What is it about?
Memory and attention deficits are hallmarks of Alzheimer's disease, partly because of a deficit in a brain chemical called acetylcholine. Donepezil, the most widely used drug for Alzheimer's, works by boosting acetylcholine levels. THN201 is a new combination of donepezil and mefloquine designed to enhance this effect. In this study, we temporarily disrupted acetylcholine signaling in 152 healthy volunteers using scopolamine, a well-established model of Alzheimer-like cognitive impairment and tested whether donepezil or THN201 could protect memory and attention. We measured cognitive performance and brain electrical activity (EEG). While scopolamine reliably impaired both cognition and brain signals, neither donepezil nor THN201 showed a significant protective effect. These findings suggest that boosting acetylcholine alone may not be sufficient, and that more targeted approaches will be needed to effectively treat cognitive decline in aging and Alzheimer's disease.
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Why is it important?
This is one of the largest pharmacological challenge studies of its kind, enrolling 152 healthy volunteers in a rigorous double-blind, randomized design. While most research on cholinergic drugs focuses on Alzheimer's patients, we tested these treatments in a controlled experimental model of cognitive impairment (allowing us to isolate drug effects without the confounds of neurodegeneration). Two findings stand out: first, scopolamine reliably disrupted both cognitive performance and EEG markers, confirming the value of this model as a sensitive tool for detecting cholinergic effects on attention and memory; second, neither donepezil alone nor the novel THN201 combination reversed these impairments, challenging the assumption that enhancing cholinergic transmission is sufficient to restore cognition. As the field moves toward combination therapies for Alzheimer's disease, these results provide a timely and critical benchmark : highlighting the need to look beyond the cholinergic system and to leverage EEG biomarkers more systematically in early-phase cognitive trials.
Perspectives
This publication holds a special place for me, as it represents the culmination of a long and genuinely collaborative journey — bringing together clinical pharmacologists, neurologists, and neuroscientists from several French research centers. As someone whose work sits at the intersection of cholinergic pharmacology and EEG-based cognitive neuroscience, I found this study both humbling and energizing. Humbling, because negative results are never easy to publish — yet they are arguably among the most valuable contributions we can make to a field. Energizing, because the robustness of the scopolamine model and the sensitivity of EEG parameters confirmed something I deeply believe: that electrophysiological biomarkers have an underexplored potential in early-phase cognitive trials. If this paper encourages even a handful of researchers to think differently about cholinergic strategies (or to take EEG more seriously as a translational tool) then it will have done its job. Cognitive decline in aging populations is one of the defining public health challenges of our time. We owe it to patients to be honest about what works, and what doesn't yet.
Thibaut Dondaine
Lille University
Read the Original
This page is a summary of: Comparison of the effect of donepezil and a combination of donepezil and mefloquine (THN201) on cognition during a scopolamine challenge in healthy participants., Experimental and Clinical Psychopharmacology, April 2026, American Psychological Association (APA),
DOI: 10.1037/pha0000825.
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