Abstract
Background: The temporal relationship of cognitive deficit and functional
impairment in Alzheimer’s disease (AD) is not well characterized. Recent analyses suggest
cognitive decline predicts subsequent functional decline throughout AD progression.
Objective: To better understand the relationship between cognitive and
functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in
several clinical trials.
Methods: Data included placebo patients with mild AD pooled from two
multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2)
studies, and from AD patients participating in the Alzheimer’s Disease Neuroimaging
Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment
Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living
instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ),
respectively. ARCL panel analyses evaluated relationships between cognitive and functional
impairment over time.
Results: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores
significantly predicted future functional impairment at 5 of 6 time points, while
functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data
from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted
subsequent function, but not vice-versa.
Conclusions: Analyses from three databases indicated cognitive decline
precedes and predicts subsequent functional decline in mild AD dementia, consistent with
previously proposed hypotheses, and corroborate recent publications using similar
methodologies. Cognitive impairment may be used as a predictor of future functional
impairment in mild AD dementia and can be considered a critical target for prevention
strategies to limit future functional decline in the dementia process.
