Exploring the potential of cinnamic acid analogues in alzheimer's disease.

BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Oxidative stress, exacerbated by mitochondrial dysfunction, metal dyshomeostasis, and impaired antioxidant defenses, plays a central role in synaptic dysfunction and cognitive decline. OBJECTIVES: This review evaluates the therapeutic potential of hydroxycinnamic acids as multi-target modulators of AD pathology, emphasizing mechanistic actions, structure–activity relationships, pharmacokinetic limitations, formulation strategies, and clinical evidence. METHODS: A narrative review was conducted using structured searches of PubMed, Scopus, Web of Science, and Google Scholar to identify relevant in vitro, in vivo, pharmacokinetic, formulation, and clinical studies on hydroxycinnamic acids in AD. RESULTS: Hydroxycinnamic acids, including ferulic acid, caffeic acid, chlorogenic acid, rosmarinic acid, and salvianolic acids, exhibit pleiotropic neuroprotective effects involving antioxidant, neuroinflammation, amyloid and tau modulation, and mitochondrial protection. Translation is limited by poor oral bioavailability, rapid metabolism, and restricted blood–brain barrier penetration. Nanoformulation and prodrug approaches show promise in improving CNS exposure in preclinical models. Clinical evidence remains limited, heterogeneous, and exploratory, with no compound demonstrating disease-modifying efficacy. CONCLUSION: Hydroxycinnamic acids hold promise as multi-target AD candidates. Clinical translation requires rigorous human PK studies, biomarker-driven trials, optimized formulations, and long-term safety evaluation.