Aveneau_2025_J.Alzheimers.Dis__13872877251387159

Background: Histopathological cholinergic pathways destruction is described in numerous neurodegenerative diseases (including Alzheimer's disease [AD], dementia with Lewy bodies [DLB]). Detecting biological acetylcholine (ACh) deficits is however challenging due to its rapid post-mortem degradation and low concentration in cerebrospinal fluid (CSF). Our team collaborated in the development of a reliable liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) technique for the measurement of ACh and choline (Ch) in CSF.ObjectiveOur study aimed to assess potential ACh concentration differences among patients by clinical diagnosis. Methods: This monocentric cross-sectional study included patients with AD (n = 149), DLB (n = 20), and neurological controls (NC, n = 45) from the CHOLINE study (NCT03090854) or as additional controls (CSF from locoregional anesthesia). CSF samples were analyzed for ACh and Ch (LC-MS/MS), and acetylcholinesterase activity (enzymatic technique). Cholinergic markers were compared between groups using multivariate linear regression, adjusted for potential confounders (age, sex, cardiovascular risk factors). Results: No significant difference in ACh or Ch levels was found between diagnostic groups. A significant difference (p = 0.03) was observed for acetylcholinesterase activity, with a lower value in the DLB group versus the AD and NC groups. Conclusions: The absence of intergroup ACh differences suggests CSF ACh is an unreliable diagnostic marker or indicator of cholinergic pathway damage. This could reflect a functional deficit or a dissociation between CSF and brain ACh levels. Larger studies are required to confirm our results and evaluate these markers for therapeutic target engagement of treatments designed to protect cholinergic pathways.