Apart from age, the e4 variant of the APOE gene on chromosome 19 is the
best-documented risk factor for Alzheimer's disease. Although possession of
the variant is neither necessary nor sufficient for developing Alzheimer's,
those individuals who have the variant and develop Alzheimer's succumb to the
illness a good decade earlier than do persons who have the other two variants
of the gene—2 and e3—and who develop Alzheimer's.
The e4 gene variant is suspected of putting people on the fast track for
Alzheimer's by accelerating the rate of breakdown of myelin sheaths that
insulate brain nerves, a new study suggests. The greatest breakdown occurred
in those with the e4 variant, the next greatest breakdown in those with the e3
variant, and the least breakdown in those with the e2 variant.
The investigation was headed by George Bartzokis, M.D., director of the
University of California at Los Angeles Memory Disorders and Alzheimer's
Disease Clinic. The results were published in the January Archives of
Myelination is arguably the most uniquely human aspect of the human brain.
It results in the high processing speeds that underlie people's cognitive
functions. Myelination reaches a maximum in midlife, then declines with normal
aging. Moreover, persons with Alzheimer's are known to have more severe myelin
breakdown than healthy older subjects, and the APOE gene is known to transport
lipids for myelin maintenance and repair.
Thus, Bartzokis and his colleagues suspected that the means by which the
APOE e4 gene variant hastens the development of Alzheimer's might be by
hastening the breakdown of myelin. They decided that the first step toward
confirming this hypothesis would be to see whether myelin breakdown in healthy
older individuals is linked with the type of APOE gene variant they
The researchers recruited 102 healthy individuals between the ages of 55
and 75 for the study. They found that 12 had the e2 variant, 70 had the e3
variant, and 20 had the e4 variant. There were no significant differences
between the three gene-variant groups in terms of age, education, gender, or
Mini-Mental State Examination scores.
They then used magnetic resonance imaging coupled with a technique called
transverse relaxation rate measures to assess indirectly the structural
integrity of myelin sheaths in the three gene-variant groups. The areas of the
brain they focused on included both early-myelinating regions—say, the
visual pathway circuits of the corpus callosum splenium—and
late-myelinating nerve regions—for example, the frontal lobes. They were
particularly interested in the latter since they support executive functions
and recent memories, are especially eroded with normal aging, and are
especially degraded by Alzheimer's.
They found that the breakdown of late-myelinating nerve circuits, but not
of early-myelinating nerve circuits, was linked with APOE gene status. The
greatest decline in late-myelinating circuits occurred in subjects with the e4
variant, the next greatest decline in those with the e3 variant, and the least
decline in those with the e2 variant.
The investigators thus believe that by linking the e4 variant to the
accelerated breakdown of late-myelinating nerves, they have partially
confirmed their hypothesis that the APOE e4 variant hastens the development of
Alzheimer's by hastening the breakdown of myelin.
However, only prospective studies can explain how possession of the e4
variant might actually speed up myelin breakdown, the scientists wrote in
their study report. They will now be conducting such studies, Bartzokis told
Also, "combining APOE status with noninvasive measures of myelin
breakdown may be useful in assessing treatment strategies for the primary
prevention of Alzheimer's," the scientists wrote.
"Funding possibilities for such novel primary-prevention strategies
are being pursued," Bartzokis told Psychiatric News.
Jeffrey Cummings, M.D., added, "These findings set the stage for
studies that will investigate the effects of diets and medications that
contribute to myelin maintenance." Cummings is director of the UCLA
Alzheimer's Disease Research Center and was one of the study
The study was funded by the National Institutes of Health, California
Department of Health Services, Sidell-Kagan Foundation, and Department of
An abstract of "Apolipoprotein E Genotype and Age-Related
Myelin Breakdown in Healthy Individuals" is posted at<http://archpsyc.ama-assn.org/cgi/content/short/63/1/63>.▪
Arch Gen Psychiatry20066363