A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action ofCurcuma longaextracts in Alzheimer’s disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components ofCurcuma longaextracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Aβ-peptide. When the CYC and curcumin metabolite tetrahydrocurcumin (5, THC) were inserted into an anionic lipid solution, a significant modification of the AβCD curves was detected. These data were implemented by EPR experiments, demonstrating that CYC reaches the inner part of the bilayer, while the other curcuminoids are localized close to the membrane interface. Computational studies provided a model for the curcuminoid-Aβinteraction, highlighting the importance of a constrained “semi-folded” conformation to interact with Aβanalogously to the pattern observed in α-helical coiled-coil peptide structures. This combined approach led to a better understanding of the intriguingin vitroandin vivoactivity of curcuminoids as anti-Alzheimer agents, paving a new path for the rational design of optimized druggable analogues.