Summary: Zinc-APOE4 interaction and toxicity in the central nervous system (CNS) Alzheimer’s disease (AD) stands as the most widespread form of dementia globally, and its prevalence is on a steep ascent with the increasing aging population. Among the genetic risk factors contributing to AD, the Apolipoprotein E (ApoE) gene, particularly its 4 allele, occupies a central role, accounting for over half of all AD cases. Meanwhile, the emerging concept of zinc (Zn) dyshomeostasis has gained prominence, owing to its intriguing association with AD pathogenesis. Zinc, an essential trace element in human biology, assumes a paradoxical role as it can be neurotoxic at elevated concentrations while also modulating crucial cellular processes. Notably, multiple studies suggest that Zn can instigate the aggregation of Aβ protein, the primary constituent of senile plaques frequently observed in AD brains. In neurological conditions marked by apoptotic neuronal death, chelatable Zn tends to accumulate within neurons, either preceding or coinciding with degeneration. Given the substantial evidence for apoptotic neuronal demise in AD, the involvement of Zn in this process warrants thorough exploration. Notably, clinical trials have shown promise in using PBT2, a copper/zinc ionophore, for AD treatment. Moreover, recent insights indicate that interactions between brain metal ions and Apolipoprotein E4 (APOE4), the most potent genetic risk factor for AD, may constitute one of the mechanisms driving neurodegeneration. APOE exhibits isoform-dependent affinity for Zn, with ApoE2 > ApoE3 > APOE4. This interaction influences Aβ aggregation, with APOE2 mitigating Zn-induced Aβ precipitation, while APOE4 carriers exhibit a greater abundance of neurotoxic fragments. Dysregulated Zn levels in AD patients could potentially exacerbate neurodegeneration by affecting ApoE expression, particularly APOE4. However, the precise alterations in Zn concentration and the effects of Zn overload or deficiency in AD across patients, animal models, and cell lines remain areas of debate. To address these crucial questions, this study unfolds in two main aims: Firstly, to investigate the interactions between Zn and APOE4 and their potential impact, utilizing molecular docking, spectroscopy, and Surface Plasmon Resonance (SPR) to comprehend how Zn influences APOE4 conformation, and exploring the role of metal ion chelators like EDTA. Secondly, to examine the toxicity of Zn- APOE4 interactions across various brain cell types, encompassing cell viability, cytotoxicity, glial cell activation, inflammation, mitochondrial dysfunction, and caspase activation, aiming to elucidate their contribution to AD pathology. These investigations may offer novel insights into Zn’s role and potential therapeutic avenues for AD by targeting Zn dyshomeostasis.