Numerous medicinal plants have proven valuable in managing Alzheimer’s disease (AD). This research selected the oleo-gum-resin of Ferula persica, referred to as sagapenum, to examine its potential to inhibit enzymes linked to the development and advancement of AD. In addition, a previously unreported phytochemical profile was established. Inhibitory effects of dichloromethane, methanol, and aqueous extracts were evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) employing the adapted Ellman’s assay. The most effective extract underwent detailed phytochemical examination via multiple column chromatography approaches. The dichloromethane extract displayed marked selective inhibition of BuChE (IC₅₀ = 23.41 µg/mL), relative to the standard drug donepezil (IC₅₀ = 1.97 µg/mL). Analysis of this extract yielded the isolation and characterization of aurapten, farnesiferol A, umbelliprenin, farnesiferol C, farnesiferone A, karatavicinol, ferocaulidin, and ligupersin A, all of which were screened for cholinesterase (ChE) inhibition. Farnesiferol A proved to be the strongest and most selective BuChE inhibitor (IC₅₀ = 31.46 µg/mL). Furthermore, it demonstrated substantial inhibition of β-secretase 1 (BACE1) (IC₅₀ = 5.14 µM), when benchmarked against the reference compound OM99-2 (IC₅₀ = 0.014 µM), suggesting its potential as a multi-target agent for AD therapy. The pronounced selective BuChE inhibition by the dichloromethane extract of sagapenum, along with the activity of farnesiferol A—particularly its BACE1 suppression—could be instrumental in formulating novel dietary supplements for AD.
