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LEADING THE FEDERAL EFFORT ON AGING RESEARCH

Attention to Nongenetic Risk and Protective Factors Pays Off


Epidemiologic studies, animal studies, and clinical trials are all important in identifying potential factors that may contribute to or protect people from AD risk—separately or interactively with genetics. In the past several years, two areas of focus have emerged: lifestyle factors and the management of health conditions. Scientists also have continued their research interest in looking at estrogen and AD.

Lifestyle Factors and AD
Several elements of a healthy lifestyle, including a nutritious diet, regular physical activity, not smoking, and strong social networks, can help people stay healthy as they grow older. An important reason for this benefit is that lifestyle choices strongly affect the risk of several chronic diseases, including heart disease, diabetes, and stroke, that commonly affect people as they age. Evidence is emerging that AD may share some of these risk factors. Findings from epidemiologic research, basic studies in animals, and limited clinical trials suggest that an array of lifestyle factors may influence the risk of developing age-related cognitive decline, aMCI, or even AD.

  • As part of a large longitudinal study of older women, researchers at the San Francisco Coordinating Center and California Pacific Medical Center Research Institute examined the relationship between quality of sleep and cognitive function (Blackwell et al., 2006). The investigators found that disruptions to sleep, rather than the total amount of sleep, were consistently related to reductions in cognitive function. Another study of cognitively healthy women living in the community found a similar association between cognitive decline and sleep quality but not total sleep time (Yaffe et al., 2007).
  • It is well recognized that the damage of AD often adds to and interacts with other changes in the brain to cause cognitive impairment. Two studies from the Memory and Aging Project provide supporting evidence for this observation. In one analysis of more than 600 cognitively healthy people, investigators found that chronic psychological distress was associated with a nearly threefold increased risk of AD; change in a global measure of cognition; and change in episodic memory, the clinical hallmark of AD (Wilson et al., 2006). In a separate study, researchers found that social engagement might also modify the severity of dementia (Bennett et al., 2006b). Although individuals with larger social networks did not have fewer plaques or tangles than more isolated individuals in the study, AD pathology had a smaller effect on the cognition of the more socially connected individuals. This correlation was similar to the protective effect provided by years of formal education.
  • Investigators with the Group Health Cooperative in Seattle, Washington, have been following 1,740 older adults in the Adult Changes in Thought Study (Larson et al., 2006). Every 2 years, participants undergo physical and cognitive tests, answer questions about their lifestyles, and are assessed for dementia. After 6 years, the investigators found that the risk of AD in people who exercised three or more times per week, at least 15 minutes per day, was 31 percent lower than in those who exercised fewer than three times per week. This result suggests that regular exercise is associated with a delay in the onset of AD.

Epidemiologic studies correlate lifestyle factors with altered cognitive function. Epidemiology cannot, however, establish a cause-and-effect relationship. To directly examine cause and effect, NIA is sponsoring several clinical trials to test the questions raised by observational and animal studies and to specifically look at the effects of one lifestyle factor—physical activity and exercise—on cognitive function in older adults.

  • Researchers from the University of Illinois at Urbana-Champaign conducted functional magnetic resonance imaging (MRI) tests on older adults before and after a 6-month program of brisk walking (Erickson et al., 2007). Results showed that neuronal activity in the frontal cortex increased with increases in participants’ cardiovascular fitness. A similar trial conducted by University of Illinois investigators showed that brain volume increased as a result of a walking program (Colcombe et al., 2006). These findings suggest a strong biological basis for the role of aerobic fitness in helping to maintain the health and cognitive functioning of adults as they age, at least in the short term.
  • A small-scale clinical trial is looking at the effects of 1 year of aerobic fitness training on cognition and brain activity and structure in older adults. Other small trials are examining the role of aerobic exercise on electrocortical and behavioral measures in older adults and assessing the effects of a short aerobic conditioning program on cognitive function in older adults with aMCI.
  • A 3-year trial of a group exercise and health education intervention in people with aMCI is examining a variety of issues, such as whether the exercise intervention will slow the progression from aMCI to dementia. More recently, researchers at Wake Forest University started a pilot study to assess whether an intervention involving physical activity and cognitive training reduces significant cognitive decline in memory-impaired older individuals. The Seniors Health and Activity Research Program-Pilot (SHARP-P) will compare the outcomes of physical activity, cognitive training, and combined physical activity and cognitive training with those of health education.

Additional clinical trials are critical to discern whether physical activity and exercise can, in fact, prevent or delay long-term cognitive decline or AD and, if so, to determine the type and amount of physical activity necessary.

Advising the Public Before All the Scientific Results Come In

Although the evidence to date suggests that physical activity and other lifestyle choices, such as mentally stimulating activity, a healthy diet, and social engagement, have positive effects on brain function and may reduce risks of cognitive decline and AD, results from definitive clinical trials will not be available for several years.

