Alzheimer's Disease and the Neuroscience of Aging
Alzheimer's disease (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 now estimate that as many as 4.5 million people currently suffer with the disease, and this number is expected to increase to 13.2 million persons by 2050, an almost threefold increase.6
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. A diagnosis of AD is also associated with a sharply reduced lifespan; for example, the overall median survival for 70-year-olds in the United States is 15.7 years for women and 12.4 years for men, but a recent study found that this drops to 8.0 years and 4.4 years, respectively, for women and men with AD.7
The Genetics of Alzheimer's Disease
To date, only four of the approximately 30,000 genes in the human genome have been conclusively shown to affect the development of AD pathology. Three genes, amyloid precursor protein (APP), presenilin (PS) 1, and PS 2, are linked to the early-onset form of familial AD, which accounts for only a small percentage of all AD cases. A form of a fourth gene, APOE-ε4, which occurs in about one-fourth of the population, is a risk factor gene for late-onset AD (LOAD), and about half the AD cases have the ε4 form of the APOE gene. Geneticists have suggested that as many as four additional and as yet unidentified genes, at least one of which may be located on a specific region of chromosome 10, may be risk factor genes for LOAD. Finding new risk factor genes will help to identify pathways affecting the development or progression of AD, which can be become potential targets for treatment interventions.
Changes in Gene Activity in Early Aging and Alzheimer's Disease. Analysis of gene activity in discrete brain regions can provide important insights into the activities that underlie both normal brain aging and the pathological processes of neurodegeneration. Two recent studies demonstrate the utility of this approach. In one, investigators concluded that accelerated DNA damage may contribute to reduced gene expression, particularly the activity of genes involved in learning, memory and neuronal survival, and initiate a program of brain aging that starts early in adult life—in this case, around age 40. In a separate study, researchers show widespread changes in the genomic regulation of multiple pathways that involve the overactivity of tumor suppressor genes, as well as in genes involved in the differentiation of cells associated with myelinated axons. This suggests a provocative, but plausible, new model of AD pathogenesis that could account for the characteristic progression of AD throughout the brain along myelinated axons.
Genetic Variations Among Individuals Influence the Severity of Alzheimer's Disease. Insulin degrading enzyme (IDE) degrades amyloid β, a major component of amyloid plaques. In a recent study, the stretch of genetic material on chromosome 10 that contains the IDE gene and two other nearby genes was assessed for changes at a single point in the genetic code—known as a single nucleotide polymorphisms or SNP—and for haplotypes, which are stretches of DNA inherited in common among groups of people, in AD and control samples. Quantitative measures that are important to AD diagnosis and severity were also clinically assessed. Data strongly indicated the presence of alleles (alternative forms of a gene) and haplotypes that confer risk for AD within this region, and suggested that genetic variation within or extremely close to the IDE gene impacts both disease risk and traits related to the severity of the disease. Implementation of this approach on a broader scale is likely to be an effective tool in genetic analysis of complex diseases.
Early Diagnosis of AD
Early diagnosis of AD would be beneficial. For patients and their families, a definitive early diagnosis provides the opportunity to plan and pursue options for treatment and care, while the patient can take an active role in decisionmaking. For clinicians, accurate early diagnosis facilitates the selection of appropriate treatments, particularly as new interventions are developed. For researchers, earlier and more accurate diagnosis facilitates clinical studies of new therapies and preventive measures by allowing early and more targeted intervention, before cognitive loss becomes significant. Research suggests that the earliest AD pathology begins to develop in the brain long before clinical symptoms yield a diagnosis, and scientists are searching for reliable, valid, and easily attainable biological markers that, along with genetic, clinical, and neuropsychological assessments, could identify cases very early in the course of disease.
Abnormal PET Scans in Young Adults at Genetic Risk for Alzheimer's Disease. Using positron emission tomography (PET), patients with AD typically show decreased glucose metabolism, which correlates with brain activity, in specific brain regions. Other studies have shown decreases in metabolism in these same brain regions in nonsymptomatic middle-aged people who are at risk for AD. In a recent study, investigators extended these findings to show that cognitively normal people who are APOE ε4 carriers show the characteristic decreases in brain metabolism while in their 20s and 30s—decades before the possible onset of symptoms, and considerably earlier than previously recognized. These findings provide direct evidence that pathologic changes in the brains of APOE ε4 carriers can be seen many years before the onset of detectable cognitive decline and are consistent with the idea that AD may develop over decades. Many experts believe that the degeneration leading to AD should be treated as early in the course of the disease as possible, so as promising drug treatments develop, it will be even more important to identify those at risk and make early diagnoses.
