Natural flavonoids in multiple sclerosis: molecular insights and emerging therapeutic strategies.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid-β (Aβ) deposition and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. It leads to synaptic failure and, ultimately, cognitive decline [,]. AD is a central nervous system disorder predominantly impacting individuals aged 65 and older. Over 5 million people in the United States currently have a diagnosis of this condition, with mortality rates rising by 89% since the year 2000 [,]. Around 50 million individuals worldwide are affected by dementia, and it is estimated that the number will increase threefold by the year 2050 []. Although advancing age and genetic susceptibility, most notably the APOE ε4 allele, remain the predominant determinants of AD risk, growing evidence indicates that metabolic dysregulation plays a crucial role in shaping disease onset and progression [,]. Within this metabolic framework, the adipokine adiponectin has emerged as a biologically compelling factor linking peripheral metabolic health to central neurodegenerative pathways []. Recent studies have highlighted a potential biological interaction between vitamin D (VD) and L-cysteine (L-Cys), two metabolic regulators that converge on glutathione (GSH) homeostasis and VD activation pathways. Co-supplementation with VD and L-Cys has been reported to increase circulating adiponectin levels, with their combined antioxidant and anti-inflammatory effects positioning them as plausible modulators of the adiponectin-related metabolic and neuroinflammatory pathways [,,]. Together, these findings suggest a mechanistic framework in which VD and L-Cys act synergistically to regulate adiponectin, redox balance, and neuroinflammatory pathways, which may influence biological pathways implicated in AD. This review highlights current evidence supporting the VD–L-Cys–adiponectin triad as a potential metabolic–neuroprotective axis and explores its relevance to AD pathophysiology and future therapeutic research. Although accumulating experimental evidence supports the neuroprotective functions of adiponectin, human studies remain inconsistent and have produced the so-called adiponectin paradox []. Furthermore, although VD and L-Cys have independently been shown to influence oxidative stress, glutathione metabolism, and adiponectin expression [,], their potential interactions within the context of AD have not been comprehensively synthesized. Addressing these knowledge gaps provides the rationale for the present review.