# Long-term effect of discontinuing anticholinesterase treatment on cognitive decline and mortality in Alzheimer's disease in France: a quasi-experiment and target trial emulation study

## TL;DR

A study in France found that stopping cholinesterase inhibitors in Alzheimer's patients led to faster cognitive decline over four years, suggesting these drugs may still be beneficial.

## Contribution

The study provides real-world evidence of the long-term cognitive benefits of cholinesterase inhibitors in Alzheimer's disease.

## Key findings

- Discontinuing cholinesterase inhibitors led to a 1.81-point greater decline in MMSE scores after four years.
- No significant difference in mortality was observed between groups over five years.
- The study supports the clinical relevance of cholinesterase inhibitors for mild-to-moderate Alzheimer's.

## Abstract

In 2018, France withdrew reimbursement for cholinesterase inhibitors (ChEIs) in Alzheimer's disease, citing modest efficacy, lack of long-term benefit, and safety concerns. This policy shift provided a unique opportunity to assess ChEI effectiveness in real-world settings, by evaluating, among patients treated with ChEI between 01/08/2017 and 01/08/2018, the impact of treatment discontinuation on cognitive decline (MMSE score) and survival.

Using the French National Alzheimer's Database (BNA) and Meotis databases, we emulated a pragmatic, intention-to-treat trial comparing patients who discontinued ChEIs after delisting to those who continued treatment, under quasi-experimental conditions. To model cognitive trajectories, we used the inverse probability treatment-weighted (IPTW) cohort and applied mixed-effects models with random intercepts across all follow-up visits. Survival was estimated with a pooled logistic regression including treatment group, follow-up time, and an interaction between treatment and time.

The mean difference in MMSE decline between discontinuers and continuers after one year was 0·97 points (95% CI 0·68–1·27, p < 0·001), reaching 1·81 points (0·91–2·71, p < 0·001), after four years. No significant difference in mortality (RR 1·10, 95% CI [0·95–1·29]) was observed over a five-year period.

Our findings confirm and extend prior trials by demonstrating the sustained cognitive benefits of ChEIs in a real-world setting. While acknowledging the limitations associated with its retrospective nature, our study argues for reconsidering the 2018 delisting decision, as ChEIs remain safe and clinically relevant for mild-to-moderate Alzheimer's disease.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.