The Role of Clinical Trials in Preclinical Alzheimer\u2019s Disease Drug Development Programs

Abstract

Alzheimer’s disease (AD) has a 15-20 year preclinical phase during which the individuals have normal cognition by conventional measures and have state measures of AD pathology including elevated levels of brain amyloid when assessed with positron emission tomography (PET) and abnormally decreased levels cerebrospinal fluid (CSF) amyloid beta-protein (Aß) and increased levels of total tau and hyperphosphorylated tau (p-tau) (1, 2). Recognition of this long-preclinical phase and the presence of biomarker changes affords, the opportunity to plan secondary prevention trials to prevent or delay the onset of cognitive impairment and progression to dementia. The US Food and Drug Administration (FDA) facilitated planning of clinical trials for participants in the preclinical phase of AD by defining two stages of the preclinical period: in stage 1 participants have characteristic pathophysiologic changes of AD but no evidence of clinical impact; in stage 2 participants have characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. Stage 3 participants are no longer in the preclinical phase of AD; they have mild cognitive impairment (MCI)/prodromal AD with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. Stages 4, 5, and 6 describe patients with mild, moderate and severe AD dementia. Biomarker, clinical definitions, and regulatory engagement have set the stage for planning and conduct of trials in preclinical AD.