Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)-associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month-old mice revealed CNTF resistance in the older animals associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non- raft cortical membrane domains. This age-dependent membrane remodelling prevented both the formation of active CNTF-receptor complexes and the activation of pro-survival STAT-3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing towards dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing associated receptors to respond appropriately to anti-AD agents.