Imaging Amyloid in the Living Brain. Until recently, there have been no imaging techniques that could effectively visualize characteristic AD pathologic features in the living human brain. However, investigators have developed a compound, Pittsburgh Compound B (PIB), that binds to brain amyloid and enables it to be imaged using PET. Another compound currently under development, IMPY, has shown promise in imaging amyloid plaques using single photon emission computerized tomography (SPECT) in a mouse model of AD. Although further research is needed, PIB, IMPY, and related compounds may ultimately play an important role in AD diagnosis, as well as studies of the pathology and course of the disease and evaluation of drug therapies targeted against amyloid deposits.
Changes in Cognitive Performance Over Time in People at Risk for AD. Scientists tested cognitively intact individuals, ages 48–77, on several components of memory over a two year period. APOE ε4 carriers 60 and older showed a significantly greater decline over time in new learning of a list of words, as compared with noncarriers. No difference in verbal learning ability was seen between carriers and noncarriers younger than 60 years old. These results suggest that longitudinal assessment of new learning may be a sensitive measure for detecting early cognitive changes in presymptomatic people who are at risk for AD.
Preventing Alzheimer's Disease
No intervention has been proven to prevent AD or even delay its onset, but scientists continue to seek risk and preventative factors for the disease, as interventions that impact the effect of a risk or preventative factor could potentially delay the onset of the disease or prevent it altogether.
Diabetes and Decline in Cognitive Function. Diabetes mellitus (DM) affects about one in five persons over age 60 years,8 and it has been associated with a variety of adverse health effects. Recently four large-scale studies—the Religious Orders Study (ROS), the Nurses' Health Study (NHS), the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial, and the Rancho Bernardo Study (RBS)—linked DM to changes in cognitive function. The studies suggested the following: women with DM have an increased risk of developing substantial cognitive decline (NHS, MORE Trial, RBS); postmenopausal women whose blood glucose levels are elevated, but not yet in the “diabetic” range, i.e., “prediabetic,” are also at risk for significant cognitive impairment (MORE Trial); and oral hypoglycemic agents may ameliorate the increased risk in women (NHS, RBS). One study (ROS) suggested that men and women with DM have an increased risk of developing AD, and that, for both sexes, DM affects different cognitive systems differently. Together, these results indicate that a successful public-health prevention strategy for DM may also have major consequences for preventing or delaying AD. They further suggest that patients with DM who receive treatment for their condition may receive some protection from cognitive decline, in addition to the therapeutic benefit for DM.
Abnormalities in Lipid Metabolism in Nerve Cells Linked to AD. The pathogenesis of AD is tightly linked to amyloid beta (Aβ) deposition and oxidative stress, the cellular damage caused by free radicals, which are byproducts of normal cellular metabolism. However, it remains unclear how these factors result in dysfunction and death of brain cells. In a recent study, NIH researchers measured amounts of different lipids in brain cells from AD and control patients and found that AD patients had much higher levels of cholesterol and a lipid called ceramide specifically in brain regions important for learning and memory. These increases were associated with increased damage to nerve cells caused by free radicals. When cultured nerve cells were exposed to Aβ, similar overproduction of cholesterol and ceramide occurred. The increases were prevented and the nerve cells were protected when they were treated with the antioxidant vitamin E or a drug that prevents the accumulation of ceramide. These findings suggest a model of AD development that involves the disturbance of ceramide and cholesterol metabolism. This research further suggests that diets and drugs that target lipid abnormalities may be beneficial in the prevention and treatment of AD. Such drugs include cholesterol-lowering drugs, or statins, and earlier epidemiologic studies have shown a strong association between the use of statins and lower rates of AD. In January 2003, the NIA initiated the Cholesterol Lowering Agent to Slow Progression of AD (CLASP) study, a clinical trial to investigate the safety and effectiveness of the cholesterol-lowering drug simvastatin to slow the progression of mild to moderate AD. It is expected to be completed in November 2006.
Treating AD and Cognitive Impairment
To date, the Food and Drug Administration (FDA) has approved four medications for the treatment of mild to moderate AD symptoms. The first, tacrine (Cognex®), has been replaced by three newer drugs— donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®). In 2003, the FDA approved memantine (NamendaTM), the first drug to treat moderate to severe AD. These drugs improve some patients' ability to carry out activities of daily living, help with behavioral symptoms, such as delusions and agitation, and can also maintain thinking, memory, and speaking skills for a period of time. However, none of these drugs can stop or reverse the disease process, and they appear to help only some patients and only for a period of months to a few years. Finding a truly effective intervention will depend on research progressing on a number of fronts, both in model systems and humans, and a major clinical research focus lies in testing the effectiveness of therapies in people without symptoms or who have only slight memory problems.
