Polygenic testing shows promise in the early identification of Alzheimer’s associated symptoms
Researchers from UC San Francisco (CA, USA) and UC San Diego (CA, USA) have designed a new test, the polygenic hazard score (PHS), that combines the effects of more than 30 genetic variants in an effort to better establish the likelihood of patients developing Alzheimer’s disease.
Results, published in Annals of Neurology, suggest that using a polygenic or combined approach (taking advantage of variants with individually low risk association with Alzheimer’s) was more accurate than previous efforts to pre-empt the development of Alzheimer’s and associated symptoms.
Previous research has utilized the well-known genetic variant APOE E4 as the long-considered strongest predictor of whether a patient may develop Alzheimer’s disease. APOE E4 is only carried by 10–15% of the population and more recent research suggests that the effects of the variant have been overestimated.
The new test accounts for the remaining 85–90% of the population who are not carriers of APOE E4 copies, but that have a combination of other genetic variants that put them at risk of developing Alzheimer’s. The PHS test enables the calculation of an age-specific risk of Alzheimer’s development based on an individual’s share of 31 genetic variants and APOE E4.
“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,” commented Chin Hong Tan (UC San Francisco).
Over 5 years, 1081 individuals without dementia were studied from the National Alzheimer’s Coordinating Center. In these individuals, the PHS test was able to predict how long it would take to for them to progress to Alzheimer’s dementia and how extreme their cognitive decline would be, despite their APOE E4 carrier status.
The test was able to make it’s predictions by using genetic data from more than 70,000 people in the National Alzheimer’s Coordinating Center database, the International Genomics of Alzheimer’s Disease Project and the Alzheimer’s Disease Genetics Consortium.
In patients who did ultimately develop Alzheimer’s, autopsies demonstrated that a higher PHS was associated with an increased level of Alzheimer’s hallmarks including neural protein aggregates and amyloid plaques. Patients also experienced more extreme declines on cognitive tests over their lifetimes. Older patients with the highest PHS scores exhibited the highest incidence of Alzheimer’s, diagnosed by cognitive tests and brain pathology, regardless of their APOE E4 carrier status.
Despite previous beliefs that Alzheimer’s may be a disease associated with aging, recent research could suggest that Alzheimer’s may actually be the result of a disease process beginning a long time before any symptoms of dementia develop, which may explain why so many Alzheimer’s drugs tested on an older population with dementia have failed in clinical trials. Tests like the PHS could help in earlier detection and identification of Alzheimer’s, allowing earlier and potentially more successful interventions.
“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,” explained Anders Dale (UC San Diego).
Rahul Desikan (UC San Francisco) concluded: “Unlike other polygenic risk scores, the continuous PHS measure is based on a survival framework and incorporates U.S.-based Alzheimer’s incidence rates. Rather than a diagnostic test, PHS may serve as a genetic ‘risk factor’ for preclinical Alzheimer’s disease.”
Sources: Tan CH, Hyman BT, Tan JJX et al. Polygenic hazard scores in preclinical Alzheimer disease. Ann. Neurol. 82(3), 484–488 (2017); www.ucsf.edu/news/2017/09/408356/multi-gene-test-predicts-alzheimers-better-apoe-e4-alone
