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

Alzheimers Dement. 2020 Mar;16(3):552-560. doi: 10.1016/j.jalz.2019.09.074. Epub 2020 Jan 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aging
  • Alzheimer Disease / diagnostic imaging*
  • Australia
  • Biomarkers*
  • Cognitive Dysfunction / complications*
  • Disease Progression*
  • Female
  • Humans
  • Positron-Emission Tomography
  • Prodromal Symptoms*

Substances

  • Biomarkers