Managing Chronic Illness: A Possible Preventive Strategy for AD?

As we’ve seen with exercise and diet, evidence suggests that what may be good for the heart may be good for the brain. Moreover, metabolic changes that occur in a variety of chronic diseases of aging, such as heart disease, stroke, high blood pressure, and diabetes, may contribute to the development of AD, affect the severity of AD, or cause vascular dementia (Luchsinger et al., 2005; Curb, 2005).

However, it has been difficult to untangle the association between AD and these chronic diseases. Scientists have offered several possible explanations. For example, many believe that atherosclerosis, which may or may not be clinically apparent as heart disease or stroke, may add to or accelerate cognitive decline in people who already have AD. Or, it is possible that metabolic changes related to chronic disease, such as elevated insulin levels in diabetes, may actually increase the amount of AD pathology that accumulates in brain tissue and directly contribute to the development of AD. Other possibilities or a combination of factors also may explain the associations. As we develop new strategies to treat AD, it will be important to know whether the metabolic changes related to chronic vascular disease actually increase the amount of AD pathology or whether they independently cause dementia.

These relationships need to be sorted out because heart disease and stroke are major causes of illness and death. Diabetes, high blood pressure, and other risk factors for these chronic diseases can, to a large extent, be modified by diet, exercise, and other lifestyle changes, so it is important to know whether reducing risks of or controlling diabetes and high blood pressure also may reduce AD risk.

Heart Disease and Stroke

Currently, much of our knowledge about the associations between heart disease, stroke, cognitive decline, and dementia comes from epidemiologic studies. For example, the NHLBI’s Cardiovascular Health Study and NIA’s Cardiovascular Health Cognition Study have provided valuable data about the relationships between cardiovascular risk factors and AD because they include cognitive decline and dementia related to vascular disease as a key element of their design. In two recent analyses of CHS data, University of Pittsburgh investigators explored the relationships between cardiovascular disease and dementia. In the first study, the investigators showed that the risk of AD was 30 percent higher in people who had a history of cardiovascular disease other than stroke, compared with those without such a history (Newman et al., 2005). In the second study, investigators showed that vascular dementia and mixed dementia (vascular dementia and AD occurring simultaneously) account for a large proportion of new dementia cases (Kuller et al., 2005). An important result of the study was that it demonstrated the value of MRI as a diagnostic tool (see "Major AD Research Initiatives" for more on NIA’s Neuroimaging Initiative).

Investigators working with HAAS data explored whether men with beta-amyloid plaques and NFTs had an increased chance of crossing the threshold to clinical dementia if they also had cerebrovascular damage (Petrovitch et al., 2005). These Pacific Health Research Institute investigators found that, indeed, in men who had NFTs, dementia increased with increasing plaque density, particularly in the presence of cerebrovascular damage. This association was strongest in men who had the fewest plaques, suggesting that preventing cerebrovascular damage may be critically important in preserving cognitive abilities in older people.

As this area of research has blossomed, investigators have conducted studies of additional groups to explore associations between vascular disease and AD. For example, researchers from the Rush University Alzheimer’s Disease Center have included cerebrovascular disease measures when examining brain tissue samples from deceased participants of the Religious Orders Study, a long-term study of aging among members of 40 religious communities (Bennett et al., 2005). Consistent with other studies, participants who had amnestic MCI had evidence of intermediate levels of both AD and stroke damage in their brain tissue. They also had clinical symptoms that were in between those of people without cognitive impairment and those of people with dementia.

Findings from these and other studies have provided sufficient evidence for NIA to support several clinical trials to investigate the association between heart disease risk and AD:

• Simvastatin and AD progression. This 18-month Alzheimer’s Disease Cooperative Study trial, which began in 2003, is testing whether simvastatin (Zocor), a commonly prescribed cholesterol-lowering drug, can safely and effectively slow the rate of cognitive decline in people with mild to moderate AD. Data from some, but not all, epidemiologic studies suggest that high blood cholesterol levels are a risk for late-life cognitive decline and AD. In animal studies, high cholesterol levels increase AD plaques and affect cognition, and these effects are reversed by statin treatment. Nevertheless, few positive data about cognition have emerged to date from statin longitudinal studies or drug trials. The ADCS trial will be a rigorous test of the statin hypothesis in people who already have AD. The trial is being conducted in dozens of sites around the country, and the enrollment of 406 participants is complete. Data are now being collected and analyzed. Some participants receive 20 mg of simvastatin for 6 weeks and then 40 mg of the statin for the rest of the study period. Others receive a placebo during the entire study. Clinical trial staff are tracking changes in participants’ cognitive functioning by measuring a number of indicators, including mental status, functional ability, behavioral disturbances, and quality of life.
• Supplements to reduce homocysteine and slow the rate of cognitive decline. Previous studies have shown that elevated levels of the amino acid homocysteine are associated with both heart disease and AD and that high homocysteine levels make some neurons vulnerable to dysfunction and death. Homocysteine levels can be reduced by high-dose supplements of folate and vitamins B6 and B12. NIA is currently supporting an ADCS clinical trial to determine whether reduction of homocysteine levels with high-dose supplements of folate, vitamin B6, and vitamin B12 will slow the rate of cognitive decline in older adults with AD. Participants in this clinical trial, which began in 2003, are divided into two groups: 60 percent of participants receive daily high-dose supplements (5 mg of folate, 25 mg of vitamin B6, and 1 mg of vitamin B12) and 40 percent receive a placebo. The research team has completed the enrollment of 400 participants, and data collection and analysis are ongoing.
• Preventing cognitive decline in women. This trial is an add-on to two ongoing NHLBI clinical trials of chronic disease prevention in women—the Women’s Health Study (WHS) and the Women’s Antioxidant Cardiovascular Study (WACS). WHS tested low-dose aspirin and antioxidant supplementation in healthy women, and WACS tested antioxidant and folate supplements in women who already had heart disease. Scientists hypothesize that these agents also may prevent AD. The add-on trial is examining whether these treatments provided any protection against cognitive decline. Both WHS and WACS have been completed, and study investigators are analyzing study results.

