Cerebrospinal fluid acetylcholine is not a reliable diagnostic marker for Alzheimer's disease and dementia with Lewy bodies

Abstract

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.

Objective

Our 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.