Cognitive impairment networks in Alzheimer's disease: Analysis of three double-blind randomized, placebo-controlled, clinical trials of donepezil.

Psychometric 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. Based 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). A 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 score networks. The donepezil 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). This suggests that for those who were treated with donepezil compared with placebo, cognition is a more unified construct. 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. Comprehension of spoken language apears to be most sensitive to psychopharmaceutical interventions and should therefore be closely monitored. Overall, our 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 of cognitive impairment  that may translate into future treatment targets.
Competing Interests: Declaration of Competing Interest Drs Rotstein, Levine, Yoshida, Samara and Goldberg have nothing to disclose. Dr. Iwatsubo: has served as a consultant of Eisai, Roche and Biogen in the last 3 years. Dr. Cipriani: has received research and consultancy fees from INCiPiT (Italian Network for Pediatric Trials), CARIPLO Foundation and Angelini Pharma. Dr. Leucht has received honoraria as a consultant or for lectures for LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson & Johnson, TEVA, MSD, Sandoz, Sanofi-Aventis, Angelini, Sunovion, Recordati and Gedeon Richter. Dr. Furukawa reports personal fees from Mitsubishi-Tanabe, MSD and Shionogi, a grant from Mitsubishi-Tanabe, outside the submitted work, and has a patent 2018-177688 pending.
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