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.2,3 As the population ages, the numbers of people with AD and costs associated with increased prevalence could rise significantly.
The following section on AD 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 decision-making. 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 facilitate clinical studies of new therapies and preventive measures by allowing early intervention, before cognitive loss becomes significant.
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. They are searching for reliable, valid, and easily attainable biological markers that can identify cases very early in the course of disease. 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.
Recently, researchers have made progress in several areas related to early diagnosis of AD:
- Tracking changes in brain metabolism. Investigators in several recent studies have identified specific metabolic changes in the brain that are characteristic of AD, and in one study have demonstrated that measuring patterns of brain metabolic changes can be used to diagnose AD with a high degree of accuracy.
- Tracking changes in brain structures. AD is associated with changes in many brain structures. Investigators have found that atrophy of the hippocampus, a part of the brain affected by AD, is a sensitive marker of AD-related pathologic damage and changes in cognitive function. MRI measurement of hippocampal volume may be useful for identifying early AD or for assessment of cognitive decline
- Imaging and evaluating AD's unique pathologic features. Researchers are developing new ways to view and track AD's characteristic amyloid plaques in the brain. In one study in mice, investigators developed a radioactive tracer that is attached to an antibody that binds to the plaques, enhancing the ability to image them. In another mouse study, researchers developed a dye-based compound that also binds to plaques, again facilitating imaging. Preliminary human studies using amyloid tracers have been described.
These and other techniques may also provide effective methods of tracking early AD changes in brain as well as treatment effectiveness, particularly through imaging amyloid burden in the brain.
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.
Prevalence of Cognitive Impairment Is High Among a Group of Older Community-Dwelling Individuals. Scientists are trying to determine the prevalence of cognitive impairment that is not dementia. Individuals with dementia are forgetfulness and have impairments in thinking, judgment, and the ability to perform daily activities. The condition called Mild Cognitive Impairment, or MCI, is not dementia, but it may be related to the eventual development of dementia and AD. Results from the first population-based study of cognitive impairment in the United States, composed of 2212 African-American residents of Indianapolis, Indiana, ages 65 and older, indicate that 23.4 percent of the community-dwelling participants and 19.2 percent of the nursing home residents had MCI. The prevalence of cognitive impairment grew significantly with age, with rates increasing by about 10 percent for every 10 years of age after age 65. MCI was almost five times more common in the community than dementia. In addition, the scientists found that 26 percent of those characterized with MCI at the start of the study went on to become demented only 18 months later, although 24 percent of participants who were first diagnosed with MCI appeared normal after 18 months.
These results suggest that the condition may affect a significant proportion of older people. The factors that influence whether or not MCI will progress to dementia have not yet been defined. Whether the prevalence of cognitive impairment short of dementia in the Indianapolis group is any higher or lower than other population groups is unclear, although the results appear to be consistent with the few studies done so far in other countries.
Neurons Know Where We're Going. Researchers are finding out the ways in which we spatially orient and maneuver ourselves in the environment. In a study of monkeys, they found that neurons in the brain's medial superior temporal area (MST) appear to encode information about direction of heading, path and place. These functions allow an individual to orient spatially in the environment. Since anatomical pathways from MST are associated with other brain areas that connect to the hippocampus (which is involved in AD pathogenesis), MST could play an important role in the spatial disorientation that is seen in AD and other neurodegenerative disorders.
Environmental Factors and AD
There is a great deal of interest in finding risk and preventative factors for age-related cognitive decline and AD. Of particular interest are those factors that are modifiable, because interventions that decrease the effect of a risk factor or facilitate a preventative factor could potentially delay the onset of the disease or prevent it altogether.
Can Diet Affect Risk of AD and Dementia? Scientists increasingly believe that the answer to this question may be "yes." For example, researchers recently found that elevated blood levels of the amino acid homocysteine were associated with a significantly increased risk of AD. The association between homocysteine and AD was found to be strong and independent of other factors. Blood levels of homocysteine can be reduced by increasing intake of folic acid and vitamins B6 and B12; the use of these compounds is being explored in ongoing and planned clinical trials for the treatment and prevention of cognitive decline and AD.
In fact, NIH investigators are elucidating the mechanisms by which folate deficiency and elevated homocysteine can influence risk of neurodegenerative disease. In a recent study, they found that folate deficiency renders neurons in the hippocampus, an area of the brain critical to learning and memory, vulnerable to degeneration in a mouse model of AD. Additional studies showed that homocysteine increases the vulnerability of neurons to being killed by amyloid beta-peptide, a toxic protein whose organization into plaques is a hallmark of the condition. In a mouse model of Parkinson's disease (PD), folate deficiency resulted in increased damage to specialized neurons in an area of the brain called the substantia nigra, worsening motor dysfunction as a result. When infused directly into either the substantia nigra or striatum, homocysteine promoted neuronal degeneration and motor dysfunction. The researchers also determined the mechanism through which homocysteine endangers neurons: It promotes oxidative stress (cellular damage caused by molecules generated during normal energy metabolism) and impairs the repair of damaged DNA, thereby triggering a form of programmed cell death called apoptosis.