Vaccine That Removes Plaques May Also Remove Tangles. One way to treat AD successfully may be to interfere with early pathological changes in the brain, including the development of amyloid-β deposits (plaques) and the formation of tau-based neurofibrillary tangles, which are the hallmark pathological lesions of AD. Previous research has shown that in mice, immunization against Aβ can result in removal of amyloid plaques and maintenance of cognitive function. Now, researchers have found that a vaccine designed to clear amyloid plaques may also be effective against tau-based neurofibrillary tangles. Investigators injected “triple transgenic” mice, in which plaques, tangles, and AD-like brain damage are all present, with an antibody to Aβ. They found that Aβ was removed from both around and—unexpectedly—within neural cells. More surprisingly, they found that the antibody also removed early-stage accumulations of tau, though not late-stage tau lesions that resemble human neurofibrillary tangles. The reduction of tau pathology following an anti-Aβ treatment suggests a direct link between these two hallmarks of AD, and indicates that targeting the removal of Aβ early in the disease course might also eliminate tau pathology—thus removing or reducing both cardinal features of AD.
Donepezil May Have Short-Term Benefit for Mild Cognitive Impairment. The first NIH AD prevention trial, comparing the effects of vitamin E, donepezil (Aricept®), or placebo in preventing AD in people diagnosed with mild cognitive impairment (MCI), recently concluded at more than 70 sites across the U.S. The study is part of the Alzheimer's Disease Cooperative Study (ADCS) clinical trials consortium supported by NIA. Preliminary data from this study indicated that people with MCI taking donepezil, but not Vitamin E, were at reduced risk of progressing to AD for the first 18 months of the 3-year study when compared with their counterparts on placebo. The reduced risk of progressing from MCI to a diagnosis of AD among participants on donepezil disappeared after 18 months, and by the end of the 3-year period, the probability of progressing to AD was the same as that for the Vitamin E and placebo groups. However, among the subjects who did develop AD, those in the donepezil group experienced a statistically significant delay of almost 6-months in the development of AD compared to the placebo group.
Raloxifene May Reduce Risk of Cognitive Impairment in Postmenopausal Women. Studies of hormonal influences on cognitive aging in women have reported conflicting results, with some studies demonstrating a decreased risk for AD among users of hormone therapy and others, notably the Women's Health Initiative Memory Study (WHIMS), showing that postmenopausal women on certain regimens were actually at higher risk for cognitive decline. In a recent study—the Multiple Outcomes of Raloxifene Evaluation (MORE) trial—the selective estrogen receptor modulator (SERM) raloxifene (Evista®), frequently prescribed for the prevention and treatment of osteoporosis, appeared to reduce the risk of cognitive impairment in postmenopausal women. SERMs are compounds that mimic estrogen's actions in some tissues, but block the action of the body's naturally occurring estrogen in others. Raloxifene, like estrogen, promotes bone growth; however, it has antiestrogenic actions on the breast and uterus that reduce possible cancer-causing stimulation of these tissues postmenopause. Over 5,000 MORE participants were assigned to either 60 mg/day of raloxifene, or 120 mg/day of raloxifene, or placebo, and their cognitive function was assessed over the three years of the study. The researchers found that women taking 120 mg/day had a 33 percent lower risk of developing mild cognitive impairment (MCI), frequently a precursor condition to AD, than the other participants. They may also have a reduced risk of developing AD or other dementia, although this finding was not statistically significant. Risk of cognitive impairment did not differ between the 60 mg/day and placebo groups. Although extremely preliminary, these results suggest that treatment with raloxifene may offer women cognitive benefits, with fewer health risks than traditional hormone therapy.
People With Early AD Can Still Learn. In a recent study of cognitive rehabilitation among AD patients, who were taking medications to slow disease progression, subjects were randomly assigned to either a “cognitive rehabilitation” (CR) group or a control “mental stimulation” (MS) group. The subjects in the CR group participated in a series of biweekly sessions in which they were taught practical strategies for enhancing their ability to perform routine tasks such as face-name recognition, making change, and balancing a checkbook. The subjects in the MS group participated in activities that required memory, concentration, and problemsolving skills. At the end of the study, those in the CR group showed significantly improved ability to associate faces and names, had faster mental processing speeds, were better oriented to time and place, and were better able to make correct change for purchases than those in the MS group, although neither group showed memory improvement for manipulating objects or balancing a checkbook. The improvements were still evident three months after the intervention ended. These findings suggest that by combining specific cognitive rehabilitation strategies, people with AD can be helped to remain engaged in daily activities and retain a connection to their family and friends and the world as a whole for a longer period of time.
