DIMENSIONS Spring 2008

FOCUS ON RESEARCH
ADRC researchers confirm Alzheimer’s disease begins years prior to diagnosis, as early as 50 years old

by Dana Martin and Elizabeth Sharpe

illustration of Beta amyloid Although we commonly think of Alzheimer’s disease (AD) as a disease of old age, studies have shown that AD is actually a progressive illness which begins years prior to diagnosis. Identifying people at increased risk of developing Alzheimer’s disease, when they have not yet developed symptoms of the disease, is important. Not only is it important for the benefit of those individuals at high risk, but also for researchers to better develop and test new preventative therapeutics, says ADRC Associate Director Dr. Elaine Peskind. But identifying these individuals is a difficult task, considering how little is still known about how and when Alzheimer’s disease begins.

Peskind and her collaborators are working to uncover pieces of this mystery. In July 2008, Peskind will present results from a recent cross-sectional study of 308 mentally healthy volunteers between 21 and 100 years of age at the International Conference on Alzheimer’s Disease in Chicago, results that were not only surprising, says Peskind, but downright scary.

photo of Elaine Peskind Peskind was lead author of a landmark study of 184 healthy volunteers published in the July 2006 issue of the Archives of Neurology. The results of the study suggested that amyloid plaques characteristic of Alzheimer’s disease may start forming between 50 and 60 years of age, much earlier than previously assumed.

By the age of 85, nearly half the population has dementia, and at least 70 percent of those cases are Alzheimer’s disease. The disease is clearly age-related, says Peskind. Every five years after the age of 65, the disease doubles in prevalence. But what’s scary, says Peskind, is that the slowly evolving process leading to the disease is beginning much, much earlier. Between the ages of 50 and 60 something happens, she says, explaining the “something” is like flipping a switch, a period when the action starts and a transformation takes place. Peskind and researchers from six medical centers are trying to uncover that “something” in the disease process.

In the previously published study, they looked at what happens across the adult life span to one of the most studied markers for Alzheimer’s disease, amyloid beta 42 (Aß42), and how this protein is affected by age and the presence of one form of apolipoprotein E (APOE*4), a genetic risk factor for Alzheimer’s disease. Amyloid beta 42 is the toxic form of amyloid that makes up brain plaques in Alzheimer’s disease. In the just-finished, larger study using 308 volunteers, Peskind and researchers from four of the original six sites confirmed that APOE*4 had a very strong effect on the levels of cerebrospinal fluid amyloid beta 42 (Aß42) in both men and women. Cerebrospinal fluid is the clear fluid that the brain literally “floats” in. The fluid is inside and outside the brain and runs down around the spinal cord, too. Previous studies have shown that cerebrospinal fluid Aß42 levels decrease in patients with Alzheimer’s disease and Aß42 levels in the brain increase. These studies used mouse models of Alzheimer’s disease and positron emission tomography (PET) imaging of living humans with and without Alzheimer’s disease using the Pittsburgh compound. PET imaging using the Pittsburgh compound, which is only used for research, produces a color-enhanced image of the brain which highlights areas in the brain where the Pittsburgh compound attaches to amyloid plaques. Cerebrospinal fluid Aß42 levels likely go down because Aß42 is being deposited into plaques in the brain. Plaques work like a trap for the Aß42; they pull the Aß42 out of the spinal fluid.

How did a person’s age, gender, and the presence of apolipoprotein E (APOE*4) influence the levels of cerebrospinal fluid Aß42? University researchers in Washington, California, Oregon, Pennsylvania, and Indiana analyzed results of cerebrospinal fluid samples from men younger than 60 years old in the study. They found the levels of cerebrospinal fluid Aß42 decreased slightly, but not significantly, regardless of APOE*4. Men in the study who were older than 60 years of age and who had the APOE*4 also had significantly lower levels of cerebrospinal fluid Aß42.

Women in the study had a different pattern than men. Prior to age 50, cerebrospinal fluid Aß42 levels were constant in all the women. There was no change. After the age of 50, however, cerebrospinal fluid Aß42 levels decreased significantly for the women in the study who had APOE*4 when compared to the women in the study who did not have APOE*4.

Peskind cautions against assuming that having APOE*4 means a person will definitely develop Alzheimer’s disease. People without APOE*4 have also been diagnosed with the disease. Half of Alzheimer’s patients do not have an APOE*4 gene at all. Results of this study support previous epidemiological findings that APOE*4 causes earlier onset of Alzheimer’s disease. Individuals with APOE*4 will develop the disease about ten or fifteen years earlier than those without the APOE*4. So, if the same individual without APOE*4 would be diagnosed with Alzheimer’s disease by the age of 85, then the individual with APOE*4 would likely be diagnosed by the age of 70 or 75.

The results of the study also show Aß42 deposits in the brain may be already starting between the ages of 50 and 60, a period in which most individuals are cognitively normal. So, researching preventive therapies at the age of 65 or older is too late. To determine therapeutic benefits, Peskind says, we’ve got to be investigating long-term effects of preventive therapies on people as young as 45.

Peskind adds that more research is needed and a follow-up study will be done, including an enhanced study on healthy individuals between the ages of 45 and 60. She says volunteers are needed here in Seattle to take part in the enhanced study.

For more information on the study and to participate, call the ADRC Research Line at 1-800-317-5382.

Sources:

Results of the latest study will be presented at the International Conference on Alzheimer’s Disease in July 2008 (abstract title: “Age and APOE Related CSF AD Biomarker Changes in Normal Controls”). Researchers include Ge Li, Douglas R. Galasko, Joseph F. Quinn, Jeffrey A. Kaye, Christopher M. Clark, Martin R. Farlow, Charles DeCarli, Murray A. Raskind, Eric C. Petrie, James Leverenz, Jane Shofer, Gerard D. Schellenberg, Barbara Cottrell, and Elaine R. Peskind.

Results of the original study were published in volume 63 of the Archives of Neurology: “Age and Apolipoprotein E*4 Allele Effects on Cerebrospinal Fluid Beta-Amyloid 42 in Adults With Normal Cognition.” Researchers on the study included: Elaine R. Peskind, Ge Li, Jane Shofer, Joseph F. Quinn, Jeffrey A. Kaye, Chris M. Clark, Martin R. Farlow, Charles DeCarli, Murray A. Raskind, Gerard D. Schellenberg, Virginia M.Y. Lee, and Douglas R. Galasko.

Research was supported by grants from the National Institute on Aging; the National Alzheimer’s Coordinating Center; Friends of Alzheimer’s Research; Alzheimer’s Association of Western and Central Washington; an anonymous foundation; and the Department of Veterans Affairs.


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