid peptide was predicted from its amino acid sequence and was then used as a molecular probe to search the 100,000 or so genes present in human DNA for the specific gene that produces amyloid. Several research groups found the gene, naming it the amyloid precursor protein (APP) gene. By the mid 1990s, three mutated genes causing major forms of inherited early-onset AD were identified: the APP gene itself, as well as genes named presenilin 1 and presenilin 2.

These discoveries initiated the modern era of AD research. Building on this basic research, primarily funded by NIH, scientists from all sectors zeroed in on the proteins made by these genes and their metabolic pathways, uncovering major biological clues to the sequence of events in the development of AD pathology. Understanding these pathways and gene products now allows the design of treatments targeted to the early events that underlie the pathology of AD. By interfering with the disease early on, this approach aims to arrest disease before it affects brain function and causes clinical symptoms.

A major advance was developing the first animal models of AD by inserting mutated human APP genes into mouse eggs and observing formation of amyloid plaques and other AD-like pathologies in the brains of these "transgenic" mice as they age. Since then, numerous transgenic models have been developed, allowing scientists to understand better how a complex array of intercellular pathways can interact to affect the production of AD plaques. These transgenic animal models are also beginning to provide a means of testing the efficacy of different treatments on reducing build up of plaques and on cognitive function.

Much research has focused on the possibility that amyloid may play a causative role in AD. Interfering with amyloid production or its aggregation into plaques may represent an approach to treating or preventing disease. Using both transgenic animal models and experiments in tissue culture, scientists now understand more about how amyloid is snipped out of APP, how amyloid aggregates into plaques, and how plaques might lead to the brain destruction of later stages of AD. Importantly, these discoveries are also facilitating discovery of ways in which plaque production may be slowed. Many leads are being pursued, including development of compounds to halt amyloid deposition at various steps along the pathway, or to prevent downstream harmful effects of amyloid deposits.

During the past year, NIH- and industry-funded scientists provided evidence that one of the proteins (enzymes) that snip amyloid out of APP may actually be identical to one of the genes, presenilin 1, whose mutations can cause inherited early onset AD. Scientists from several pharmaceutical companies also identified the other snipping enzyme. Now, more effective drugs to inhibit production of amyloid by these enzymes can be developed. Prototypes are being developed and tested for safety in industry-sponsored trials.

Recent papers describing a potential vaccine for preventing plaque formation have excited AD researchers. Testing this unconventional approach in transgenic mice that make human amyloid in brain tissue, one industry scientist found that injecting an amyloid solution into the mice provoked an immune reaction to the injected amyloid. Further, this study indicated, if mice were immunized repeatedly for many months, plaque development was all but halted. This breakthrough has been successfully replicated in different strains of transgenic mice by a number of NIH-funded laboratories. One recent report shows that nasal inhalation of the amyloid can also retard plaque production, in a route of delivery that may be better tolerated than repetitive injections. A report at the recent Alzheimer's Disease World Congress went even further, demonstrating that vaccination prevented cognitive decline in a transgenic mouse model.

Though very preliminary safety testing of the injected vaccine in humans has shown promise for its tolerability so far, it is much too soon to know if such a vaccine could work in humans as it has in mice. Both technical and theoretical hurdles need to be overcome. Would there be harmful side effects? Preliminary industry-sponsored human safety trials have shown no harmful effects of one vaccine injection and trials looking at effects of multiple injections are ongoing. Will an intervention that prevents plaque formation indeed have an effect on the neuronal death and symptoms of AD? Ultimately, clinical trials in humans will provide answers to these questions.

Early Diagnosis of AD

The earlier an accurate diagnosis of AD is made, the better. This holds true for everyone involved, from individuals and their families to clinicians and researchers. For patients and their families, a definitive diagnosis early on provides an opportunity to plan and to pursue options for treatment and care while the patient can still take an active role in decision making. Clinicians increasingly will need effective tools for identifying people in the early stages of the disease, as new interventions are developed to stop or slow progression of symptoms. In research, earlier and more accurate diagnosis will simplify and improve recruitment for clinical trials to test new, preventive drugs.