Exercise Plus Behavioral Management Improves Physical Function and Mental Health in AD Patients. Research has shown that even the oldest adults can improve cardiovascular functioning and increase flexibility, balance, and strength with systematic exercise training. However, it is unknown whether an exercise program would help reduce functional dependence and delay institutionalization among patients with AD. In a recent clinical trial, AD patients received either routine medical care or participated in an exercise plus behavioral management program. The exercise program consisted of aerobic/endurance activities, strength training, balance, and flexibility training. At three months, outcomes in the patients in the intervention group improved while routine care patients declined, and these differences remained up to two years later.
Caregiving of AD Patients
Most of the over four 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.
Sustained Benefit of Supportive Intervention for Depressive Symptoms in Caregivers of AD Patients. Family caregivers of relatives with Alzheimer's disease are at high risk for psychological distress, particularly clinical depression. This risk persists over the many years of caregiving and even after caregiving ends with the death of the care recipient. Investigators followed 406 participants in the NYU Spouse-Caregiver Intervention Study, a long-running study of an intervention for family caregivers of people with AD. Half of the spouse-caregivers received an initial period of intensive counseling, attended weekly support groups, and were encouraged on an ongoing basis to contact counselors for support. The second group of spouses was assigned to receive the “usual” support services for families of AD patients at the Center, which included information about resources and advice upon request, but no formal counseling.
When they began the study, the two groups showed comparable levels of depressive symptoms, but after one year, 29.8 percent of caregivers in the enhanced treatment group had symptoms of clinical depression compared with 45.1 percent of those in the usual care group. Significant differences between the two groups were found through the third year of followup. These results offer evidence that distress and depressive symptoms in family caregivers can be effectively eased and that the benefits can be sustained over a long period of time.
Long-Term Care Placement of Dementia Patients and Caregiver Health and Well-Being. In a recent study of the transition experience caregivers undergo when institutionalizing a relative, investigators found that race/ethnicity, caregiver burden, and global cognitive function of the patient were important predictors of institutionalization. They also found that caregivers who reported that providing help to their relative made them feel more useful, needed, appreciated, and important were less likely to institutionalize the patient. After the patient was institutionalized, half of spouse caregivers and one-quarter of nonspouse caregivers reported visiting the care recipient at least once a day, and nearly all reported visiting at least once a week. Spouses reported higher levels of depression both before and after placement and more anxiety after placement than nonspouse caregivers. These findings suggest that although caregiver bereavement studies have shown that caregivers demonstrate recovery in response to the death of their loved one, there appears to be less benefit to the caregiver from institutionalizing the relative, possibly because the caregiving role is not wholly relinquished after institutionalization.
Initiatives: AD and the Neuroscience of Aging
Advances in neuroimaging have the potential to transform the way we predict, diagnose, monitor, and even treat mild cognitive impairment and AD. The NIA is currently developing an Alzheimer's Disease Neuroimaging Initiative, a longitudinal, prospective, natural history study of normal aging, mild cognitive impairment, and early AD to evaluate neuroimaging techniques (e.g., MRI, PET) and other potential biomarkers of the disease. Biomarkers may decrease the time and cost of clinical trials, which would increase the safety and efficiency of drug development. An important aspect of this initiative is that the clinical, imaging, and biological data and samples will be made available promptly to all qualified scientific investigators in academic as well as industrial research communities. The initiative is planned as a partnership among the NIA/NIH and several other private and government organizations.
The NIA is accelerating the pace of Alzheimer's disease genetics research with its AD Genetics Initiative, a major new program to speed the process of creating a large repository of DNA and cell lines from families with multiple AD cases. The goal of this initiative is to develop the resources necessary for identifying the remaining late-onset AD (LOAD) risk factor genes, associated environmental factors, and the interactions of genes and the environment. The AD Genetics Initiative will intensify sample collection and encourage data sharing by providing access to the repository to qualified investigators.
- Hebert, op.cit.
- Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, and Kukull WA: Survival after initial diagnosis of Alzheimer disease. Ann Intern Med 140: 501-509, 2004.
- See http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm. Statistics are taken from the 1999-2001 National Health Interview Survey and 1999-2000 National Health and Nutrition Examination Survey (estimates projected to year 2002).