Active Lifestyle Generates New Neurons in Aged Brains. Human studies suggest that a mentally and physically active lifestyle gives some protection against developing dementia and neurodegenerative disorders, and a recent NIA-supported study suggests that this may be due to increased neurogenesis, or development of new neurons, in active individuals' brains. Investigators found that mice housed in an "enriched" environment (including exercise and play equipment) for up to 10 months showed a fivefold higher level of neurogenesis in the hippocampus (a brain area central to learning and memory) than mice housed in standard bare cages. "Enriched" mice also demonstrated improvements in learning, exploratory behavior, and motor activity, and showed fewer lipofuscin deposits, an age-related indicator of neural degeneration, in hippocampal neurons.
Diabetes, ApoEp4 and the Risk for Alzheimer's Disease. Researchers evaluated the connection between type 2 diabetes, dementia, and APOEp4 http://diabetes.diabetesjournals.org (the major AD susceptibility gene) in a large group of Japanese-American men. They found that participants with both type 2 diabetes and the APOE http://diabetes.diabetesjournals.org allele had a risk for AD 5.5 times higher than those with neither risk factor. At autopsy, participants with type 2 diabetes and the http://diabetes.diabetesjournals.org allele had a higher number of AD's characteristic amyloid plaques and neurofibrillary tangles in the hippocampus, the region of the brain where AD is thought to start. They also had a higher incidence of amyloid deposition in the blood vessels in the brain. Further investigation is needed into the underlying pathology and effects of treatment of diabetes on the incidence of AD.
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.
A Tale of Two Proteins. Investigators engineered a fruit fly model that carried genes for human Hsp70 and alpha-synuclein, two proteins that when altered are implicated in the development of PD and other neurodegenerative diseases. Hsp70 is a chaperone protein, meaning that it aids in the proper folding of other proteins, and scientists are using this model to elucidate the roles of chaperone proteins in neurodegenerative diseases. Results to date suggest that finding ways to enhance and appropriately target chaperone proteins' activity may be an effective approach to treating neurodegenerative diseases such as AD and PD that are accompanied by altered protein conformation and aggregation.
Prions, Misshapen Proteins, and Out-Of-Shape Brains. Prions are infectious proteins that transform a normal cellular protein (PrPC) into an abnormal virulent form (PrPSc) that accumulates in the central nervous system, producing fatal neurological disease characterized by sponge-like holes in the brain that result in movement, emotional, sleep, and cognitive disturbances. These and other neurodegenerative diseases, including AD, PD, and Huntington disease (HD), now are thought to be diseases of protein conformation in which a misfolded version of a normal cellular protein aggregates and causes neurodegeneration.
Investigators have made a number of advances in our understanding of prion diseases. In the first study, researchers noted that, although chemically the same, PrPC and PrPSc differ in structure. A fragment of the mouse prion protein with a single alteration that causes Gertsmann-Sträussler-Scheinker disease (a prion disease) can induce this disease in transgenic mice only if it is in the pathological form, indicating that prion proteins must exist in a particular structure to become infectious and produce neurodegeneration. The specificity of the prion structure may also limit transmission of prion diseases between different species: Researchers have demonstrated that breaching of the species barrier involves the generation of prions with different structural templates that slowly accumulate over multiple transmissions in recipients. In another study, investigators identified a neurodegenerative disorder that mimics the symptoms of HD, but lacks HD's characteristic genetic mutation. Instead, the disorder is associated with mutations in the prion protein gene. Finally, researchers have found that, in mice, specially engineered antibodies can inhibit interaction between PrPC and PrPSc, which is necessary to PrPSc replication. In cells treated with the most potent antibody, prion replication was halted and existing prions were rapidly cleared, suggesting that the antibody may cure established infection.
Identification of Learning-Associated Genes in the Rat. The specific genes and proteins involved in the maintenance of long-term memory and learning remain largely unknown. NIH researchers recently trained rats in a maze, then used cDNA miroarrays - chips containing information from thousands of genes, which are electronically assessed and compared - to analyze the activity of genes known to be active in the hippocampus, a brain area central to learning and memory. They identified 18 known genes and 10 previously uncharacterized genes whose activity increased after the maze learning. These findings provide the groundwork for future, more focused research to elucidate the contribution of these genes in learning and memory processes.