Research suggests that earliest AD pathology may begin to develop in the brain 10 to 20 years before clinical symptoms yield a diagnosis. Scientists have been actively looking for ways to diagnose AD in its presymptomatic or preclinical stages, and enormous progress has been made in this area. Described below are recent advances in imaging and clinical assessment that will help to identify patients in very early stages of AD. Eventually, combinations of specific imaging strategies with genetic, clinical, and neuropsychological assessments may become the key to identifying people at very high risk of developing AD.

Use of Positron Emission Tomography (PET) Imaging To Identify Presymptomatic Decline in Brain Function. The gene APOE-ε4 has been associated with increased risk of AD. Scientists have been increasingly interested in whether the brain and brain function of people who carry one or more copies of APOE-ε4 are different from those of individuals who do not carry the gene to ultimately see whether AD-like symptoms can be identified before the disease is diagnosed clinically. PET imaging can provide information on metabolic function of specific brain regions. Recent studies using PET show that, despite similarities in age, gender, education, family history of dementia, and baseline performance on memory and other cognitive tasks, individuals with the APOE-ε4 gene(s) have reduced cerebral glucose metabolism in several areas of the brain compared to people who have none. The differences in metabolism were even greater two years after initial evaluation. Lower baseline metabolism at the start of the study predicted a greater cognitive decline in subjects at genetic risk for AD. Though longer follow-up studies are needed to determine how many of the APOE-ε4 carriers actually develop AD, these findings suggest that a combination of cerebral metabolic rate and genetic risk factors may be one way to help detect AD preclinically. actually develop AD, these findings suggest that a combination of cerebral metabolic rate and genetic risk factors may be one way to help detect AD preclinically.

Use of Magnetic Resonance Imaging (MRI) To Predict Development of AD. A recent study used a much more common technique than PET imaging, MRI, to determine whether persons in a very early phase of developing AD could be identified prior to a clinical diagnosis. Participants received MRI scans at the start of the study and then were followed for three years to determine who subsequently developed changes that met clinical criteria for AD. The researchers found that they could identify people who would develop AD over time with high accuracy, based on significantly smaller baseline volume measurements for specific brain regions, likely reflecting loss of brain cells in these areas. This study implicates specific brain areas in the underlying early pathology of AD and suggests that, by focusing on these areas, it may be possible to use existing imaging techniques to better identify people at greatest risk for AD. This promising MRI technique will need further research, refinement, and validation before it can become a part of standard clinical practice

In Vivo Detection of Amyloid Plaques. Scientists have been searching for a marker to be used in living patients (in vivo) to identify amyloid plaques that may be present in brain long before clinical diagnosis of the disease. A new molecular probe has recently been developed that sensitively labels plaques in post mortem AD brain sections. This probe now has been shown as well to label plaques throughout the brain after intracerebral injection in living transgenic mice. This probe is a prototype for molecules that could be used for radiological imaging of plaques in the brains of living people, permitting monitoring of the development and progression of AD as well as the clearance of plaques in response to antiamyloid therapies.

Standardized Clinical Information Can Predict Conversion to AD. Researchers have identified components of a standardized clinical assessment instrument that also appear to predict which individuals with very mild impairment (symptoms) or "questionable" AD have a high likelihood of converting to AD over time. The assessment instrument was the Clinical Dementia Rating (CDR), a clinical interview which stages AD from normal to severe based on six functional categories. After receiving a CDR rating of normal or questionable, participants were followed for three years to determine who converted to probable AD. Likelihood of progression to AD during follow-up was related to the sum of the scores in the six CDR categories. This score, combined with selected clinical interview questions, identified 89% of those questionable individuals who subsequently converted to AD in the study. These findings provide guidelines for using a clinical assessment to identify patients most likely to convert from questionable AD to AD, improving the possibility of earlier diagnosis and earlier implementation of available interventions.

