Distinct medical and substance use histories associate with cognitive decline in Alzheimer’s Disease

INTRODUCTION Phenotype clustering reduces patient heterogeneity and could be useful when designing precision clinical trials. We hypothesized that the onset of early cognitive decline in patients would exhibit variance predicated on the clinical history documented prior to an Alzheimer’s Disease (AD) diagnosis METHODS Self-reported medical and substance use history (i.e., problem history) was used to cluster participants from the National Alzheimer’s Coordinating Centers (NACC) into distinct subtypes. Linear mixed effects modeling was used to determine the effect of problem history subtype on cognitive decline over two years. RESULTS 2754 individuals were partitioned into three subtypes: minimal (n = 1380), substance use (n = 1038), and cardiovascular (n = 336) subtypes. The cardiovascular problem history subtype had significantly worse cognitive decline over a two-year follow-up period (p = 0.013). DISCUSSION Our study highlights the need to account for problem history to reduce heterogeneity of outcomes in AD clinical trials.