Enriching the design of Alzheimer's disease clinical trials: Application of the polygenic hazard score and composite outcome measures

Introduction: Selecting individuals at high risk of Alzheimer's disease (AD) dementia and using the most sensitive outcome measures are important aspects of trial design. Methods: We divided participants from Alzheimer's Disease Neuroimaging Initiative at the 50th percentile of the predicted absolute risk of the polygenic hazard score (PHS). Outcome measures were the Alzheimer's Disease Assessment Schedule-Cognitive Subscale (ADAS-Cog), ADNI-Mem, Clinical Dementia Rating-Sum of Boxes (CDR SB), and Cognitive Function Composite 2 (CFC2). In addition to modeling, we use a power analysis compare numbers needed with each technique. Results: Data from 188 cognitively normal and 319 mild cognitively impaired (MCI) participants were analyzed. Using the ADAS-Cog to estimate sample sizes, without stratification over 24 months, would require 930 participants with MCI, while using the CFC2 and restricting participants to those in the upper 50th percentile would require only 284 participants. Discussion: Combining stratification by PHS and selection of a sensitive combined outcome measure in a cohort of patients with MCI can allow trial design that is more efficient, potentially less burdensome on participants, and more cost effective.