Normal Age-Related Cognitive Change

Improved characterization of normal cognitive function and underlying brain changes over the life course will help in distinguishing and understanding normal from abnormal changes in memory, learning, and attention with age. Such understanding will help either confirm or, hopefully, alleviate the anxiety of many older Americans and their families, who may observe modest but perceptible changes in cognitive function in themselves or in a loved one and fear that such changes are the harbingers of a decline into AD or dementia.

Imaging Studies of Age Differences in Performing Memory Tasks. A recent study has shown that older adults show activation of more brain regions when performing a memory task than young adults. While both age groups were similarly accurate in performing the memory task, the older group was slower than the younger. Using PET imaging to measure cerebral blood flow, investigators reported activation of both frontal lobes of the brain among older people performing the memory task whereas young adults showed activation of only one of the frontal lobes. These results imply that the older brain is either changing or is compensating in some fashion in order to maintain appropriate cognitive function. Discovering more about why the older brain may perform differently will enable scientists to better determine how to maintain the ability to perform cognitive tasks. To date, intervention trials of cognitive training or aerobic exercise show selective but beneficial effects on cognitive function among older study participants. Understanding the relationship between these environmental modifications and brain function will permit even greater understanding of normal cognitive capacity in the elderly and offer clues for maintaining or improving cognitive function.

Early Life Environmental Factors and AD

Early Life Childhood and Adolescent Environment is Associated with the Risk of AD. Early-life environment has been implicated as a risk factor for many adult chronic diseases. A recent study looked at the association of AD risk with factors including mother's age at patient's birth, birth order, number of siblings, and area of residence prior to age 18. Results indicated that an increased number of siblings was associated with increased risk of AD and growing up in the suburbs was associated with a decreased risk. These associations were not explained by patients' educational level or APOE status. Such results are consistent with possible linkage of socioeconomic or environmental variables with altered brain growth and development, which in turn may affect the risk of developing AD later in life.

Preclinical Research

None of the treatments presently approved for AD alter the progressive underlying pathology of the disease. Early pathologic changes in the brain, including amyloid deposits and formation of neurofibrillary tangles, may play a causative role in AD. Interfering with these processes may be one way to treat or prevent the disease. Two promising approaches were reported this year; one involves blocking the activity of enzymes involved in the formation of amyloid and the other focuses on stopping the development of amyloid plaques by immunization. A new fruit fly model of Parkinson's disease (PD), another neurodegenerative disease, has been developed and could provide information about the etiology of these types of disorders.

Identification of the Amyloid-ß Forming Enzymes Offers New Targets for Drug Development. Amyloid is a small peptide fragment produced as a result of snipping (cleavage) of the much larger amyloid precursor protein (APP) by two enzymes known as beta (ß) and gamma (γ) secretases. For years, scientists knew that something was snipping the APP into fragments and they even went so far as to name the suspect secretases. But no one had been able to physically and precisely identify the enzymes that did the actual clipping of APP until the past year, when the identities of the ß and γ secretases at last were revealed.

The identity of ß secretase was discovered simultaneously by several drug companies. However, γ secretase has proven more elusive. Its activity was known to be affected by mutations in one of the genes (presenilin 1 or PS1) that cause AD in early onset families. PS1 was identified several years ago and structural evidence suggested it might actually be the γ secretase. To test this possibility, scientists identified a radioactive molecule that binds tightly to the active site of the enzyme, thus labeling the enzyme molecules. They found that PS1 was the labeled protein, strongly suggesting that it itself is the γ secretase. It is believed this line of research could lead to the discovery of drugs that inhibit the production of amyloid without inhibiting other essential functions these secretase enzymes might have. Ultimately, clinical trials on such secretase-inhibiting drugs will show whether this approach will work.

