An infection-fighting protein that helped human ancestors survive the transition from trees to life on the African plains is now a major genetic risk factor for Alzheimer's disease, the sixth leading cause of death in 21st century America.
The protein, called ApoE4, helped protect early hominids from their pathogen-laden environment but now promotes Alzheimer's and heart disease in modern humans who live about twice as long as their distant ancestors, said Dale Bredesen, a faculty member at the Buck Institute for Research on Aging in Novato.
But after scoring a scientific breakthrough in revealing how the protein contributes to the scourge of Alzheimer's, Bredesen's team is pursuing a potential drug therapy for the degenerative brain disease that afflicts 5.4 million Americans and threatens to spike in prevalence as the population steadily ages.
A drug candidate identified by Bredesen's lab is going into human clinical trials in Australia and could, if all goes well, gain U.S. government approval in three to five years, Bredesen said.
Rammohan Rao, a co-author of the Buck report, said that one of the researchers' goals was "to identify a safe, nontoxic treatment that could be given to anyone who carries the Apo4E gene to prevent the development of Alzheimer's disease."
An international scientific scramble is on to stem Alzheimer's, which costs more than $200 billion and claims 83,500 lives a year in the United States, including nearly 250 in Sonoma County.
Sonoma's death rate for Alzheimer's disease is 51 per 100,000 population, nearly the same as Marin County, and far higher than Lake (33) and Mendocino (19) and the statewide rate of 29 per 100,000 population, according to a California Department of Public Health report this year.
Even taking into account Sonoma County's unusually large senior population, the region's age-adjusted Alzheimer's death rate of 33.8 percent is still nearly four percentage points higher than the state average.
Alzheimer's disease mortality nationwide increased nearly 40 percent between 2000 and 2010, while the death rates for four other major killers — diabetes, cancer, heart disease and stroke — declined, according to the U.S. Centers for Disease Control.
Absent a cure or a therapy to slow its progress, Alzheimer's will afflict 16 million Americans and cost $1 trillion by 2050, the Alzheimer's Association says.
A connection between the ApoE4 protein and Alzheimer's was established in the 1990s, but Bredesen's lab — in a paper published earlier this month — was the first to pinpoint the biological mechanism involved.
"It's just a gorgeous piece of science," said Caleb Finch, a professor of gerontology and biological science at the University of Southern California. "It could be one of the top 10 scientific papers in the year 2013."
Finch, the founder of USC's Alzheimer Disease Research Center in 1984, said the Buck research "opens up the inner clockwork of the ApoE4 mechanism in a profound and exciting way."
In simple terms, Bredesen said, ApoE4 lowers the body's production of an anti-aging protein called SirT1, the same entity whose activity is enhanced by resveratrol, an ingredient in red wine.
The reduction of SirT1 was observed in both lab tests and in the brains of deceased Alzheimer's patients with ApoE4, he said. "It's potentially important because ApoE4 is such a common and critical risk factor for Alzheimer's disease.
Humans can have zero, one or two copies of each gene, and people with one ApoE4 gene — one-fourth of the population — have a three-fold higher risk of Alzheimer's, compared with the general population.
About 2.5 percent of the population has two ApoE4 genes, giving them a 10- to 12-fold greater risk of Alzheimer's, he said.
Those statistics justify genetic testing for the ApoE4 genes, the earlier the better, allowing those with the gene to take steps to reduce the risk of Alzheimer's, Bredesen said.
Even without an effective Alzheimer's drug therapy, people at risk can take basic preventive measures, including a low-carbohydrate diet, regular exercise, stress reduction and adequate sleep.
"All the things your mother told you to do," Bredesen said.
The sedentary, carb-heavy, stressed American lifestyle "some would argue is the major risk factor for Alzheimer's," he said.
About one-third of people with Alzheimer's have no ApoE4, proving there is no single cause, or cure, for the disease.
Alzheimer's is "a roof with 36 holes," he said.
You can reach Staff Writer Guy Kovner at 521-5457 or guy.kovner@pressdemocrat.com.
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