Table 3.

FDA suggestions for endpoints in clinical trials for early AD.

Clinical trial population—AD stage	Definition according to clinical and biomarker characteristics	Characteristics of recommended endpoints
Stage 1	Pathophysiological features demonstrated by assessment of various biomarkers measures in completely asymptomatic participants	•An effect on the characteristic pathophysiological changes of AD, as demonstrated by an effect on various biomarkers •Alternative approach would include to perform a study long enough to evaluate measures recommended for stage 2
Stage 2	Characteristic pathophysiological features of AD on biomarkers, and subtle detectable abnormalities on sensitive neuropsychological assessment without functional impairment	•Consider studies with significant duration to allow endpoints suggested for stage 3 •Sensitive measures of neuropsychological performance, requiring consistency across multiple individual tests, or a large magnitude effect •Additional arguments for approval be predicated on certainty of diagnosis, certainty of expected clinical course, and certainty of the relationship of the observed effects and characteristic pathophysiologic changes
Stage 3	Characteristic pathophysiological features of AD on biomarkers, and subtle or more apparent abnormalities on sensitive neuropsychological measures, and mild functional impairment, which is but detectable but not severe enough for dementia diagnosis	•Outcome will provide an assessment of meaningful cognitive function •Integrated scale that adequately and meaningfully assesses both daily function and cognitive effects •Independent assessment of daily function and cognitive deficits is an acceptable approach
Stage 4	Patients with overt dementia	•Discussion on outcomes at these stages were not included on the FDA statement