Unknown treatment effects of donepezil in Alzheimer’s disease: Network analysis of three double‐blind randomized, placebo‐controlled, clinical trials

Abstract

AbstractBackgroundPsychometric network analysis is an alternative theoretically‐driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer’s disease differently than was previously assumed and consequently detect unknown treatment effects.MethodBased on individual participant data, extracted from three double‐blind, randomized placebo‐controlled clinical trials, psychometric networks were computed on observed Alzheimer’s Disease Assessment Scale Cognitive Subscale scores at baseline (N = 1,554) and on predicted change scores at 24 weeks of follow‐up for participants who received donepezil (N = 797) or placebo (N = 484).ResultA novel conceptualization of cognitive impairment in Alzheimer’s disease was displayed through the baseline network, that had 90% (n = 27) positive statistically significant (p<0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change networks. The donepezil change network had more statistically significant (p<0.05) positive associations and a higher global strength (n = 15; S = 1.22; p = 0.03), than the placebo network (n = 8; S = 0.57), suggesting that for those who were treated with donepezil cognition is a more unified construct. Less for those given placebo. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network, suggesting that comprehension of spoken language is most sensitive to pharmaceutical interventions.ConclusionOverall, psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer’s disease, points to previously unknown treatment effects and highlights well‐defined aspects that may translate into future treatment targets.