Objectives: The study aimed to evaluate and quantify the temporal link between cognitive and
functional decline, and assess the impact of the apolipoprotein E4 (APOE-e4) genotype on Alzheimer’s
disease (AD) progression.
Methods: A nonlinear mixed-effects Emax model was developed using longitudinal data from 659 patients
with dementia due to AD sourced from the Alzheimer's disease neuroimaging initiative (ADNI)
database. A cognitive decline model was first built using a cognitive subscale of the AD assessment
scale (delayed word recall) as the endpoint, followed by a functional decline model, using the functional
assessment questionnaire (FAQ) as the endpoint. Individual and population cognitive decline from the
first model drove a functional decline in the second model. The impact of the APOE-e4 genotype status
on the dynamics of AD progression was evaluated using the model.
Results: Mixed-effects Emax models adequately quantified population average and individual disease
trajectories. The model captured a higher initial cognitive impairment and final functional impairment in
APOE-e4 carriers than non-carriers. The age at cognitive decline and diagnosis of dementia due to AD
was significantly lower in APOE-e4 carriers than that of non-carriers. The average [standard deviation]
time shift between cognitive and functional decline, i.e. the time span between half of the maximum
cognitive decline and half of the maximum functional decline, was estimated as 1.5 [1.6] years.
Conclusion: The present analysis quantifies the temporal link between a cognitive and functional decline
in AD progression at the population and individual level, and provides information about the potential
benefits of pre-clinical AD treatments on both cognition and function.