CSF Findings Present Target For Alzheimer's Testing

Apart from age, the e4 variant of the APOE gene on chromosome 19 is the best-documented risk factor for Alzheimer's disease. People with Alzheimer's who have the variant develop the illness about 10 to 15 years earlier than they otherwise would.

How the e4 variant puts people on the fast track for alzheimer's may now have been discovered by Elaine Peskind, M.D., a University of Washington professor of psychiatry, and her co-workers. It accelerates the deposition of plaques in the brain.

Plaques, one of the major hallmarks of Alzheimer's, are composed mostly of the beta-amyloid 42 protein. Yet a decreased concentration of the protein in cerebrospinal fluid (CSF) is a diagnostic biomarker for established Alzheimer's disease. Although the reasons for this apparent contradiction are not clear, it also seems to be the case for lab animals. Specifically, mice genetically engineered to overexpress the beta-amyloid 42 protein experience as they grow older a parallel increase in plaques and a parallel decrease of the protein in CSF. Furthermore, plaques are known to take root in the brain years before Alzheimer's becomes clinically evident. So Peskind and her colleagues suspected that the protein's concentration in CSF would begin declining years before Alzheimer's symptoms emerged and that the decline would be markedly accentuated by the e4 variant.

To test this hypothesis, they analyzed CSF from 184 cognitively normal community volunteers ranging in age from 21 to 88 years for levels of beta-amyloid 42. Then they compared the levels according to the ages and APOE status of their subjects.

They found that without the e4 variant, beta-amyloid 42 levels rose slightly until around the age of 50, then fell slightly in subsequent years. But with the e4 variant, beta-amyloid 42 levels already declined slightly in young adulthood and plummeted rapidly after age 50 or so.

“These findings are consistent with acceleration by the APOE e4 allele of pathogenic beta-amyloid 42 brain deposition starting in later middle age in persons with normal cognition,” Peskind and her group concluded in their study report, which was published in the July Archives of Neurology.

In an accompanying editorial, Roger Rosenberg, M.D., editor of the Archives of Neurology, concurred.

The findings also have practical implications, he pointed out. Individuals with abnormally low CSF levels of beta-amyloid 42 for their age would be ideal candidates for testing possible Alzheimer preventives.

In their study report, Peskind and her team agreed. “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.”

The team will continue its efforts to further understand how the APOE e4 variant speeds up the development of Alzheimer's.

“First we want to increase the number of [cognitively] normal persons in our sample to at least 500 and to widen the age range,” Peskind told Psychiatric News. “We now have participants up to 101 years old and want to lower the age boundary to 18 years.”

The study also found a possible trend—women subjects largely accounted for the aging/APOE e4 variant effect, although there were not enough subjects to have a statistically significant interaction with gender. Peskind said, “We want especially to focus on women in the years between 50 and 60.”

The study was funded by the 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.

An abstract of “Age and Apolipoprotein E4 Allele Effects on Cerebrospinal Fluid Beta-Amyloid 42 in Adults With Normal Cognition” is posted at<http://archneur.ama-assn.org/cgi/content/abstract/63/7/936>.▪