Polygenic Risk Score Effectively Predicts Risk of Depression Onset in Alzheimer’s Disease

Introduction: Depression is a common, though heterogenous, comorbidity in late-onset Alzheimer’s Disease (LOAD) patients. In addition, individuals with depression are at greater risk to develop LOAD. In previous work, we demonstrated shared genetic etiology between depression and LOAD. Collectively, this evidence suggested interactions between depression and LOAD. However, the underpinning genetic heterogeneity of depression co-occurrence with LOAD is largely unknown.Methods: Major Depressive Disorder (MDD) genome wide association study (GWAS) summary statistics were used to create polygenic risk scores (PRS). The Religious Orders Society and Rush Memory and Aging Project (ROSMAP) and National Alzheimer’s Coordinating Center (NACC) datasets were utilized to assess the PRS performance in predicting depression onset in LOAD patients.Results: The developed PRS showed marginal results in standalone models for predicting depression onset in both ROSMAP (AUC=0.540) and NACC (AUC=0.534). Full models, with baseline age, sex, education, and allele count, showed improved prediction of depression onset (ROSMAP AUC: 0.606, NACC AUC: 0.583). In time-to-event analysis, standalone PRS models showed significant effects in ROSMAP (=0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in LOAD for both datasets (<0.001 for all).Discussion: This study provided new insights into the genetic factors contributing to depression onset in LOAD and advanced our knowledge of the genetics underlying the heterogeneity of depression in LOAD. The developed PRS accurately predicted LOAD patients with depressive symptoms, thus, has clinical implications including, diagnosis of LOAD patients at high-risk to develop depression for early anti-depressant treatment.

Duke Scholars

Author Ornit Chiba-Falek Neurology, Behavioral Neurology