16 May 2011

Alzheimer's risk gene begins disrupting brain 50 years before disease hits

by Kate Melville

Degeneration of myelin in the brain's white-matter fiber pathways is increasingly considered to be a key component of Alzheimer's disease and researchers now say that the process begins when we are young and that nearly 90 percent of Caucasians are vulnerable. The risk gene to blame is called clusterin (CLU) and it begins to damage the brain a full 50 years before people normally get Alzheimer's.

Reporting his findings in the Journal of Neuroscience, UCLA's Paul Thompson explained 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 later in life.

The researchers used MRI to scan the brains of around 400 adults. They compared those carrying a C-allele variant of the CLU gene with those who had a different variant, the CLU T-allele.

Thompson said that CLU-C carriers had 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.

"Alzheimer's has traditionally been considered a disease marked by neuronal cell loss and widespread gray-matter atrophy," Thompson explained. "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 about this gene's function:

But 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, Thompson hypothesizes, because the brain can compensate. "The brain has a lot of built in redundancy - miles and miles of brain connections," he said. "Still, 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. It's likely the reduced fiber integrity represents an early developmental vulnerability that may reduce brain resilience to later Alzheimer's disease pathology. In 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."

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Source: University of California - Los Angeles