Phytotherapeutic targeting of mitochondria in Alzheimer’s disease: A narrative review

Alzheimer’s disease (AD) is now recognized as a disorder involving not only amyloid-β and tau proteostasis but also progressive impairment of neuronal energy metabolism and mitochondrial quality control. Mitochondrial abnormalities in AD encompass impaired oxidative phosphorylation, excessive production of reactive oxygen species, disrupted calcium handling, defective mitophagy, altered fission–fusion dynamics, mitochondrial DNA damage, and activation of intrinsic apoptosis. These interconnected defects emerge early and can exacerbate amyloidogenic processing, tau phosphorylation, neuroinflammation, synaptic dysfunction, and neuronal loss. Phytotherapeutics are of interest in this context because many plant-derived compounds target multiple components of this pathological network. This narrative review synthesizes mechanistic, preclinical, and clinical evidence for mitochondria-directed phytotherapeutics, focusing on curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, berberine, standardized Ginkgo biloba extract, ginsenosides, and bacosides. These agents have been reported to activate Nrf2-dependent antioxidant defense, AMPK–SIRT1–PGC-1α signaling, mitochondrial biogenesis and mitophagy; stabilize membrane potential and respiratory-chain function; normalize mitochondrial dynamics; and suppress mitochondria-mediated apoptosis. Nevertheless, clinical translation is limited by poor oral bioavailability, uncertain brain exposure, variability in botanical preparations, insufficient pharmacodynamic confirmation, small heterogeneous trials, and limited safety data for long-term combination use. Current evidence supports these agents as promising experimental or adjunctive candidates rather than established disease-modifying therapies. Future research should employ chemically standardized products, quantify circulating and brain-relevant metabolites, incorporate mitochondrial target-engagement biomarkers, stratify participants by disease stage and metabolic phenotype, and evaluate rational formulations or combinations in adequately powered trials.