Even so, experts can recommend that older adults (and other age groups) participate in these activities. These low-risk, low-cost interventions have many proven benefits for overall healthy aging. For example, regular physical activity and a healthy diet help reduce the risk of age-related diseases and conditions, such as heart disease and type 2 diabetes. Social activities with friends and family and the pursuit of mentally stimulating activities help people feel engaged.

Health Conditions and AD
A growing body of evidence suggests that the metabolic changes that occur in a variety of age-related chronic diseases, such as heart disease, stroke, high blood pressure, and type 2 diabetes, may contribute to the development of AD, affect the severity of AD, or cause vascular dementia (a loss of thinking and reasoning abilities caused by stroke or other forms of brain injury related to damage to the brain’s blood vessels). However, these relationships are complex. Several studies in the past year have attempted to untangle them.

  • Investigators with the Memory and Aging Project examined the brain tissue of deceased participants who had donated their brains to the study (Schneider et al., 2007). Results showed that about one-third of the participants had evidence of strokes, which increased the odds of having AD-related reductions in memory function.

  • At least four long-term studies have linked diabetes with a decline in cognitive function. In one of these studies, a Columbia University research team examined whether diabetes is related to an increased risk of aMCI (Luchsinger et al., 2007). Working with a large multiethnic population with a high prevalence of diabetes, the researchers found that diabetes was associated with a significantly increased risk of aMCI as well as other types of MCI.

  • Evidence increasingly suggests that overweight and obesity may increase AD risk. Two studies explored this issue by examining the relationship of obesity or overweight at midlife and cognitive performance or AD in later life. In the first study, conducted at the Kaiser Permanente Division of Research in Oakland, California, and supported by NIDDK, investigators found that participants who were obese (a body mass index of 30 or more) during midlife had a threefold increase in AD risk (Whitmer et al., 2007). Those who were overweight (a body mass index of 25 to 29) had a twofold increase in AD risk.

    In the second study, Boston University School of Medicine researchers used data from 1,814 Framingham Study participants to examine whether obesity at midlife affected the impact of hypertension (a key risk factor for heart disease) on cognitive abilities (Wolf et al., 2007). The study, supported by NIA, NHLBI, and NINDS, found that participants with a high measure of abdominal obesity and hypertension did worse on tests of executive function and visuomotor skills than did those who weighed less and had normal blood pressure. Furthermore, hypertensive participants who were most obese did less well on the tests compared with those who were not as obese. This finding suggests that obesity may have exacerbated the impact of hypertension on the brain. The researchers concluded that controlling abdominal obesity and blood pressure in midlife may help reduce the risk of cognitive problems and dementia in later life.

As noted earlier, epidemiologic studies cannot determine cause-and-effect relationships even though they provide valuable information about associations between chronic diseases and aMCI or AD. As a result, NIA is supporting several clinical trials to see whether managing these conditions might reduce the risk of cognitive decline and dementia.

Clinical trials have examined whether two treatments—simvastatin (a cholesterol-lowering drug) and vitamin supplements that reduce homocysteine (an amino acid linked to heart disease and AD)—could slow the rate of cognitive decline in older adults with AD. These trials were recently completed, and the data are being analyzed.

Other clinical trials are underway to examine whether diabetes-related interventions can prevent or delay the progression of cognitive decline or AD:

  • ACCORD-MIND (ACCORD-Memory in Diabetes). This NIA-funded trial is nested within NHLBI’s Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which is evaluating whether intensive glucose, blood pressure, and lipid management can reduce cardiovascular disease in people with type 2 diabetes. ACCORD-MIND will test whether these interventions also can reduce the rates of cognitive decline and structural brain change in 2,800 of the ACCORD study participants over a 4-year period. Participants will undergo periodic cognitive testing and MRI scans to assess change over time (Williamson et al., 2007).
  • RECALL. In this 18-month multi-center trial, researchers from the University of Washington will test the effects of the drug rosiglitazone on attention and memory skills in older adults with aMCI. Rosiglitazone has anti-inflammatory properties and improves the body’s ability to use insulin. This trial will examine the medication’s effects on brain structures that support memory and other cognitive abilities, as well as on biological markers associated with inflammation, insulin resistance, and cardiovascular disease. As with most clinical trials, participants will be divided into two groups—one will receive rosiglitazone, the other a placebo (an inactive substance). Participants also will have MRIs before and at the end of treatment to determine whether rosiglitazone slows the rate of atrophy in brain structures that support memory. The RECALL trial will provide valuable data about the effects of improved insulin sensitivity, reduced insulin levels in the body, and reduced inflammation on cognitive function and biological markers in aMCI.
  • SNIFF 120. This 4-month clinical trial will examine the effects of a nasal-spray form of insulin on cognitive function, ability to carry out daily activities, glucose metabolism in the brain, and levels of beta-amyloid in people with aMCI or AD. AD is associated with reduced levels of insulin in cerebrospinal fluid, and treatment with insulin has been shown to improve memory performance. Insulin injections can be problematic because they can result in hypoglycemia (low blood sugar). A nasal spray delivers insulin directly to the brain. Preliminary data on this way to administer insulin show that people with AD improved their verbal memory and did not develop hypoglycemia. This clinical trial will provide useful data on the safety, feasibility, and potential efficacy of this innovative treatment approach, which investigators may use to plan future large-scale clinical trials.
  • Metformin. This NIA-funded clinical trial’s primary aim is to determine whether metformin, a drug used safely and effectively to treat diabetes, reduces the risk of cognitive decline. Very high blood insulin levels have surfaced as a potential risk factor for AD. Half of the population 60 years and older may have such high insulin levels, and the prevalence is increasing with the epidemic of overweight and obesity. The research team at Columbia University hypothesized that metformin could prevent cognitive decline by reducing insulin levels in overweight and obese people who do not have diabetes but who do have aMCI. In this new, 12-month pilot trial, 60 people with aMCI will receive either metformin (1,000 mg twice a day) or a placebo. The investigators also want to determine whether metformin prevents the decrease in brain metabolism that is characteristic of the transition from aMCI to AD.
  • POEM (Pioglitazone or Exercise). Metabolic syndrome is an increasingly prevalent medical condition that raises a person’s risk of developing diabetes and heart disease. Its cardinal features are insulin resistance (a condition in which muscle, fat, and liver cells are not able to use insulin properly), physical inactivity, and abdominal obesity. Recently, several large studies have linked metabolic syndrome to the development of cognitive impairment. In a new NIA-funded pilot trial, investigators at the University of Colorado, Denver, will examine whether treatments for metabolic syndrome in older people with aMCI can improve, stabilize, or lessen the decline in cognitive function compared with a no-treatment group. Investigators plan to test the diabetes drug pioglitazone and endurance exercise training, both of which have been shown to ameliorate many components of metabolic syndrome, including insulin resistance, and to have positive effects on cognition. This pilot trial also will evaluate how the interventions affect cognition and inflammatory biomarkers.

