Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD.

Abstract

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. 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. 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. Early "subtle cognitive decline" among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.