Natural Compounds as Multitarget Agents in Alzheimer's Diseases: Evidence from In Vivo and In Vitro Models

Abstract

Introduction: Alzheimer's disease (AD), the most common cause of dementia, is marked by a gradual decline in cognitive function driven by amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic failure, neuroinflammatory responses, and mitochondrial dysfunction. Despite extensive research efforts, currently available pharmacological treatments provide only limited symptomatic relief and do not prevent disease progression. These shortcomings have fuelled growing interest in natural compounds, which possess pleiotropic biological properties and may more effectively target the multifaceted pathology of AD. Methods: This systematic review was performed in compliance with the PRISMA 2020 guidelines. Comprehensive literature searches were conducted across PubMed, Scopus, and ScienceDirect to identify preclinical and clinical studies examining the effects of natural compounds in in vitro and in vivo models relevant to AD. Eligible studies assessed phytochemicals, herbal formulations, marine-derived substances, or nutraceuticals and their impact on core AD-related pathological features. Results: A total of 41 studies fulfilled the inclusion criteria, including 25 in vivo and 16 in vitro investigations. Across these studies, natural compounds consistently exhibited neuroprotective effects via multiple mechanisms associated with AD pathogenesis. These included the reduction of oxidative stress and neuroinflammation, inhibition of apoptotic pathways, modulation of amyloidogenic processes, attenuation of Aβ aggregation, regulation of tau-associated signalling, and preservation of synaptic function and cognitive outcomes. Conclusion: Overall, the available evidence suggests that natural compounds confer multitarget neuroprotective effects that directly engage with key pathological mechanisms underlying AD. Nonetheless, significant translational challenges remain, particularly with respect to bioavailability, compound standardisation, and clinical efficacy. Further robust, well-controlled clinical trials are essential to establish the therapeutic value of these agents as potential disease-modifying interventions for AD.