Patient-Derived PSEN1 Cerebral Organoids Revealed Parallel Development of Amyloid-β Accumulation and Network Dysfunction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-β (Aβ) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated Aβ42/40 and Aβ aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that Aβ dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential Aβ-induced changes in excitability during the preclinical stages of AD.