Early signs of the development of Alzheimer's disease can be seen in the cerebrospinal fluid of middle-aged adults who are genetically predisposed to the neurologic condition, according to a report in the July issue of the Archives of Neurology, one of the JAMA/Archives journals.
The two strongest risk factors for Alzheimer's disease are aging and the presence of an allele (type of gene) known as apolipoprotein E*4 (APOE*4), according to background information in the article. Those with the APOE*4 allele develop clinical dementia about 10 to 15 years earlier than those who do not have the APOE*4 allele. Previous studies have shown that the plaques that form in the brain during Alzheimer's disease, which are made of proteins known as β-amyloids, begin forming years before affected individuals experience any symptoms of the disease. As β-amyloid proteins, predominately of a type known as Aβ42, clump together, fewer are available to circulate through the nervous system. Therefore, lower levels of the Aβ42 in the cerebrospinal fluid surrounding the brain and spinal cord serve as biomarkers or chemical indicators of the development of Alzheimer's disease.
Elaine R. Peskind, M.D., VA Puget Sound Health Care System and University of Washington School of Medicine, Seattle, and colleagues estimated the combined effect of aging and the APOE*4 allele on levels of Aβ42 and another β-amyloid, Aβ40, in 184 adults (94 men and 90 women, average age 50 years). The participants underwent clinical and laboratory screening and were found to be cognitively normal-that is, they had no difficulties with thinking, learning or memory. Researchers took samples of cerebrospinal fluid in the morning after an overnight fast and measured participants' Aβ42 and Aβ40 levels in addition to determining whether each individual had the APOE*4 allele.
Those who were older and who had the APOE*4 allele were more likely to have lower levels of Aβ42. For those who did not have the APOE*4 allele, Aβ42 levels rose slightly until about age 50 years then begin to decline slowly. On the other hand, those with the APOE*4 allele experienced a slight decline in Aβ42 in their younger years and then a dramatic drop between ages 50 and 60 years. Levels of Aβ42 were not associated with scores on any cognitive or memory tests. "In persons with the APOE*4 allele, decline in cerebrospinal fluid Aβ42 concentration possibly begins in young adulthood, followed by marked acceleration of this decline beginning in midlife-decades before clinical manifestations of Alzheimer's disease," the authors write. The same relationship did not hold true for Aβ40, which, although it is also found in amyloid plaques, is less prevalent there than Aβ42; levels of Aβ40 did not change with age in those with the APOE*4 allele and decreased with age in those without the APOE*4 allele.
"These findings have implications for the preclinical diagnosis of Alzheimer's disease, as well as for treatment," the authors conclude. "Therapeutic strategies aimed at prevention of Alzheimer's disease may need to be applied in early midlife or even younger ages to have maximal effect on amyloid deposition. Primary prevention trials for Alzheimer's disease targeting elderly persons may be too late to affect the early stages of disease pathology."
This study was supported by grants from the U.S. National Institute on Aging; the National Alzheimer's Coordinating Center; Friends of Alzheimer's Research; Alzheimer's Association of Western and Central Washington; and the Department of Veterans Affairs.
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