Modelling Decline in Cognition to Decline in Function in Alzheimer's Disease.

Abstract

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. 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. 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. 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.