Introduction: Demonstrating the "clinical meaningfulness" of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid-β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression.
Methods: Cox regression analyses were used to determine whether 3-year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative.
Results: Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta-analytic estimates were 5.47 (95% CI: 3.25-9.18) for MCI diagnosis and 4.49 (95% CI: 2.84-7.09) for Clinical Dementia Rating>0 in those with subtle decline (>-.14 to -.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing.
Discussion: Early "subtle cognitive decline" among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.
Keywords: Alzheimer's disease; Amyloid; Clinical meaningfulness; Clinical trials methodology; Outcome research; Preclinical; Secondary prevention.
© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.