A genetic risk score for Alzheimer’s is associated with a known marker of the disease in healthy, young adults, according to the results of a new study. Researchers calculated the risk scores from the results of a genome wide association study (GWAS) that compared genetic variations in patients with or without Alzheimer’s disease. The findings need to be confirmed in larger groups of participants, according to the authors publishing in Neurology.
Dr. Dimitrios Avramopoulos, Associate Professor, Institute of Genetic Medicine and Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine (webpage):
Expertise: Genetics of complex disorders; Genetics of psychiatric disorders (bipolar, Alzheimer’s, schizophrenia)
“The authors have used a polygenic risk score, a relatively new tool derived from genome wide association studies (GWAS), to explore how the risk score affects Alzheimer’s disease markers in patients with dementia and also pre-Alzheimer’s disease markers in a younger population without dementia.
“Genome wide association studies calculate the effect that each genetic variant has on disease risk across the genome, as well as the probability that it is a true effect. By using those probabilities to select genetic variants enriched for true effects, one can sum up their effects on risk to calculate a polygenic score—reflecting a person’s burden of high-risk variants across the genome.
“The results here are interesting, showing that the genetic score is indeed strongly associated with pre-Alzheimer’s disease markers in healthy individuals. The statistical support is strong, however the polygenic score only explains a small fraction of the variation in these pre-Alzheimer’s disease marker measurements, meaning it is still far from being useful for prediction. Nevertheless it is an important first attempt. Prediction will improve as genome wide association studies become larger increasing confidence on which are the true risk variants.
“These data support the notion that the processes leading to Alzheimer’s disease start early and progress for a long time before leading to a clinically detectable disease. This underlines the importance of accurate predictions, which can allow early lifestyle modifications or treatments. Genetic risk scores will certainly have a place in these predictions.”
Dr. Sudha Seshadri, Professor of Neurology, Boston University School of Medicine (webpage):
Expertise: Epidemiology of dementia and Alzheimer’s disease, genomic and epigenetic variation of brain aging, stroke, Alzheimer’s
“This is an interesting study regarding a genetic risk score that is based on a very large number of genetic variants, most of which are only associated with risk of Alzheimer’s disease at a ‘suggestive’ level. The authors look to see if, in aggregate, the variants alter the levels of various Alzheimer’s disease related biomarkers.
“Interestingly, a genetic risk score restricted to only 18 variants known to be associated with dementia risk was not associated with the Alzheimer’s markers. However, it was found that the polygenic risk scores, based on thousands of variants, do affect Alzheimer’s markers. This result suggests that there is still a lot of undetected genetic variation underlying the risk of Alzheimer’s disease. This is consistent with other papers on larger samples, showing the limited predictive ability of a genetic risk score that included only variants known to be associated with Alzheimer’s disease.
“The effect of polygenic risk scores was statistically significant but small. Hence such polygenic risk scores will help in ‘risk stratification’- for example identifying a higher risk sample for enrollment in a clinical trial. It will not be particularly useful for risk prediction. Family history of Alzheimer’s disease can also be used, similarly to a polygenic risk score, to identify high risk individuals.”
Declared interests (see GENeS register of interests policy):
Dr. Dimitrios Avramopoulos: Dr. Avramopoulos is a consultant for the pharmaceutical company Ono Pharma, Inc.
No other interests declared.
‘Polygenic risk of Alzheimer disease is associated with early- and late-life processes’, published in Neurology, Wednesday July 6th