Diabetes and AD

The possible association of diabetes, insulin processing, and AD also is generating much interest among AD investigators. Type II diabetes mellitus is a major public health problem in the U.S. because it affects about one in five Americans older than 65 and has many serious health complications. A number of epidemiologic studies have suggested that people with diabetes have an increased risk of late-life cognitive problems, including MCI and AD, either as a direct result of high levels of blood sugar (hyperglycemia) or because of the conditions that are often associated with diabetes, namely high blood pressure, abnormal blood cholesterol levels, or too much insulin in the blood (Launer, 2005). Laboratory studies also have identified several pathways through which hyperglycemia can reduce neuronal viability (Launer, 2005). These include increases in oxidative stress, damage to endothelial and vascular function, and changes in gene transcription and expression in neurons.

This evidence has spurred research on a variety of fronts, from epidemiologic studies, to test tube and animal studies, to clinical trials. The objective of these studies is to determine whether diabetes is a risk factor for cognitive decline, and if so, whether treatment for diabetes may help lower risk of cognitive decline or AD. NIA is currently funding several diabetes clinical trials to see whether treating one or other aspect of diabetes will affect cognitive health and AD progression:

• ACCORD-MIND. This trial is an NIA-funded sub-study nested within NHLBI’s Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. ACCORD is aimed at evaluating whether intensive glucose, blood pressure, and lipid management can reduce cardiovascular disease in people with diabetes. ACCORD-MIND (ACCORD-Memory in Diabetes) will test whether these intensive 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. ACCORD-MIND participants will undergo periodic cognitive testing and MRI scans to assess change over time.
• Glucose regulation and memory in AD. There is growing evidence suggesting that insulin’s role in the brain’s energy metabolism is not properly regulated in AD. Individuals with AD are at increased risk of insulin resistance (a condition in which muscle, fat, and liver cells are not able to use insulin properly; people who are insulin resistant are at high risk of developing diabetes). A key hypothesis that has emerged from work on diabetes and AD is that insulin resistance induces inflammation and elevations in free fatty acid levels, which interact with insulin-associated increases in damaging beta-amyloid. In this short-term trial, researchers from the University of Washington will test this hypothesis by examining the effects of induced and improved insulin resistance on cognition, beta-amyloid levels, and inflammation. They predict that inducing insulin resistance will increase beta-amyloid levels and inflammatory markers and will impair cognition, and that these effects will be greater for participants with AD and those who are overweight. The trial also will determine whether improved cognition after treatment with rosiglitazone (Avandia), a drug that has anti-inflammatory properties and that improves the body’s ability to use insulin, will be associated with reduced levels of insulin, free fatty acids, and inflammation. The researchers hope that this study will provide valuable information about the mechanisms through which insulin resistance increases the risk of AD and about possible treatment approaches for reducing this risk.
• Rosiglitazone and amnestic MCI. In this 18-month multi-center trial, researchers from the University of Washington also will test the effects of rosiglitazone on attention and memory skills in older adults with amnestic MCI. This trial will examine the effects of this medication on brain structures that support memory and other cognitive abilities, as well as on biological markers associated with inflammation, insulin resistance, and cardiovascular disease. Study participants will be divided into two groups—one group will receive rosiglitazone, the other a placebo. 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. This 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 amnestic MCI.
• Innovative insulin administration and cognitive function. A 4-month clinical trial is being conducted to examine the effects of administering 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 AD. AD is associated with reduced levels of insulin in cerebrospinal fluid, and treatment with insulin has been shown to improve memory performance. However, insulin injections (a common way to administer insulin) can be problematic because they can sometimes result in hypoglycemia (low blood sugar). A nasal spray delivers insulin directly to the brain. Preliminary data on this alternative 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.

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