SORL1 variant links endosomal amyloid precursor protein mis‐sorting to axonal transport defects and neuronal dysfunction

INTRODUCTION: SORL1 encodes the sorting receptor SORLA, a major genetic contributor to Alzheimer's disease (AD). Although SORL1 loss disrupts endosomal trafficking and promotes amyloidogenic amyloid precursor protein (APP) processing, the functional consequences of specific missense variants in human neurons remain unclear. METHODS: We used isogenic induced pluripotent stem cell (iPSC)-derived NGN2 neurons and 3D cerebral organoids carrying wild-type, SORL1 p.Y1816C knock-in, or SORL1 knockout alleles. We analyzed SORLA maturation and shedding, APP localization, amyloid-β (Aβ) secretion, endosomal morphology, axonal transport of Rab5+ endosomes and APP, and network activity. RESULTS: The p.Y1816C variant impaired SORLA maturation and shedding and, together with knockout, caused enlarged early endosomes, APP retention, elevated Aβ secretion, amyloid deposition in organoids, axonal swellings, disrupted axonal transport, and neuronal hyperexcitability. CONCLUSIONS: The SORL1 p.Y1816C variant is pathogenic in human neurons, and we reveal novel roles for SORLA in axonal transport and neuronal excitability. These findings highlight endosomal trafficking disruption as a central mechanism in AD pathogenesis.