Root of the problem? Mutations in mitochondrial DNA may trigger late-onset Alzheimer's disease.

Mutations Tied to Common Form of Alzheimer's

The most common form of Alzheimer's disease isn't inherited, and little is known about its causes. Now, researchers have found a handful of DNA mutations that arise more frequently in patients with the disorder. The results bolster earlier suggestions that Alzheimer's is caused partly by deficits in cells' energy plants.

Researchers have found some of the genes involved in the familial form of Alzheimer's, which accounts for about 10% of cases and typically strikes people in their 60s, but they've had little success finding genetic glitches associated with the more common, late-onset form. Some evidence has pointed to a lifelong buildup of mutations in the DNA inside mitochondria, the energy-producing organelles inside cells. For example, Douglas Wallace, now at the University of California, Irvine, and colleagues found that a small percentage of Alzheimer's patients carried a specific mutation in their mitochondrial DNA. But that simply couldn't account for the large number of late-onset victims. So they kept up the search.

After examining every mitochondrial gene that codes for a protein, to no avail, Wallace's team decided to check for mutations in a short DNA region that regulates expression of mitochondrial genes and helps copy mitochondrial DNA when cells divide. Comparing DNA from the brains of 23 Alzheimer's patients against 40 healthy brains matched for age, the team found one mutation that occurred exclusively in Alzheimer's brains--65% of diseased brains contained this mutation, the team reports online this week in the Proceedings of the National Academy of Sciences. Other mutations were also more prevalent in Alzheimer's patients. In addition, the team noticed that brains of people who died of Alzheimer's before age 80 harbored a few mutations in many cells, whereas those who died later carried a greater variety of mutations in fewer cells. That suggests that mutations that occur early in life and accumulate in brain cells may heighten the risk of disease.

The mitochondrial DNA mutants the team discovered "are worth looking into," says neurogeneticist Rudolph Tanzi of Harvard Medical School in Boston. But although the data fit with other evidence linking mitochondria to Alzheimer's, he cautions that the study's sample size is so small that the results should be considered preliminary.

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