There are currently no effective, generally useful treatments for AD—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.
Common Compounds May Be Effective Against Alzheimer's Disease. Recent research has suggested that use of several common, over-the-counter compounds may be associated with reduced risk of AD and dementia. For example, epidemiologic research indicates that there is a correlation between long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), such ibuprofen and a reduced risk of developing AD. Several recent studies are consistent with the hypothesis that NSAIDs are effective against AD, in part through inhibition of inflammation-promoting cells within the central nervous system Clinical trials are necessary to test directly whether NSAIDs can prevent AD and dementia, and such trials are currently ongoing.
Likewise, researchers are developing new "antioxidant" drugs that ameliorate or prevent cell damage or death caused by oxidative stress, a form of cell damage caused by molecules generated during normal energy metabolism. Oxidative stress is implicated in a number of diseases, including AD and PD, as well as in normal aging. Recently, investigators tested the activity of three new compounds in mice lacking one form of a key antioxidant enzyme; the researchers found that the drugs increased the lifespan of the diseased mice by up to 3-fold and prevented harmful pathological and behavioral changes. Continued research on such antioxidant compounds may lead to new approaches to the treatment of AD, and perhaps other degenerative processes of aging.
Beneficial Effects of an Anti-Diabetes Hormone on Metabolism and Brain Function. Investigators have found that GLP-1, a gut peptide hormone that is present in the blood and that has generated interest as a potential treatment for type 2 diabetes, may have beneficial effects on brain functions. In a recent study, GLP-1 and its long-acting analog, exendin-4, stimulated the growth of nerve cells in culture. Moreover, GLP-1 and exendin-4 protected neurons in culture and in the brains of adult rats against injury and death in experimental models relevant to the pathogenesis of stroke and AD. Both prevented the loss of acetylcholine, a neurotransmitter that plays a critical role in learning and memory, and which is depleted in AD. These studies suggest that GLP-1 and related peptides may be useful in reversing or halting the neurodegenerative processes that occur in disorders such as stroke and AD.
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 30 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, taking 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 AD 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.
Supporting Caregivers of Persons With Dementia. The National Institute on Aging's REACH Project (Resources for Enhancing Alzheimer's Caregiver Health), a large, multi-site intervention study aimed at family caregivers of AD patients, was designed to characterize and test promising interventions for enhancing family caregiving. Nine different social and behavioral interventions and two types of control conditions (usual care or minimal support) were tested at six different sites, and 1,222 culturally and ethnically diverse caregiver/patient pairs participated in the study. The investigators found that the combined effect of interventions alleviated caregiver burden, and that active treatments that enhanced caregiver behavioral skills reduced depression. The results also show that subgroups of caregivers benefit in different ways from the same interventions. Women caregivers, Hispanic caregivers, non-spouse caregivers, and those with high school or lower education benefited significantly more from active intervention when compared to similar individuals in control conditions. These results indicate that individualized, but tested, caregiver interventions and the means to deliver them are critically needed. The second phase of the study, REACH II, has combined elements of the diverse interventions tested in REACH into a single multi-component psychosocial behavioral intervention and is ongoing.
Selected Future Research Directions in AD and the Neuroscience of Aging
The NIA will continue to focus major efforts on two major areas of neuroscience research. The first is to characterize normal age-related changes in the nervous system, with its associated changes in function, and the other is to understand and treat the most common neurodegenerative disease of later life, AD, and related dementias. Trans-NIH initiatives are addressing these two areas. The Healthy Brain Initiative is a collaboration across Institutes to identify and understand factors impacting healthy brain aging. The AD Prevention Initiative is a similar trans-Institute collaboration with the ultimate intent of developing treatments to prevent the development of AD in susceptible individuals.
Specific initiatives will be pursued to identify imaging and biological markers for prediction, diagnosis, and charting the progression of AD; to test new approaches for drug develoment for AD; and to understand how genetics, environment, and age-related changes in the brain affect the development of AD.
Another important focus is the identification of risk factors for mild cognitive impairment (MCI) and AD. Since individuals with MCI are at a high risk of developing AD, it is critical for researchers to be able to define MCI and to differentiate it from normal cognitive aging and from AD. This is important not only in elucidating etiology and in targeting possible interventions, but also in understanding what the conversion rates from MCI to AD are in the general population and how this will impact the numbers of people with cognitive impairment and AD in the future.
- Small, G. et al. Diagnosis and treatment of Alzheimer disease and related disorders. JAMA 16: 1363-1371, 1997
Ernst, RL, et al. Cognitive function and the costs of Alzheimer's disease, Arch Neurol 54: 687-693, 1997.