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Experts Discover How a Genetic Mutation Causes Early-Onset Alzheimer's
By Kathleen Doheny
WebMD Health News
Reviewed by Laura J. Martin, MD
June 10, 2010 -- Researchers have discovered how mutations in a gene long known to be associated with early-onset Alzheimer's disease cause the brain disorder.
''We think we have the principal mechanism by how the gene is affected and causes the early onset of Alzheimer's," says researcher Ralph Nixon, MD, PhD, professor of psychiatry and cell biology at the New York University Langone Medical Center and director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research.
Nixon's team found that the gene normally helps clean ''debris'' from the brain, but the mutation hampers its ability to do so.
The discovery may eventually lead to treatments not only for early-onset Alzheimer's, but also the more common form that occurs later in life, Nixon tells WebMD.
The report is published online in the journal Cell.
Back Story: The Early-Onset Alzheimer's Gene
About 5.3 million Americans have Alzheimer's, the brain disorder that includes memory loss and loss of other intellectual abilities, according to the Alzheimer's Association. Of that 5.3 million, about 200,000 have the early-onset form.
Fifteen years ago, researchers found that mutations in a gene, named presenilin 1, were linked with early-onset Alzheimer's, which can affect people as young as in their 30s.
But no one understood, until now, exactly how the genetic mutation led to the disease, Nixon says. "Like in a lot of diseases, a gene is found and [then there is] a prolonged search for how it may cause the disease."
Focusing on the Presenilin 1 Gene
Nixon and his colleagues studied mouse models of Alzheimer's disease and the skin cells of early-onset Alzheimer's patients linked with presenilin 1 mutations.
They found that the gene normally performs a crucial function that enables cells to digest unwanted proteins. This was an unexpected function of the gene, Nixon says, the task of "getting rid of waste proteins, garbage proteins in the brain cells."
"It would be similar to a house cleaning where you have to get rid of material accumulating -- garbage and waste," Nixon tells WebMD. "The cell has a recycling system, taking that waste and digesting and processing it, so it can be used again."
''When that system doesn't work, you have an accumulation of proteins that are potentially toxic to the [brain] cells. It's similar to a house filling up with garbage and causing health problems."
Most efforts to develop drugs to treat Alzheimer's have focused on ridding the brain of microscopic protein fragments known as beta-amyloid, Nixon says. Some researchers say problems in the production, accumulation, or disposal of beta-amyloid fragments are what causes Alzheimer's.
But Nixon says his findings suggest there are alternative pathways that also could be targets of drug therapy and that the toxic buildup of amyloid may not be responsible for all the ''havoc'' in the brain.
Although the finding may seem to be helpful only for early-onset disease, not so, Nixon says. "The gene is mutated only in early onset, but the disruption it causes is seen not only in this form but in all forms," he says. The same type of damage is seen in regular Alzheimer's but perhaps occurs by a different mechanism, he says. What they learn in the future about how to correct the effects of the presenilin 1 mutations may apply to late-onset disease, too.
Genetic Mutations and Alzheimer's: Other Opinions
The study is preliminary, cautions William Thies, PhD, the chief medical and scientific officer for the Alzheimer's Association, one of the organizations funding the study.
The new report is the first to describe the presenilin1 gene's "ability to act as a cleanup agent," Thies says. ''It may become useful," he says, although more research is needed.
''One of the important things to remember here is, it's a mouse model," Thies says.
He acknowledges the finding is not of immediate benefit to Alzheimer's patients but may eventually prove useful in terms of treatment. "It may be more important for children of people with Alzheimer's," he says.
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Ralph Nixon, MD, PhD, professor of psychiatry and cell biology, New York University Langone Medical Center; director, Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research.
William Thies, PhD, chief medical and scientific officer, Alzheimer's Association.
Lee, J. Cell, June 25, 2010, vol 141: pp 1-13.
Alzheimer's Association: "What is Alzheimer's?"
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