EARLY PATHOGENIC EVENTS IN ALZHEIMER’S DISEASE: PSEN MUTATIONS DRIVE A DEVELOPMENTAL STRESS PHENOTYPE IN HUMAN ORGANOIDS

Background: While Alzheimer’s disease (AD) is defined by age-related degeneration, growing evidence points to aberrant neurodevelopment as a critical vulnerability factor. We utilized PSEN-mutated human cortical organoids (hCOs) to model these early pathogenic events.
Methods: We analyzed 5-week hCOs using an integrated multi-omics approach (scRNAseq and proteomics). Functional pathways were deciphered using IPA, KEGG, and GO enrichment analyses.
Results: Integrated multi-omics analysis identified a profound dysregulation in protein homeostasis and organelle function. We observed significant enrichment of Unfolded Protein Response (UPR), ER stress, and ubiquitin-proteasome pathways, concurrent with mitochondrial dysfunction and disrupted vesicle trafficking (COPII, endocytosis). This suggests a compromised metabolic capability. Structurally, hCOs exhibited defects in Extracellular Matrix (ECM) organization and focal adhesions. Crucially, signaling pathways governing cell fate and guidance (WNT, NOTCH, SHH, Slit/ROBO) were dysregulated. These developmental alterations directly impacted synaptogenesis signaling, altered ion channel transport, and dysregulated calcium signaling.
Conclusion: PSEN mutations trigger a "developmental stress" phenotype in human organoids characterized by organelle failure and impaired connectivity. These findings suggest that AD pathogenesis begins as a neurodevelopmental deviation, establishing a cellular vulnerability threshold that predisposes the brain to neurodegeneration long before amyloid accumulation.