Unique transcriptional profiles of adult human immature neurons in healthy aging, Alzheimer’s disease, and cognitive resilience

The existence and putative functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remains an open question. While rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus under both healthy conditions and in Alzheimer’s disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD and dementia-resilient human hippocampus to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. Employing a novel experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles reflecting ‘juvenile’ cellular functions, which are compromised in AD. Our findings suggest that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus, and cognitive resilience in AD.