IntroductionAlzheimer’s disease (AD) features progressive cognitive decline, Aβ aggregation, neurofibrillary tangles, mitochondrial dysfunction and central insulin resistance, lacking effective disease-modifying treatments. Liuwei Dihuang Pills (LWDHP) exert neuroprotective effects, while its dual regulatory mechanisms targeting mitochondrial homeostasis and cerebral IRS/AKT/GSK3β insulin signaling remain unclear.MethodsAPP/PS1 transgenic mice were used as AD models. Morris water maze assessed spatial cognition; immunofluorescence detected Aβ and MAP2; transmission electron microscopy observed neuronal/synaptic ultrastructure; western blot quantified synaptic proteins and insulin signaling cascade molecules.ResultsLWDHP significantly rescued spatial learning and memory deficits, reduced cerebral Aβ plaques and tau hyperphosphorylation. LWDHP balanced mitochondrial fusion-fission via upregulating PGC-1α/MFN2 and downregulating FIS1, elevated synaptic structural proteins (MAP2, PSD-95, SYN), restored cerebral insulin sensitivity by elevating InsR, normalizing IRS-1/AKT/GSK3β phosphorylation, and suppressing tau hyperphosphorylation.DiscussionLWDHP alleviates AD cognitive impairment through dual regulation of mitochondrial homeostasis and IRS/AKT/GSK3β insulin signaling, providing solid preclinical evidence for its anti-AD application.