Identification of a Cascade of Changes in Activities of Daily Living Preceding Short-Term Clinical Deterioration in Mild Alzheimer's Disease Dementia via Lead-Lag Analysis

Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer's disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer's dementia (AD; MMSE= 23.9 +/- 2.88) were followed at 12 and 24 months. Leadlag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 neuropsychological subtest scores from the CERAD+ test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (Delta MMSE 5.8 +/- 8.64; Delta CDR-SOB 4.32 +/- 4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures.