By analyzing the journey of 5,700 patients who continued or stopped their treatment in 2018, teams from Lille University Hospital and the Brain Institute showed a moderate but maintained cognitive benefit over four years. A methodological and scientific advance, published in The Lancet Regional Health Europewhich gives a voice back to patients and their loved ones.
Defunded but not ineffective: the French paradox
In France, there is still no curative treatment for Alzheimer’s disease. The medications available only act on the symptoms. They do not attack the biological mechanisms at the origin of neurodegeneration, but attempt to mitigate its consequences, particularly on memory and cognitive functions.
In 2018, following an unfavorable opinion from the High Authority for Health (HAS), the Ministry of Health decided to de-reimburse acetylcholinesterase inhibitors, due to a lack of data deemed sufficient on their effectiveness and long-term safety in real conditions. Twenty years after the marketing of donepezil, leader of this therapeutic class, the signal is strong.
At the time, experts were concerned about a lack of robust evidence in patients who were older and more frail than those included in clinical trials. The available data comes mainly from controlled studies, carried out on selected populations, far from the complexity of memory consultations.
It is precisely this pivotal moment that the teams from the Memory Resources and Research Center of the Lille University Hospital, the Lille Neuroscience & Cognition Research Center, the Public Health Epidemiology, Health Economics and Prevention department of the Lille University Hospital, in collaboration with the Brain Institute in Paris, chose to study.
Their work, published in the journal The Lancet Regional Health Europeis based on a simple and deeply human question: what happens to patients who stop their treatment, and to those who continue it?
Four years of follow-up, 5,700 patients: a moderate but real benefit
Researchers analyzed data from 5,700 people with Alzheimer’s disease in 2018, the year of delisting. Some stopped their treatment, others continued it. All were followed over four years.
The assessment was based on the MMSE (Mini Mental State Examination), a 30-point benchmark test widely used to measure changes in cognitive functions. The results are nuanced, but clear.
At one year, the average difference in MMSE score between patients who continued their treatment (“continuers”) and those who stopped it (“continuers”) is 0.97 points after one year. After four years, it reached 1.81 points. Concretely, this corresponds to “time saved” on cognitive decline estimated at 6.5 months after one year and 11.3 months at four years.
A seemingly modest gain. But for a family faced with the gradual erosion of memory, a few additional months of autonomy or recognition can profoundly change daily life. Dr Simon Lecerf, from Lille University Hospital, underlines: “Cognitive evolution shows typical effect of acetylcholinesterase inhibitors on symptoms”.
© Lille University Hospital
Evolution of the MMSE score among pursuers and discontinuers.
His colleague Octave Guinebretiere, from the Brain Institute, specifies: “In terms of cognitive performance, the gap between chasers and stoppers widens very quickly, then the curves remain generally parallel..
In other words, the treatment does not stop the progression of the disease, but it seems to shift the trajectory of decline, with no additional mortality observed between the two groups. This lack of increase in the risk of death is a crucial point, while long-term safety constituted one of the arguments leading to delisting.
A new method for illuminating “real life”
Beyond the results, the originality of the study lies in its methodology: an “emulated trial”. In situations where a randomized clinical trial would be difficult or impossible to conduct—for ethical, logistical, or financial reasons—this approach involves using observational data to replicate, as much as possible, the conditions of a controlled trial.
The researchers relied on the National Alzheimer Bank, a database powered by more than 600 memory consultations across the country, as well as on the Méotis regional register in Hauts-de-France. A rare and valuable photograph of daily clinical practice.
Thomas Nedelec, researcher at the Brain Institute, explains: “The idea here is to exploit the natural variability of observational data to reproduce the conditions of a randomized clinical trial, without suffering the logistical constraints..
Of course, this is an observational study. Despite rigorous statistical adjustment — notably by inverse probability weighting — residual bias cannot be completely excluded. But these results match those of the British DOMINO trial, published in 2012 in the New England Journal of Medicinewhich had already shown a benefit from maintaining treatments at advanced stages of the disease. At the time, this data was not enough to influence the French decision, considered unrepresentative of “real life”.
Professor Thibaud Lebouvier, neurologist and researcher at Lille University Hospital, believes today that lighting is changing: “Thanks to this emulated trial, our analysis covers a much larger population than DOMINO, more representative of daily clinical practice, including patients at an early stage of the disease and followed over a longer term. They help to answer the questions asked by the transparency commission, by showing the maintenance of long-term effectiveness and apparent safety of use of acetylcholinesterase inhibitors used in real conditions..
And now ?
These results do not turn acetylcholinesterase inhibitors into miracle treatments. They do not erase the inexorable progression of the disease, nor the weight it places on caregivers. But they invite us to look differently at these symptomatic medications, often disqualified, sometimes abandoned in public debate.
In a pathology where each month of autonomy counts, where each MMSE point reflects a fragment of preserved memory, the question of whether or not to maintain treatment cannot be solely a matter of accounting.
At a time when research is exploring new therapeutic avenues, these data point to the obvious: science is also moving forward by re-evaluating what we thought was acquired. And behind the statistical curves, there are faces, first names, stories hanging from a few points of memory.