title: Modeling Alzheimer's disease progression using the disease system analysis approach.
abstract: A novel mechanistic model based on a disease system analysis paradigm was developed to explore the role of homeostatic mechanisms involved in Alzheimer's disease (AD) progression. We used longitudinal AD Assessment Scale-cognitive subscale (ADAS-cog) scores from 926 subjects with AD on stable acetylcholinesterase inhibitor therapy randomized to placebo treatment in two 54-week clinical trials. Alternative mechanistic models were evaluated by assuming that the rate of change of ADAS-cog over time was jointly regulated by a process characterizing the deterioration of ADAS-cog and by a process associated with a compensatory regulatory response. The model based on a time-varying deterioration rate of ADAS-cog performed better than the model based on a time-varying homeostatic control. The covariate analysis indicated that baseline Mini-Mental State Examination score, education, age, and apolipoprotein ɛ4 genotype had a significant effect on the level and shape of the trajectories of the mean model predicted ADAS-cog change from baseline.
authors.affiliation: Pharmacometrics, GlaxoSmithKline R&D, Upper Merion, PA, USA. roberto.a.gomeni@gsk.com
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
authors.forename: Monica
authors.initials: M
authors.lastname: Simeoni
authors.forename: Marina
authors.initials: M
authors.lastname: Zvartau-Hind
authors.forename: Michael C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: Daren
authors.initials: D
authors.lastname: Austin
authors.forename: Michael
authors.initials: M
authors.lastname: Gold
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000175:diagnosis* / Q000188:drug therapy; D053327:Apolipoprotein E4 / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003072:Cognition Disorders / Q000209:etiology*; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D018450:Disease Progression; D005260:Female; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009483:Neuropsychological Tests; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
chemical_list: D053327:Apolipoprotein E4; D002800:Cholinesterase Inhibitors