Genetic risk factors for Alzheimer's are not as cut-and-dry as it might seem.
Decades of research on genetics has revealed some possible reasons for why Alzheimer’s develops in some brains and not others. We know that chances of Alzheimer’s are increased by carrying a gene called ApoE4, and we even know the genes associated with early-onset Alzheimer’s. But the genetic risk factors for Alzheimer’s are not as cut-and-dry as it might seem.
There are many genes that play a part in Alzheimer’s disease, and a test called the polygenic risk score takes each into account. The test combines dozens of genetic variants that, by themselves, only raise the risk of Alzheimer’s by a small percent. The risk score is a reflection of the combination of all those genes, and studies show it’s more accurate at predicting who will develop Alzheimer’s than the ApoE4 gene, which has long been considered the best genetic indicator.
Now, for the first time, the polygenic risk score has been used to identify people with mild cognitive impairment, or MCI, who are in their 50s—which is when scientists start to see changes in the brain that indicate Alzheimer’s, even though symptoms don’t show up for several more years.
“Current studies of the Alzheimer’s disease polygenic risk score typically occur in adults in their 70s, but the Alzheimer’s pathological process begins decades before the onset of dementia,” said William S. Kremen, Ph.D., professor of psychiatry and co-director of the Center for Behavior Genetics of Aging at UC San Diego School of Medicine. “By focusing on a younger population with cognitive impairment, we may be better able to identify patients for critical early interventions and clinical trials.”
MCI can be a red flag that indicates serious problems are ahead: About one-third of those diagnosed with MCI go on to develop dementia in the next five years, and eight out of 10 develop dementia within seven years.
Researchers looked at 1,329 men who were an average age of 56. When they ranked the men by the polygenic risk score for Alzheimer’s disease, they found that those in the top 25 percent had a two and a half to three times higher chance of having MCI than those in the bottom 25 percent.
“Our research team found that the polygenic score could differentiate individuals with mild cognitive impairment from those who were cognitively normal,” said Kremen.
The test is not yet available outside of a research setting, but Kremen said it could be a crucial tool in reducing the number of Alzheimer’s cases by getting earlier treatment for those who are high-risk once it becomes available.
“The Alzheimer’s Association and others have modeled how the impact of delaying the onset of Alzheimer’s by five years could reduce the number of cases by nearly 50 percent by 2050. We want to do what we can to make this projection a reality,” said Kremen.
This study was published in the journal Molecular Psychiatry.
