A new test developed by researchers at UC San Francisco and UC San Diego can better predict which cognitively normal adults will develop Alzheimer’s dementia later in life than testing for the well-known genetic variant APOE E4 alone, according to a new study.
The study, titled “Polygenic hazard scores in preclinical Alzheimer disease,” was published in the Annals of Neurology.
APOE E4 is the most thoroughly researched gene variant known to be associated with Alzheimer’s disease, but only 10 to 15 percent of people at risk of developing the disease carry the variant. Some studies even suggest that its effects as a disease predictor may be overestimated. As a result, a more powerful test was needed to help determine the risk of developing Alzheimer’s.
Through the use of genetic data from 70,000-plus people in the NACC (National Alzheimer’s Coordinating Center), the International Genomics of Alzheimer’s Disease Project, and the Alzheimer’s Disease Genetics Consortium database, researchers were able to identify 31 genetic variants, in addition to APOE E4, that could be used to effectively provide risk estimates for developing Alzheimer’s dementia.
This data allowed researchers to develop the PHS (polygenic hazard score) test, which can calculate age-specific risk estimates of developing Alzheimer’s disease.
The PHS combines 31 genetic variants that were individually discovered to be associated with a small risk of Alzheimer’s disease, and the combination of these individual variants, along with APOE E4, produces a powerful tool for prediction.
To test the validity of this test, researchers examined five years of data from 1,081 normal patients from the NACC that did not have dementia and demonstrated that the PHS could predict the length of time that the patients took to develop Alzheimer’s dementia and the degree of cognitive decline they experienced.
“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,” Dr. Chin Hong Tan, a postdoctoral scholar at UCSF and first author of the paper, said in a university news release.
After conducting autopsies of individuals that eventually developed Alzheimer’s disease, researchers determined that a higher PHS score correlated with a greater volume of amyloid plaques, an aggregate of proteins that generally characterizes Alzheimer’s disease, and a greater cognitive decline.
Additionally, patients in the higher percentile of PHS scores also had the highest incidence of Alzheimer’s disease, as demonstrated through cognitive tests and brain pathology. This indicates the validity of this test as a prediction tool.
Recent research has shown that rather than a disease associated with aging, Alzheimer’s may result from a process that was initiated long before any of classical symptoms appear, which could be why so many Alzheimer’s drugs that are used to inhibit or stop the disease process haven’t worked in studies.
In this manner, the PHS could help treat these patients years before they develop Alzheimer’s disease by identifying those who are at greatest risk of developing the disease.
“Our findings have strong implications for disease stratification and secondary prevention trials in Alzheimer’s, as well as direct-to-consumer genetic tests, some of which have recently received FDA clearance,” said Anders Dale, PhD, professor of neurosciences and radiology at UC San Diego and co-author of the study.
“Unlike other polygenic risk scores, the continuous PHS measure is based on a survival framework and incorporates U.S.-based Alzheimer’s incidence rates,” said Dr. Rahul Desikan, an MD and PhD, assistant professor in the Department of Radiology and Biomedical Imaging at UCSF, and co-senior author of the paper.
“Rather than a diagnostic test, PHS may serve as a genetic ‘risk factor’ for preclinical Alzheimer’s disease,” he said.
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