Genetic and functional dynamics of butyrylcholinesterase in Alzheimer's disease : from mechanisms to clinical relevance

Prešern, Uroš (author), Goličnik, Marko (author), Bavec, Aljoša (author)

Butyrylcholinesterase (BChE), once regarded as a redundant cholinesterase, has emerged as an important modulator of Alzheimer's disease (AD). Unlike acetylcholinesterase (AChE), which declines during disease progression, BChE activity is preserved or elevated in the AD brain and becomes the predominant cholinesterase in advanced stages. Beyond its enzymatic role in acetylcholine hydrolysis, BChE is directly associated with amyloid plaques and tau pathology and has been implicated in neuroinflammatory processes. Genetic variants of the BCHE gene, most notably the K-variant, further contribute to inter-individual differences in AD susceptibility, disease onset, and therapeutic response, particularly in the context of APOE4. Evidence from biochemical, histological, and clinical studies indicates that BChE influences both the pathophysiology of AD and the effectiveness of cholinesterase inhibitor therapy, with rivastigmine providing unique benefits through dual AChE and BChE inhibition. Recent efforts to develop selective or multitarget BChE inhibitors underscore the enzyme's potential as a therapeutic target, while BChE-specific positron emission tomography tracers highlight its diagnostic promise by distinguishing AD-related amyloid plaques from those of normal aging. Despite these advances, uncertainties remain regarding the precise dynamics of BChE activity across disease stages, its contribution to plaque maturation and inflammation, and its influence on responses to novel anti-amyloid antibody therapies. Overall, BChE represents a multifaceted factor in AD pathogenesis, therapy, and biomarker development, warranting further genotype-stratified and mechanistic investigations to clarify its clinical utility.

• Language: English
• Keywords: Alzheimer's disease, butyrylcholinesterase, cholinesterase inhibitors, genetic variants
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Author Accepted Manuscript
• Year: 2026
• Number of pages: 10 str.
• Numbering: Vol. 423, art. 111809
• PID: 20.500.12556/RUL-187854
• UDC: 577.2
• ISSN on article: 1872-7786
• DOI: 10.1016/j.cbi.2025.111809
• COBISS.SI-ID: 267470851
• Publication date in RUL: 15.09.2026

Record is a part of a journal

• Title: Chemico-biological interactions
• Publisher: Elsevier
• ISSN: 1872-7786
• COBISS.SI-ID: 23211013

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: Alzheimerjeva bolezen, butirilholinesteraza, zaviralci holinesteraze, genetske variante

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0170
• Name: Molekulski mehanizmi uravnavanja celičnih procesov v povezavi z nekaterimi boleznimi pri človeku