Cortex Area Thinner in Youth with Alzheimer’s-Related
Gene
A part of the brain first affected by Alzheimer’s disease (http://www.nia.nih.gov/Alzheimers/)
is thinner in youth with a risk gene for the disorder, a brain
imaging study by researchers at the National Institute of Mental
Health (NIMH), one of the National Institutes of Health (NIH),
has found. A thinner entorhinal cortex, a structure in the lower
middle part of the brain’s outer mantle, may render these youth
more susceptible to degenerative changes and mental decline later
in life, propose Drs. Philip Shaw, Judith Rapoport, Jay Giedd,
and NIMH and McGill University colleagues. They report on how variation
in the gene for apoliproprotein (ApoE), which plays a critical
role in repair of brain cells, affects development of this learning
and memory hub in the June, 2007 Lancet Neurology.
“People with the Alzheimer’s-related variant of the ApoE gene
might not be able to sustain much aging-related tissue loss in
the entorhinal cortex before they cross a critical threshold,” explained
Shaw. “But the early thinning appears to be a harmless genetic
variation rather than a disease-related change, as it did not affect
youths’ intellectual ability. Only long-term brain imaging studies
of healthy aging adults will confirm whether this anatomical signature
detectible in childhood predisposes for Alzheimer’s.”
It was already known that adults destined to develop Alzheimer’s
disease tend to have a smaller and less active entorhinal cortex
(http://www.nia.nih.gov/Alzheimers/ResearchInformation/NewsReleases/Archives/PR2000/PR20000329MRI.htm).
This structure is the first to shrink in volume and to develop
the neurofibrillary tangles (http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/Hallmarks.htm)
characteristic of the disorder.
Previous studies had also implicated in Alzheimer’s one of three
versions of a gene that produces ApoE. The ApoE4 variant occurs
in 10-25 percent of the general population, but in 40 percent of
late-onset Alzheimer’s patients. The strongest genetic risk factor
for the disease discovered to date, ApoE4 has been linked to altered
brain activity in adults and impaired neuronal development.
Shaw and colleagues suspected that youth with ApoE4 would have
a thinner entorhinal cortex. To confirm this, they compared the
MRI (magnetic resonance imaging) scans of 239 healthy children
and teens with their ApoE gene types. Many were re-scanned as they
grew up to see if there was any ongoing thinning process traceable
to ApoE4.
Each individual inherits two copies of the ApoE gene, one from
each parent. Youth with at least one copy of the relatively rare
ApoE2 variant — which may confer a protective effect against
developing Alzheimer’s — showed the thickest entorhinal cortex.
This was the first evidence that the ApoE2 version, which is carried
by 5-10 percent of the population, affects brain structure, say
the researchers. Youth with two copies of ApoE3, the most common
version (65-85 percent prevalence), had intermediate cortex thickness.
Those with one or two copies of ApoE4 had the thinnest entorhinal
cortex.
ApoE4 gene type also predicted thinning of two other brain regions
(medial temporal and posterior orbitofrontal areas) affected early
in Alzheimer’s disease, which, like the entorhinal cortex, are
involved in learning and memory. The pattern of changes resembled
that seen in early Alzheimer’s, but to a far lesser degree. For
example, the entorhinal cortex thinning seen in Alzheimer’s disease
is about 10-fold greater than in the youth with ApoE4.
Although they did not test for possible learning and memory deficits,
the researchers found no difference in IQ attributable to ApoE gene
type. Nor did the E4 variant accelerate loss of cortex tissue. The
differences were fixed, and didn't progress. In fact, the researchers
noted evidence that ApoE4 may even promote survival in infancy and
protect the brain’s thinking capacity against damage from infectious
illness.
"In the future we hope to determine whether this thinner cortex
is associated with differences in brain activity during tasks of
learning and memory in children,” said Shaw.
Also participating in the research were: Kristin Taylor, A. Blyth
Rose, Deanna Greenstein, Liv Clasen, NIMH; Jason Lerch, Jens Pruessner,
Alan Evans, Montreal Neurological Institute, McGill University.
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MRI scans revealed
that children and adolescents with the ApoE4 gene variant,
which is associated with Alzheimer’s disease, had a thinner
entorhinal cortex, the first brain area to be affected
by the brain disorder. Youth with the much rarer ApoE2
variant, thought to protect against Alzheimer’s, had the
thickest cortex. The vertical lines in the graph show ranges
of thickness, with the red dots being the averages. Source:
Philip Shaw, M.D., NIMH Child Psychiatry Branch |
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Entorhinal cortex (red)
was thinnest in youth with Alzheimer’s-related ApoE4 gene
variant. View of left entorhinal cortex from beneath the
brain, with front of brain at top. Artist’s rendering. Source:
Philip Shaw, M.D., NIMH Child Psychiatry Branch |
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website, http://www.nimh.nih.gov.
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