Abstract
INTRODUCTION: With expansion of clinical trials to individuals across the spectrum of Alzheimer disease (AD) from preclinical to symptomatic phases, it is increasingly important to quantify AD severity using methods that capture underlying pathophysiology. METHODS: We derived an AD severity measure based on biomarkers from brain imaging, neuropathology, and cognitive testing using latent variable modeling. We used data from ADNI-1 (N = 822) and applied findings to BIOCARD study (N = 349). We evaluated criterion validity for distinguishing diagnostic groups and construct validity by evaluating rates of change in AD severity. RESULTS: The AD severity factor cross-sectionally distinguishes cognitively normal participants from MCI (AUC = 0.87) and AD dementia (AUC = 0.94). Among ADNI MCI subjects, worsening scores predict faster progression to AD dementia (HR = 1.17; 95% CI, 1.13-1.22). In ADNI and BIOCARD, the pace of change in AD severity is steepest among progressors, with persisting differences by baseline diagnosis. DISCUSSION: Our content-valid latent variable measurement model is a reasonable approach for grading AD severity across a broad spectrum beginning at preclinical stages of AD.