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The intracellular accumulation of amyloid beta 42 (iAβ42) has been proposed as an early pathological indicator of familial Alzheimer’s disease (FAD). DJ-1 is a multifunctional protein sensitive to oxidative stress (OS) that has been associated with neurodegeneration; however, its role in iAβ42 pathology is unclear. In this study, we examined whether oxidized (sulfonic) DJ-1 (Cys106-SO₃) drives iAβ42 accumulation using postmortem brain samples and in vitro 3D (iPSC-derived cerebral organoids, COs) or 2D induced pluripotent stem cells (iPSC)-derived ChLNs (cholinergic-like neurons) models from a PSEN1 E280A patient and a healthy volunteer (as a control sample). Post-mortem analyses of the temporal and frontal cortices and hippocampus from FAD PSEN1 E280A patients revealed strong intracellular co-localization of sulfonic DJ-1 and iAβ42, which was absent in control samples. To validate these findings, we generated cerebral organoids (COs) from an iPSCs PSEN1 E280A FAD patient and a healthy donor. In these organoids, we observed the co-localization of oxidized DJ-1 and Aβ42 in the absence of extracellular fibrils or plaques, as confirmed by BTA-1 staining. To further support these observations, 2D iPSC PSEN1 E280A-derived ChLNs cultures showed that intracellular Aβ42 accumulates progressively in direct correlation with increasing DJ-1 oxidation, as demonstrated by immunofluorescence microscopy and Western blotting analysis. These results indicate that DJ-1 oxidation accompanies the earliest intracellular stages of Aβ42 pathology. Furthermore, complementary in silico molecular docking analysis revealed a higher affinity between Aβ42 and oxidized sulfonic DJ-1 (DJ-1 1Cys106-SO₃) compared to sulfenic (DJ-1 Cys106-SOH) or sulfinic acid (DJ-1 Cys106-SO2H) forms. Likewise, ELISA tests and seeding assays confirmed that oxidized DJ-1 binds to and decelerates Aβ42 aggregation kinetics. Together, our results identify DJ-1 oxidation as a critical molecular event in the accumulation of iAβ42 in FAD. These findings suggest that oxidized DJ-1 represents not only a potential early biomarker of intracellular pathology but also a pharmacological target. Preventing the oxidation of DJ-1 or its pathological aggregation could provide new biomarkers and therapeutic strategies for reducing the intracellular accumulation of Aβ42 and neurodegeneration in FAD.