A RE-EVALUATION OF EARLY ALZHEIMER'S DISEASE BIOMARKERS ACCOUNTING FOR INACCURACY OF THE CLINICAL DIAGNOSIS

Abstract

the timing of symptom onset in ADAD. Methods: We have collected data on ages of symptom onset from 390 ADAD pedigrees, compiled from 138 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and two large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3282 individuals, of whom 1314 were affected by ADAD with known age of symptom onset. We assessed the relative contributions of several factors in influencing age of onset, including the affected gene and amino acid location of the ADAD mutation, parental age of onset, age of onset by mutation type and family, and APOE genotype and gender. We additionally performed a confirmatory survival analysis using data from 183 ADAD mutation carriers followed longitudinally in the DIAN study. Results: We report summary statistics on age of onset and disease course for 176 ADAD mutations, and discover strong and highly significant (p 0.38) correlations between individual age of symptom onset and predicted values based on parental age of onset and mean ages of onset by mutation type and family, which persist after controlling for APOE genotype and gender. Conclusions: Significant proportions of the observed variance in age of symptom onset in ADAD can be explained by the gene and amino acid location of ADAD mutations, providing empirical support for use of these data to estimate onset in clinical research.