Alzheimer's, Dementia & Mental Health
Alzheimer's Risk Gene Disrupts Brain's Wiring 50
Years Before Disease Hits Seniors
Whopping 88% of Caucasians have this clusterin gene; good news is it gives you 50 years to try to stop Alzheimers
and it's not most dangerous gene
May 26, 2011 - What if you were told you carried a
gene that increases your risk for Alzheimer's disease? And what if you
were told this gene starts to do its damage not when you're a senior
citizen but when you're young? Brace yourself, here it comes...
Scientists know there is a strong genetic component
to the development of late-onset Alzheimer's. In 1993, researchers
discovered a gene known as ApoE4 carried by about a quarter of us
that triples the risk for getting Alzheimer's.
In 2009, three more risky
genes were discovered, and one of them, called clusterin, or CLU, was
found to up the risk of getting Alzheimer's by another 16 percent.
But nobody could explain what the CLU gene actually
did. Now, UCLA researchers know, and the explanation is a doozy: This
risk gene begins to damage your brain a full 50 years before people
normally get Alzheimer's.
In the current online edition of the Journal of
Neuroscience, Paul Thompson, a UCLA professor of neurology, and his
colleagues report that the C-allele of the CLU gene (an allele is one of
two or more forms of a gene), which is possessed by 88 percent of
Caucasians, impairs the development of myelin, the protective covering
around the neuron's axons in the brain, making it weaker and more
vulnerable to the onset of Alzheimer's much later in life.
The researchers scanned the brains of 398 healthy
adults ranging in age from 20 to 30 using a high-magnetic-field
diffusion scan (called a 4-Tesla DTI), a newer type of MRI that maps the
brain's connections. They compared those carrying a C-allele variant of
the CLU gene with those who had a different variant, the CLU T-allele.
They found that the CLU-C carriers had what
brain-imaging researchers call lower "fractional anisotropy" a widely
accepted measure of white-matter integrity in multiple brain regions,
including several known to degenerate in Alzheimer's.
In other words, young, healthy carriers of the
CLU-C gene risk variant showed a distinct profile of lower white matter
integrity that may increase vulnerability to developing the disease
later in life.
The discovery of what this gene does is interesting
on several levels, said Thompson, the senior author of the study.
"For example, Alzheimer's has traditionally been
considered a disease marked by neuronal cell loss and widespread
gray-matter atrophy," he said. "But degeneration of myelin in
white-matter fiber pathways is more and more being considered a key
disease component and another possible pathway to the disease, and this
discovery supports that."
Thompson said four things are surprising with the
discovery of this gene's function:
1. This risk gene damages your brain a full 50
years before people normally get Alzheimer's. The damage can be seen on
an MRI scan, but there are no symptoms yet.
2. It's now known what this mysterious gene does
namely, make your brain wiring vulnerable to attack by impairing the
wiring before any senile plaques or tangles develop.
3. Rather than being a gene that few people
have, a whopping 88 percent of Caucasians have it. "So I guess you could
say the other 12 percent have an 'Alzheimer's resistance gene' that
protects their brain wiring," said Thompson, who is also a member of
UCLA's Laboratory of Neuro Imaging and the UCLA Brain Research
Institute.
4. Finally, he said, knowing the role of this
gene is useful in predicting a person's risk of the disease and in
seeing if you can step in and protect the brain in the 50-year time
window you have before the disease begins to develop.
Of course, the obvious question is if most of us
have this "bad" gene, why isn't Alzheimer's rampant in young people?
Less myelination in CLU-C carriers may not
translate into poorer cognition in youth, said Thompson, because the
brain can compensate. "The brain has a lot of built in redundancy
miles and miles of brain connections," he said. Still, he said, with the
passage of time and when exacerbated by other factors, such as normal
neuron death as we age and plaque and tangle development in the early
stages of Alzheimer's reduced myelin integrity could facilitate
cognitive impairment.
"So it's unlikely we are seeing the earliest
possible signs of Alzheimer's-associated brain changes in these young
people," Thompson said. "It's more likely the reduced fiber integrity
represents an early developmental vulnerability that may reduce brain
resilience to later Alzheimer's disease pathology. Inn other words, its
mechanism of action may not be part of the classic Alzheimer's pathways
that lead to abnormal amyloid plaque and neurofibrillary tangle
accumulation in the brain."
The mapping of structural brain differences in
those at genetic risk for Alzheimer's disease is crucial for evaluating
treatment and prevention strategies, Thompson said. Once identified,
brain differences can be monitored to determine how lifestyle choices
influence brain health and disease risk.
"We know that many lifestyle factors, such as
regular exercise and a healthful diet, may reduce the risk of cognitive
decline, particularly in those genetically at risk for Alzheimer's, so
this reminds us how important that is," he said.
Notes:
Other authors included Meredith N. Braskie, Neda
Jahanshad, Jason L. Stein, Marina Barysheva, John M. Ringman and Arthur
W. Toga from UCLA; Katie L. McMahon and Greig I. de Zubicaray from the
University of Queensland in Brisbane, Australia; and Nicholas G. Martin
and Margaret J. Wright from the Queensland Institute of Medical Research
in Brisbane.
This study was supported by the National Institute
of Child Health and Human Development and the National Health and
Medical Research Council of Australia; the National Institutes of
Health; the UCLA Easton Center for Alzheimer's Disease Research; the NIH/National
Library of Medicine; the ARCS Foundation; and the National Institute of
Mental Health.
The UCLA Department of Neurology, with over 100
faculty members, encompasses more than 20 disease-related research
programs, along with large clinical and teaching programs. These
programs cover brain mapping and neuroimaging, movement disorders,
Alzheimer's disease, multiple sclerosis, neurogenetics, nerve and muscle
disorders, epilepsy, neuro-oncology, neurotology, neuropsychology,
headaches and migraines, neurorehabilitation, and neurovascular
disorders. The department ranks first among its peers nationwide in
National Institutes of Health funding.
