If Alzheimer's is ever to be prevented, it may be necessary to focus on
young adults. Plaques may already be forming in their brains, at least if they
carry the APOE e4 gene variant.
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
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
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
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
An abstract of “Age and Apolipoprotein E4 Allele Effects on
Cerebrospinal Fluid Beta-Amyloid 42 in Adults With Normal Cognition” is