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Cortex Area Thinner in Youth with Alzheimers-Related Gene

BETHESDA, Md., April 23, 2007--A part of the brain first affected by Alzheimers disease ( 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 brains 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 Alzheimers-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 Alzheimers.

It was already known that adults destined to develop Alzheimers disease tend to have a smaller and less active entorhinal cortex ( This structure is the first to shrink in volume and to develop the neurofibrillary tangles ( characteristic of the disorder.

Previous studies had also implicated in Alzheimers 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 Alzheimers 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 Alzheimers — 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 Alzheimers disease, which, like the entorhinal cortex, are involved in learning and memory. The pattern of changes resembled that seen in early Alzheimers, but to a far lesser degree. For example, the entorhinal cortex thinning seen in Alzheimers 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 brains 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.

MRI scans revealed that children and adolescents with the ApoE4 gene variant, which is associated with Alzheimers 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 Alzheimers, 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

Entorhinal cortex (red) was thinnest in youth with Alzheimers-related ApoE4 gene variant. View of left entorhinal cortex from beneath the brain, with front of brain at top. Artists 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,

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Jules Asher
NIMH Press Office


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