Aims

Acetylcholinesterase (AchE) inhibitors efficacy in Alzheimer’s disease (AD) is variable between patients, with only 20-30% being clinically responders. However, this efficacy has never been evaluated in regards to the therapeutic target engagement (acetylcholine [Ach] deficit). We aimed to determine if cerebrospinal fluid (CSF) Ach level and AchE activity measurements could predict the therapeutical response in AD patients using recent AD diagnosis criteria.

Methods

Non-randomized single-center prospective non-placebo-controlled phase 4 study, including AD patients diagnosed according to recent criteria. AchE activity was measured using an enzymatic reaction, and Ach level using a mass spectrometry technique.

Clinical response to AChEI was evaluated at 6 months using the ADAS-Cog (Alzheimer’s Disease Assessment Scale [cognitive part]) scale. Our primary outcome was to compare the mean value of CSF Ach level and AchE activity between responders (≥4 points improvement in the ADAS-Cog scale at 6 months) and non-responders AD patients.

Results

100 patients were included from 2017 to 2020, comprised of 64 women and 36 men. Mean age was 72.9 years old (SD 7.9) and mean ADAS-Cog at inclusion 18.8/70 (SD 9.8). Responders had significant lower mean Ch levels than non-responders (p = 0.04). We did not observe any other significant difference between responders and non-responders patients.

Conclusions

AChEI responders had a significant lower Ch concentration than non-responders however CSF Ach level or AchE activity were not predictive of AChEI therapeutical response.

The clinical-biological approach we used was innovative and could be extended to other treatments targeting neurotransmitters, in a personalized medicine approach (with benefit-risks balance improvement).