Determinants of approved acetylcholinesterase inhibitor response outcomes in Alzheimer's disease: relevance for precision medicine in neurodegenerative diseases.

Acetylcholinesterase inhibitors (ChEI) are the global standard of care for the symptomatic treatment of Alzheimer's disease (AD) and show significant positive effects in neurodegenerative diseases with cognitive and behavioral symptoms. Although experimental and large-scale clinical evidence indicates the potential long-term efficacy of ChEI, primary outcomes are generally heterogeneous across outpatient clinics and regional healthcare systems. Sub-optimal dosing or slow tapering, heterogeneous guidelines about the timing for therapy initiation (prodromal versus dementia stages), healthcare providers' ambivalence to treatment, lack of disease awareness, delayed medical consultation, prescription of ChEI in non-AD cognitive disorders, contribute to the negative outcomes. We present an evidence-based overview of determinants, spanning genetic, molecular, and large-scale networks, involved in the response to ChEI in patients with AD and other neurodegenerative diseases. A comprehensive understanding of cerebral and retinal cholinergic system dysfunctions along with ChEI response predictors in AD is crucial since disease-modifying therapies will frequently be prescribed in combination with ChEI. Therapeutic algorithms tailored to genetic, biological, clinical (endo)phenotypes, and disease stages will help leverage inter-drug synergy and attain optimal combined response outcomes, in line with the precision medicine model.

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Déclaration de conflit d'intérêts

Conflict of Interest SL declares no competing financial interests related to the present article. This work was conceptualized and initiated during his previous position at Sorbonne University (Paris, France) and it reflects only and exclusively his own opinion and academic expertise on the matter. AV declares no competing financial interests related to the present article, and his contribution to this article reflects only and exclusively his own academic expertise on the matter. This work was conceptualized and initiated during his previous academic position at Sorbonne University, Paris, France. AV was an employee of Eisai Inc. [Nov 2019 - June 2021]. AV does not receive any fees or honoraria since November 2019. Before November 2019 he had received lecture honoraria from Roche, MagQu LLC, and Servier. YK, and MKH are co-founding members and consultants of NeuroVision Imaging, Inc., Sacramento, CA, USA. HH is an employee of Eisai Inc. The present article has been initiated and prepared as part of his academic position at Sorbonne University, Paris, France, and reflects entirely and exclusively his own opinion. He serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019. He is inventor of 11 patents and has received no royalties: In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300; In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463; In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553; CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921; Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: Publication number: United States Patent 10921330. SJT, PL, FSG, AG, FG, NBM, CB, BPG, and RN declare that they have no conflict of interest.