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Modelling Decline in Cognition to Decline in Function in Alzheimer’s Disease

[ Vol. 17 , Issue. 7 ]

Author(s):

Helene Karcher, Marina Savelieva, Luyuan Qi, Noemi Hummel, Angelika Caputo, Valery Risson*, Gorana Capkun and the Alzheimer’s Disease Neuroimaging Initiative   Pages 635 - 657 ( 23 )

Abstract:


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.

Keywords:

Alzheimer`s disease, cognitive decline, functional decline, APOE-e4, mixed-effects model, ADAS-Cog, FAQ, ADNI.

Affiliation:

Vice President, Access Consulting, Modeling & Simulation Unit Head, Parexel, Arnold Böcklin-Str. 29, 4051 Basel, Novartis Pharma AG, Basel, Analytica Laser, Certara Company, Paris, Analytica Laser, Certara Company, Lörrach, Novartis Pharma AG, Basel, Novartis Pharma AG, Basel, Novartis Oncology, Basel



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