Directly converted human neuronal spheroids preserve donor age and model Alzheimer disease

In a new preprint, researchers developed directly induced neuronal spheroids using primary fibroblasts from young, unimpaired aged, and sporadic Alzheimer disease human donors, as well as non-human primates. The team converted fibroblasts directly into three-dimensional neuronal spheroids without pluripotency. Single-nucleus RNA sequencing confirmed that approximately 96% of cells acquired a neuronal identity. The resulting electrophysiologically active neurons preserved donor-specific epigenetic age and supported astrocytes and microglia. Spheroids from Alzheimer donors spontaneously displayed neuronal degeneration, amyloid-beta accumulation, progressive Tau pathology, and metabolic dysfunction. Multi-omics profiling separated physiological aging from Alzheimer disease. Drug tests showed oxaliplatin shifted cells toward oxidative metabolism, and trametinib modulated inflammatory and age-associated programs.