Identifying individuals with mild cognitive impairment who are at higher genetic risk of further substantial cognitive decline due to Alzheimer's disease

Background The development of tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increased attention for generating genetic risk profiles and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate AD cases from healthy controls in the ADNI cohort using individual's most recent diagnosis. In this work we have analysed whether the PRS is able to predict substantial cognitive decline towards an AD phenotype of individuals with MCI at the point of entering the study. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice. Method This longitudinal study explored the performance of the Cytox geno SCORE™ PRS algorithm as measured using ROC, AUC analysis when predicting a change in ADAS‐Cog13 score of 5,10 and 15 points at 2, 3 and 4‐year assessment timepoints. Subjects are included in the analysis based on availability of ADAS‐Cog13 data at those timepoints and availability of genetic data in the ADNI database. Change in cognition as measured by ADAS‐Cog13 was used instead of change of diagnosis given the broad spectrum of baseline cognitive performance in those individuals with MCI. Result Individuals with low PRS clearly have a lower likelihood of experiencing substantial cognitive decline (>10 points on the ADAS‐Cog13 scale over 4 years) than those individuals with higher PRS. In a population of 285 individuals with an MCI diagnosis at baseline geno SCORE™ has an accuracy as measured by area under the curve of 74% in predicting those individuals who declined substantially over 4 years, with very high negative predictive values. Conclusion Identifying individuals of higher risk for substantial cognitive decline towards AD will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.