It has been 20 years since no new active substance has enriched the range of anti- Alzheimer’s drugs and those currently available, mainly acetylcholinesterase inhibitors (AChE) have only been symptomatic and also temporary, because of their mechanism of action that aims to inhibit a target, itself condemned to disappear with neurons affected by neurodegeneration. None of the targets for the active ingredients that have been clinically tested has so far demonstrated true efficacy to stop the disease. The explanations included the difficulty in selecting patients whose condition would not be too advanced to allow them to benefit from possible curative treatment, the difficulty in having relevant preclinical animal models and the multifactorial origin of the disease requiring a multi-target approach. The latter is currently being considered more closely, and most clinical trials now combine, with the new molecules evaluated, donépézil, the most used of marketed ACHE inhibitors. CERMN itself pursues a multi-target approach, but with pleiotropic principles specifically designed to target several targets and benefit from synergy of effects, without the disadvantages of possible drug combination interactions and adherence to treatment. In this context, we chose to target both the 5-HT4 receptor to exercise a neuroprotective effect and, on the other hand, ACHE, the inhibition of which seems always relevant if it is associated with an effect that also preserves the intended enzyme. The activation of the 5-HT4 receptor, in fact, allows, apart from releasing acetylcholine (ACh), to activate alpha secrettase and promote the non-amyloidogenic cleavage of the APP precursor of the peptide -amyloid (-A) to the neurotrophic protein sAPP. Inhibition of the ACHE catalytic site preserves the freed ACH. If this effect is complemented by interaction with the anionic peripheral site (PAS) of the enzyme, the latter should no longer aggregate with oligomers -A reducing their neurotoxicity. We have recently managed, in collaboration with the Institute of Functional Genomics in Montpellier, to associate these different activities within a family of pleiotropic compounds whose leader, donécopride, seems capable of potentially having both a lasting symptomatic effect and a curative effect in Alzheimer’s disease (AD). Indeed, donecopride is a selective agonist (Ki = 8.5 nM) and partial (48.3 %) of the 5-HT4 receptor, which promotes in vitro and in vivo the release of sAPP. It is also a competitive ACHE mixed-type inhibitor (IC50 =16 nM), selective to butyrylcholinesterase (IC50 = 3530 nM), which moves the propidium iodide from the peripheral site of the latter (24 %) and may therefore prevent the AChE-dependent amyloid aggregation. These properties expressed by donecoprid resulted in in vivo in NMRI mice, at the dose of 0.3 mg/kg, by both procognitive effects, measured in the New Object Recognition Test (NOR), and anti-amnesics, established in the spontaneous alternation test by the reversal of the mnesic disorders induced by scopolamine. This pharmacological profile has led us to want to verify the possible therapeutic value of donecoprid in two animal models of MA: a 5XFAD transgenic mouse model, in which the reference 5-HT4 agonist RS67333, a reference 5-HT4 agonist, was active and a model of mice made deficient by intracerebroventricular (icv) injection of oligomers -A, in which donépézil was shown to be effective [...]