Immunization Against Amyloid-ß Can Reduce Brain Amyloid-ßDeposition. Recent studies in animal models have been important in understanding the etiology of AD and in testing potential new therapies. In transgenic mouse models showing extensive plaque formation with advancing age, researchers are now evaluating plaque-reducing drugs. The results of this research have been promising. In one breakthrough, pharmaceutical company scientists showed that repeated long-term injections of an amyloid vaccine can cause an immune response in test mice, nearly eliminating amyloid plaques and associated neuropathology, with no obvious toxicity. A number of NIH-funded scientists have confirmed and extended these observations. In a novel approach, one group administered the vaccine to mice nasally, and also induced an immune response. In that study, when young transgenic mice were repeatedly given the human amyloid-ß via the nasal route, the mice had a much lower amyloid burden at middle age than animals not receiving the vaccine. Interest in the vaccine approach heightened upon recent preliminary reports that amyloid vaccination prevents cognitive decline in another transgenic mouse model of AD, suggesting that a vaccine might indeed make a difference in the clinical symptoms of AD. Human trials are only now beginning to test both the safety and the efficacy of these vaccines as a possible therapy for people with AD.

A New Model of Parkinson's Disease (PD). There are many similarities among neurodegenerative diseases such as AD, PD, and other dementias, and research on one can provide valuable clues about the others. PD is a common age-related and progressive neurodegenerative disorder characterized by death of neurons that make the neurotransmitter dopamine. Loss of these neurons results in rigidity, tremor, slowed movement, and impaired gait. Another hallmark of PD is the formation of fibrous protein deposits, called Lewy bodies, in neurons. Mutations in the α-synuclein gene have been linked to some forms of inherited PD and insoluble α-synuclein accumulates in Lewy bodies, as well as in plaques in AD. A new α-synuclein transgenic model has been developed, using the fruit fly Drosophila, that exhibits many essential features of human PD including age-dependent onset, progressive loss of dopamine neurons and motor function, and development of Lewy body-like pathology. This model will be useful in identifying underlying mechanisms mediating α-synuclein toxicity and in identifying genes that modify the α-synuclein mediated neurodegeneration, and which may play a role in the pathogenesis of PD. These transgenic flies may also be valuable in screening potential drugs affecting the onset and progression of PD.

Clinical Trials

Today, 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.

Currently available FDA-approved drugs maintain cognitive function in a subset of AD patients, but only for a limited time. NIH-funded clinical trials are, for the first time, targeting prevention of disease. Current clinical trials are examining a number of compounds to determine what works—and what may not—to slow the onset of AD or retard its development. Interest is now focusing on compounds which directly target disease-related pathologies. These include estrogen, anti-inflammatory agents, and antioxidants. Recently completed studies have moved our knowledge forward, and it is hoped that a great deal more will be learned from newly initiated efforts. Interestingly, some important new findings, in patients who already have AD, have been negative, showing no relationship between treatment with certain drugs and an effect on progression of the disease.

The research focus now is turning to prevention trials, and a number are underway to test the effectiveness of therapies in people without symptoms or who have only slight memory problems. Under scrutiny in these studies are further examination of estrogen and studies of various classes of anti-inflammatory drugs and antioxidants.Recruitment is complete for the first NIH AD prevention trial, to 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. Ongoing trials are also examining the effectiveness of naproxen and celecoxib (anti-inflammatory drugs) in reducing the risk of AD in persons with a family history of dementia, the effect of estrogen replacement therapy in preventing AD in women with a family history of the disease, and whether treatment with a variety of agents, such as aspirin, vitamin E, antioxidants, or combined folate/B6/B12 supplementation can prevent older women from developing age-related memory impairment or AD. 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

Ongoing Research Highlights Importance of Testing Interventions. REACH (Resources for Enhancing Alzheimer's Caregiver Health) is a multisite intervention trial, at six sites and a coordinating center, to conduct social and behavioral research on interventions designed to help caregivers of patients with AD and related disorders. REACH projects are testing such interventions as educational support groups, behavioral skills training programs, family-based interventions, environmental modifications, and computer-based information and communication services. Some 1,222 caregivers and care recipients have participated in the study, which includes large numbers of African Americans, Cuban Americans, and Mexican Americans. Data from the REACH study are just being analyzed, but very preliminary general findings suggest that testing of interventions to determine effectiveness in different groups is important, and research in this area continues.

