A research team has found that a new test combining the effects of more than two dozen genetic variants does a better job of predicting which cognitively normal older adults will go on to develop Alzheimer's dementia.
The advantage of the test, known as polygenic hazard score (PHS), is relative to testing only for the well-known genetic variant APOE E4, which has been considered the strongest genetic predictor of whether someone is likely to develop Alzheimer's, a chronic neurodegenerative disease that usually starts slowly and worsens over time.
However, APOE E4 is only carried by 10 to 15 percent of the population and recent research suggests its effects have been overstated.
Reporting their findings this week in Annals of Neurology, the team led by researchers at the University of California, San Francisco, or UCSF, and the University of California, San Diego, believes that the PHS test could provide risk estimates for the remaining 85 to 90 percent of people who do not carry at least one copy of APOE E4 but still have some combination of other genetic variants that put them at risk of Alzheimer's.
By looking at five years of data on 1,081 subjects from the U.S. National Alzheimer's Coordinating Center (NACC) who did not have dementia, the researchers found that the PHS test could predict how long it would take for them to progress to Alzheimer's dementia, and how steep their cognitive decline would be.
The test enables the researchers to calculate an age-specific risk of developing Alzheimer's, based upon each person's share of 31 genetic variants, plus APOE E4. It makes predictions by using genetic data from more than 70,000 people in the NACC database, the International Genomics of Alzheimer's Disease Project and the Alzheimer's Disease Genetics Consortium.
Autopsies of those who did develop Alzheimer's showed that, even among those who did not carry a copy of the APOE E4 variant, a higher PHS was associated with a higher level of amyloid plaque, a protein aggregate that is a hallmark of Alzheimer's, in the brain. These patients also showed steeper declines on cognitive tests during their lifetimes. Older individuals in the highest PHS percentiles also showed the highest incidence of Alzheimer's.
"Beyond APOE E4 by itself, our polygenic hazard score can identify cognitively normal and mildly impaired older folks who are at greatest risk for developing Alzheimer's-associated clinical decline over time," Chin Hong Tan, a postdoctoral scholar at UCSF and first author of the paper, was quoted as claiming in a news release.
Many scientists now believe that rather than being a disease of aging, Alzheimer's may be the result of a process that begins years, perhaps decades, before symptoms appear. The new PHS could help in the search for ways to identify those at risk long before they show symptoms of dementia, so they can be treated before the disease begins ravaging their brains.
