Synergistic Role of Caffeic Acid with Conventional Neuroprotective Drugs: Potential of Combination Therapy for Managing Alzheimer's Disease.

Abstract

Introduction: Alzheimer's Disease (AD) is a complex neurodegenerative disease involving amyloid-β accumulation, formation of neurofibrillary tangles, oxidative stress, and inflammation. Current treatment options include symptomatic agents such as Acetylcholinesterase Inhibitors (AChEIs) and memantine. The present review discusses the therapeutic potential of Caffeic Acid (CA) as an adjunctive agent to conventional anti-Alzheimer's treatments, focusing particularly on its pharmacodynamics and pharmacokinetics.

Methods: An extensive search of the literature was carried out from the years 2000 to 2025 using databases such as PubMed, Scopus, Web of Science, Science Direct, Embase, Medline, Google Scholar, and others. All in vitro, in vivo, and in silico studies that have evaluated CA alone or in combination with AChEIs and memantine were included.

Results: The existing literature suggests that CA has antioxidant, anti-inflammatory, and weak cholinesterase inhibition properties, while AChEIs and memantine mainly target neurotransmission. The results suggest that CA, when combined with other anti-Alzheimer's agents, provides superior neuroprotective properties compared to monotherapy in various animal models. Nevertheless, current data support more additive rather than synergistic actions of CA with AD medications.

Discussion: Pharmacokinetic issues associated with CA use are possible due to the drug's ability to interfere with cytochrome P450 and P-glycoprotein. Moreover, issues with CA pharmacokinetics, nanoparticle delivery systems, and patient compliance might affect the translation of these findings into clinical practice.

Conclusion: CA might be used as an auxiliary substance for treating AD. Further research on pharmacokinetic/pharmacodynamic interactions and synergy between these compounds is required.