Background DHA‐H (2‐hydroxy‐docosahexaenoic acid) is a promising therapeutic approach for Alzheimer’s Disease (AD). DHA‐H gives rise to dose‐dependent increased levels of HPA (Heneicosapentaenoic acid) in blood plasma and brain whereas DHA‐H remains virtually absent from the brain of DHA‐H‐treated mice. Oral administration of DHA‐H to a transgenic model of AD (5xFAD mice) induces a significative cognitive recovery. However, the molecular mechanism underlying this neuroprotective effect remains largely unresolved. Method Screening of potential receptors for DHA‐H and HPA was performed using computational tools. PPARG (Peroxisome Proliferator‐Activated Receptor γ) activity was determined by cell‐based assays. Levels of proteins involved in amyloid production as well as synaptic markers were determined by WB and/or ELISA. β‐ and γ‐secretase activities were measured in cell‐free assays. Neuronal density was determined by immunohistochemistry. Brain levels of DHA‐H and HPA were determined by Electrospray Ionization – Mass Spectrometry (ESI‐MS). Result Both DHA‐H and HPA are activators of PPARG. We have analyzed the effect of DHA‐H treatment on the amyloidogenic route in the 5xFAD mice and this effect was related with PPARG activity. We observed a modulation of protein levels and enzymatic activities involved in β‐amyloid production as well as a prevention of synaptic and neuron degeneration in DHA‐H‐treated mice as compared with untreated controls. These changes were related with improved cognitive scores in these mice. Conclusion All these results together indicate that DHA‐H administration must prevent neuronal degeneration and cognitive decline in AD mice through its immediate metabolite HPA and without apparent involvement of PPARG.