Estrogen and AD
Production of estrogen, a hormone made by a woman’s ovaries, declines dramatically after the childbearing years. During the past 25 years, laboratory and animal research and human observational studies have suggested that estrogen may protect the brain. Experts have wondered whether using estrogen could reduce the risk of AD or slow its progression.

Clinical trials have shown that estrogen does not slow the progression of already-diagnosed AD and does not effectively treat or prevent the disease if treatment begins in later life. However, questions remain as to whether some forms of estrogen might help if started somewhat earlier than the older ages already tested. These questions are now being investigated.

  • NINDS-supported investigators at the Mayo Clinic College of Medicine have found that women who had one or both ovaries removed before menopause had an increased risk of cognitive impairment or dementia compared with a control population (Rocca et al., 2007). They also found that ovary removal at a young age (younger than age 45) further increased the risk of dementia. This risk was significantly diminished when women were treated with estrogen until the age of natural menopause. These findings underscore the relationship between estrogen and cognition and open additional avenues of investigation into estrogen’s full therapeutic effects.
Framingham Study Data Provide Insights into the Lifetime Risk of Stroke and Dementia

The Framingham Heart Study, begun in 1948, is a long-term investigation of physical and environmental factors that influence the development of cardiovascular disease in healthy individuals. The study, funded by NHLBI, is still following the remaining members of the original study group, as well as the remaining members of a group of 5,000 people who were recruited in 1971 into the Framingham Offspring Study. Investigators are now working with the third generation of volunteers in this landmark epidemiologic study.

One of the distinguishing elements of the study has been “add-on” components funded by other NIH institutes, including NIA and NIMH. These add-on components have provided a cost-effective opportunity for scientists to examine additional issues using existing study populations.

The Framingham Study’s rich harvest of data has allowed researchers to explore many dimensions of the relationship between cardiovascular risk factors, cognitive health, and AD. The fact that it has been going on for so many years also gives scientists a unique opportunity to study certain aspects of an issue. For example, in describing the burden of any disease, scientists often refer to incidence, or the number of people who may develop the disease in a given time period, usually a year. However, some investigators have argued that “lifetime risk,” or the risk of developing a disease across the remaining estimated lifespan, may provide a more accurate measure of the possible burden to a population than incidence. They note that lifetime risk reflects risk across a longer period of time rather than does risk over a single year.

Framingham investigators at the Boston University School of Medicine conducted a lifetime risk analysis using many years of follow-up data from the original group of Framingham participants. This analysis, which was supported by NHLBI, NIA, and NINDS, focused on the lifetime risk of stroke and AD, two conditions of enormous public health concern.

Using 51 years of follow-up data, the analysis showed that the lifetime risk of stroke was 1 in 5 for a middle-aged woman and 1 in 6 for a middle-aged man. For AD, using 29 years of follow-up data, lifetime risk was 1 in 5 for a middle-aged woman but only 1 in 10 for a middle-aged man. The authors concluded that measures of age- and sex-specific lifetime risk indicate that a middle-aged person has a 1 in 3 chance of having a stroke or becoming demented. These rates have serious implications for the provision and cost of future health care services.

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Page last updated Jan 06, 2009

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