Selected Future Research Directions in AD and the Neuroscience of Aging

Preventing Alzheimer's Disease: The AD Prevention Initiative. The NIA AD Prevention Initiative is an intensive, coordinated effort to accelerate basic research and the movement of basic research findings into the development of novel compounds to delay or slow the progress of AD or to prevent the disease entirely. Potentially promising strategies are being identified, based on new information about the initial stages and events in the brain that lead to AD, as well as data from studies of genetic and environmental risk factors. To follow up on these leads, NIH is implementing a five-year research initiative to speed the development of vaccine and other novel approaches for preventing AD. Another research initiative will examine changes in immune function with age, including response to different vaccination protocols. Along with the prevention initiative, other studies will continue to look at the many similarities in the biological mechanisms underlying neurodegenerative diseases such as AD, PD, and other dementias and will help to characterize age-related change in the normal, healthy brain.

As new leads are identified and developed in the test tube and in laboratory animals, findings are being translated into clinical interventions. The translation process will involve testing of drugs that target crucial pathways as well as incorporation of efficient processes for channeling drugs of interest into appropriately designed clinical trials. Plans for these clinical trials will increasingly emphasize AD prevention, including trials recruiting people with normal cognition and those with cognitive impairment. Continuing development of tools for early diagnosis will be pursued to help both clinicians and researchers in the treatment and the study of AD. Intervention studies aimed at people caring for AD patients will also be launched to develop and test additional ways of managing the daily activities and stresses of caregiving and to reduce caregiver burden. Investigations into long-term care issues involving AD will look at how to prevent hospitalizations and delay nursing home admissions.

Maintaining a Healthy Brain. Much is known and publicized about maintaining a healthy heart, but relatively little emphasis has been given to maintaining a healthy brain. Like the cardiovascular system, the brain and brain function have been shown to change over time. As people age, there can be positive changes in cognitive function such as greater wisdom or integrative prowess. Researchers have also measured performance deficits with age in the cognitive behaviors of attention, language, learning, decision making, and memory, as well as in sensory and motor systems, all of which can produce frustration and concern for older people. The molecular and cellular bases for these age-related deficits are being defined, and other possible risk factors are being assessed. Different life experiences and cultural factors, for example, are increasingly recognized as playing an important role in modulating cognitive content and performance throughout the lifespan. Scientists want to know, for example, how early life factors, education, social interactions and self-concept may influence brain health and behavior in later life through immune, endocrine, or other pathways.

Research to date has provided some basis for understanding the risk factors associated with compromised brain function. But while we are beginning to sort out the biological, environmental, and social factors that may be involved in brain health, much remains to be discovered. In an effort to accelerate the pace of scientific advances in the fields of cognition and emotion, a trans-NIH Healthy Brain Research Initiative is planned. This activity will combine the efforts of the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the NIA in these areas. To start, an analysis of trans-NIH research in these areas will identify what is known, pinpoint gaps in knowledge, and map future directions for research.

As these areas are further investigated, additional research should be conducted to describe the "normal" course of cognitive change at very advanced ages. Studies of individuals age 85 and older, the fastest growing segment of the population, will provide information on healthy cognitive aging, onset of mild cognitive impairment, or dementia in this age group. Given findings suggesting that racial and ethnic minorities may be at greater risk of developing AD, there will also be a particular focus on potential differences in healthy brain aging for older racial and ethnic minorities, including effects of education, health and other life course variables.

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