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ALZHEIMER AND DIABETES LINKED IN NEW STUDIES

MADRID—New evidence from epidemiological studies support the link between diabetes and Alzheimer disease, several research teams reported here in July at the International Conference on Alzheimer's Disease and Related Disorders sponsored by the Chicago-based Alzheimer's Association.

“There is growing evidence that midlife cardiovascular risk factors such as untreated hypertension, diabetes mellitus, hyperlipidemia, and physical activity predispose people to various forms of late-life cognitive impairment, including Alzheimer disease,” said one of the investigators, Jeannette Gustat, PhD, Clinical Assistant Professor of Epidemiology at Tulane University in New Orleans. “How early in life these factors begin to operate remains unknown.”

Dr. Gustat and colleagues mined data from the Bogalusa Heart Study, a 24-year population-based study monitoring the cardiovascular risk factors of African-American and white children in an area of Louisiana that borders southwestern Mississippi. Bogalusa was selected for the community-wide program because it mirrors the biracial makeup of many communities in the southeastern United States.

Dr. Gustat examined 72 people, ages 24 to 44 years, who were given neuropsychological tests. The test scores were correlated with cardiovascular risk factors, including systolic and diastolic blood pressure, age, and insulin level.

Among results, higher levels of insulin were associated with poor performance on standardized Wechsler tests of memory (p<.03) and memory and second recall (p<.03). In addition, she found that higher insulin levels were negatively correlated with performance on reading tests for word recognition and comprehension (p<.03).

“Even within a younger population, performance on tests of cognitive function is related to age and cardiovascular risk factors,” Dr. Gustat said. “The findings emphasize the importance of maintaining cardiovascular health throughout the life span.”

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Dr. Jeannette Gustat: “There is growing evidence that midlife cardiovascular risk factors such as untreated hypertension, diabetes mellitus, hyperlipidemia, and physical activity predispose people to various forms of late-life cognitive impairment, including Alzheimer disease.”

Investigators will continue to monitor study subjects to determine if the relationship between impaired insulin processing and declining mental functioning is validated as part of the AD continuum.

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RELATIONSHIP BETWEEN AGE, DIABETES, AND AD

That relationship looks even stronger when individuals ages 75 and older are diagnosed with borderline diabetes – defined as blood glucose levels of 7.8 mmol/L (140 mg/dl) and 11.0 mmol/l (198 mg/dl), said Laura Fratiglioni, MD, Director of the Aging Research Center at the Karolinska Institute in Stockholm, Sweden. (See “Defining Diabetes” for diagnostic measures for diabetes.)

She found that patients with that level of impaired insulin processing have a 77 percent increased risk of later developing AD than those with normal blood glucose levels. But more worrisome, she said, is that there was a six-fold increase for the risk of AD within the next 10 years for people with borderline diabetes and severe high blood pressure, a systolic reading of greater than180 mmHg.

Over a nine-year period, Dr. Fratiglioni and colleagues followed 1,173 participants, ages 75 and older, who did not have diabetes or dementia at baseline; 47 had borderline diabetes. They underwent three examinations to assess both AD and dementia using DSM-III-R criteria.

After nine years, 19 of the 47 people had developed dementia. The investigators determined that subjects with borderline diabetes had a hazard ratio risk of dementia of 1.67 compared to all other individuals who did not have diabetes. Sixteen of 19 people with dementia were diagnosed as having Alzheimer disease. The hazard ratio for Alzheimer disease specifically was 1.77.

The data support the finding that “borderline diabetes is associated with an increased risk of developing dementia and Alzheimer disease in the elderly,” Dr. Fratiglioni said.

STUDY THROUGH KAISER PERMANENTE

In a third study, investigators at Kaiser Permanente Northern California in Oakland reviewed the records of patients with type 2 diabetes whose blood sugar was not well-controlled – including 22,852 men and women, ages 50 and older enrolled in the Kaiser Permanente of Northern California Diabetes Registry. These patients had at least one glycosylated hemoglobin (HbA1c) level measured between 1994 and 1996.

Rachel Whitmer, PhD, and colleagues at Kaiser Permanente, found that 105 patients with a HbA1c greater than 15 had a 78 percent greater risk of developing dementia – Alzheimer disease or cognitive decline – in the next 10 years.

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Dr. Susan Fratiglioni and colleagues reported that subjects with borderline diabetes had a hazard ratio risk of dementia of 1.67 compared to all other individuals who did not have diabetes. The hazard ratio for Alzheimer disease specifically was 1.77.

Among other findings, 1,286 patients with HbA1c between 10 and 11.9 were 16 percent more likely to have dementia; 1,143 patients with levels between 12 and 14.9 were 25 percent more likely to have dementia.

EXPERTS COMMENT

Several experts, who were not involved in the studies, commented that the new epidemiological data support a suspected link between diabetes and Alzheimer disease. And they noted that other studies have found a pathophysiological link, as well.

“We know that diabetes affects large and small blood vessels,” said Giancarlo LoGroscino, MD, PhD, Associate Professor of Neuroepidemiology at the Harvard Medical School, Boston. “But now we also believe – we have not yet proved it – that there is a link between diabetes and Alzheimer disease due to malfunctioning of a gene that is involved in the function of the insulin-degrading enzyme (IDE).”

John C. Morris, MD, Friedman Distinguished Professor of Neurology at Washington University in St. Louis, said that “the key purpose of enzymes such as IDE is to maintain equilibrium. Sometimes we need more insulin in the blood; other times we don't. When you study things long enough, you tend to find connections.

“It turns out that IDE, in addition to regulating insulin in the body, is also responsible for degradation of beta amyloid, which is implicated in the development of Alzheimer disease.”

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Dr. Giancarlo LoGroscino: “We know that diabetes affects large and small blood vessels. But now we also believe – we have not yet proved it – that there is a link between diabetes and Alzheimer disease due to malfunctioning of a gene that is involved in the function of the insulin-degrading enzyme.”

Dr. LoGroscino said, “We now think that alterations in the genetics of IDE involved in diabetes are similarly involved in Alzheimer disease. This is the biological pathway that appears to connect the two diseases. This is difficult to study, but there is a lot of evidence of the links, especially in epidemiological studies.”

ARTICLE IN BRIEF

  • ✓ Several epidemiological studies found a link between diabetes, Alzheimer disease, and dementia.

REFERENCES

• Blomqvist ME, Chalmers K, Prince JA, et al. Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain. Neurobiol Aging 2005;26(6):795–802.
    • Farris W, Mansourian S, Selkoe DJ, et al. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol 2004;164(4):1425–1434.
      • Farris W, Mansourian S, Guenette S, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003;100(7):4162–4167.