DT‐01‐06: COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER'S DISEASE: A COMPARISON AND SYNTHESIS OF LARGE INTERNATIONAL COHORTS

Reports of cognitive decline associated with b-amyloid (Ab) pathology in cognitively normal individuals vary widely. This variation may be explained by differences in study design, length of follow-up, choice of cognitive tests, geographic region, and sampling variation. In this study, we aimed to identify the magnitude and precision of expected cognitive decline in preclinical AD and the study design features that exert influence over the trajectory of cognitive changes. In 1120 cognitively normal individuals from three multicenter studies: the Alzheimer's Disease Neuroimaging Initiative (ADNI) in North America, the Australian Imaging, Biomarker & Lifestyle Study (AIBL), and the Swedish BioFINDER study (BioFINDER), we estimated the effect of Ab pathology on decline over a spectrum of cognitive domains. Despite considerable study differences in terms of demographics, recruitment, follow-up schedule, and neuropsychological test battery, the magnitude of the differences in decline between Ab groups was consistent for the cognitive composite (PACC, the Preclinical Alzheimer Cognitive Composite) (Figure 1). To achieve 80% power with 800 subjects per arm in a simulated 4-year treatment trial in preclinical AD, estimates of the required drug effect ranged from 34% to 50%. Ab+ groups declined significantly faster on all cognitive domains in all cohorts compared to the Ab- groups (Figure 2, the only exception was Trails B in BioFINDER). Several baseline factors interacted significantly with Ab to predict cognitive decline including APOE e4-positivity, baseline cognition, and education in AIBL; age in BioFINDER; and sex in ADNI, however these interactions were cohort specific. On average, Ab+ subjects performed similarly to early MCI patients on cognitive tests 6 years after baseline.