Karen Hsiao Ashe
After studying Alzheimer’s disease for 16 years, Karen Hsiao Ashe wasn’t surprised when her own father began showing signs of the disease last year.
“My father is 90 years old, so his dementia is a sad fact of statistics,” Ashe says. “About 50 percent of people over the age of 85 have the disease.”
Ashe wants to change that with preventive medicine. Unless researchers stop its development, the next 40 years will see 28 million new cases of Alzheimer’s disease in this country. Alzheimer’s progressively impairs cognitive function and memory by destroying synapses that convey signals between neurons in the brain, then neurons themselves. Most patients die after about 10 years.
“I chose this area of research because it’s the most important unresolved medical problem facing our country [and] the world,” Ashe says. To explain her focus on prevention, she draws a comparison with polio. “Had a vaccine not been developed for polio, hospital wards would now be filled with people needing artificial ventilators to breathe. Similarly, not only is treatment of Alzheimer’s likely to be less effective than prevention, it’s also likely to be 10 to 1,000 times more expensive.”
But there can be no preventive mechanism until researchers know precisely what to prevent. Ashe is examining Alzheimer’s disease at a molecular level, looking at genetic markers and the way proteins interact with the neurons of the brain. Mounting evidence shows that Alzheimer’s-related changes develop in the brain long before the dementia can be diagnosed. Those changes distinguish the disease from other cognitive decline that can come with normal aging and make Alzheimer’s difficult to diagnose.
“The specific genes influencing ‘sporadic Alzheimer’s’”—the most common form of the disease—“have not been identified, except for the APOE e4 gene [apolipoprotein e4],” Ashe says, but “there are probably a handful, maybe even a dozen or more.” Also, APOE e4 indicates only susceptibility to the disease, not the presence of the disease itself. “The more copies of APOE e4 you have, the higher the risk you are for Alzheimer’s disease. However, you could have two copies of APOE e4 and live to be 95 and still not get Alzheimer’s,” she adds.
Other Alzheimer’s research has centered on amyloid-beta and tau proteins that are more prevalent in the brains of people with the APOE e4 gene than they are in the population at large. The proteins form a plaque in the brain that has been suspected as a killer of neurons.
Ashe wanted to understand exactly how these proteins damage cognitive function. So back in 1996, she began using mice to model the stages of Alzheimer’s that precede the onset of dementia.
“We injected into mouse embryos human DNA that had been genetically engineered to simulate human DNA from Alzheimer’s patients,” she explains. “We believe that if we can understand the stages preceding and leading up to dementia, then we might be able to prevent the disease from occurring.”
So far, her research has shown that the aggregates of amyloid-beta and tau proteins that define Alzheimer’s disease do not cause cognitive deficits in mice. However, in 2006, Ashe’s team found that a form of the amyloid-beta protein called amyloid-beta star does disrupt cognitive function. Consequently, a major focus of Ashe’s lab is determining whether amyloid-beta star is a predictive marker of Alzheimer’s.
“We’re now seeing amyloid-beta star even before mild cognitive impairment,” Ashe says. “Our hypothesis is that the amyloid-beta star protein initiates the disease.
“Our theory stipulates that amyloid-beta star initiates Alzheimer’s when it attaches to specialized nerve cell proteins years before symptoms appear,” she continues. As a result, “we believe that the most promising area for intervention is a small molecule—a compound that you can take as a pill—that blocks the chain reaction that ultimately culminates in the development of synapse loss, neuron death, and dementia.”
Ashe says she’s excited about the work in her lab and others that could block Alzheimer’s “and in a way that is cost effective and widely available to the world’s rich and poor. My dream is for the N. Bud Grossman Center for Memory Research and Care to take the lead in making Alzheimer’s prevention a reality by 2020.”