Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients

Sporadic Alzheimer’s disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity. [Display omitted] •Alzheimer's patients’ induced neurons (iNs) show transcriptional and cellular defects•Alzheimer's iNs activate de-differentiation pathways and markers of neuronal fate loss•Epigenetic erosion underlies the pathogenic hypo-mature state of Alzheimer's iNs•Rejuvenated iPSC neurons show only very mild transcriptomic disease signatures Mertens et al. generated directly induced neurons (iNs) from Alzheimer's patients’ fibroblasts that show neuronal defects and activate immature and de-differentiation signaling pathways. Aging- and cancer-associated epigenetic changes promote the underlying pathogenic hypo-mature neuronal state, and iPSC rejuvenation largely rescued the age-dependent disease phenotype.