Revisiting butyrylcholinesterase in Alzheimer's disease: A hub linking cholinergic, metabolic and affective pathways.

Selective butyrylcholinesterase (BChE) inhibition is gaining renewed attention as a potential therapeutic strategy for Alzheimer's disease (AD), particularly in advanced stages marked by a shift from acetylcholinesterase (AChE) to BChE dominance. Beyond cholinergic regulation, BChE participates in metabolic, inflammatory, and affective pathways, including the enzymatic control of acyl ghrelin that influences appetite, energy balance, and mood. Preclinical and experimental evidence suggests that selective BChE inhibition may modulate cholinergic tone, enhance cognition, and exert antidepressant- and anti-anhedonic-like effects, although clinical evidence remains limited and inconclusive. Genetic polymorphisms in BChE further shape disease progression and responses to cholinesterase therapy. This review integrates advances in BChE inhibitor development with evolving insights into BChE-dependent metabolic and neuropsychiatric mechanisms, highlighting selective BChE inhibition as a multifaceted therapeutic approach in AD.