How can secondary dementia prevention trials of Alzheimer's disease be clinically meaningful?

After clinical trial failures in symptomatic Alzheimer's disease (AD), our field has moved to earlier intervention in cognitively normal individuals with biomarker evidence of AD. This offers potential for dementia prevention, but mainly low and variable rates of progression to AD dementia reduce the usefulness of trials' data in decision making by potential prescribers. With results from several Phase 3 secondary prevention studies anticipated within the next few years and the Food and Drug Administration's recent endorsement of amyloid beta as a surrogate outcome biomarker for AD clinical trials, it is time to question the clinical significance of changes in biomarkers, adequacy of current trial durations, and criteria for treatment success if cognitively unimpaired patients and their doctors are to meaningfully evaluate the potential value of new agents. We argue for a change of direction toward trial designs that can unambiguously inform clinical decision making about dementia risk and progression.