Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer’s pathology and cognitive resilience
The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question. Although rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus both under 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 samples to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. By applying an integrated 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 to cognitive resilience in AD.
Authors
- Sarah Snoeck
- Erik Nutma (ORCID: https://orcid.org/0000-0002-7332-1636)
- Estibaliz Santiago-Mujika (ORCID: https://orcid.org/0000-0002-5809-5300)
- Kristofer Davie (ORCID: https://orcid.org/0000-0003-2182-1249)
- Jasper J. Anink (ORCID: https://orcid.org/0000-0003-1292-4529)
- Carlos P. Fitzsimons (ORCID: https://orcid.org/0000-0002-1556-2650)
- Will Macnair (ORCID: https://orcid.org/0000-0001-6357-0834)
- Dilara Ayyildiz (ORCID: https://orcid.org/0000-0002-8627-4648)
- Laurent Roybon (ORCID: https://orcid.org/0000-0002-5532-4964)
- Sandrine Thuret (ORCID: https://orcid.org/0000-0003-1260-8083)
- Suresh Poovathingal (ORCID: https://orcid.org/0000-0002-3236-2255)
- Jinte Middeldorp (ORCID: https://orcid.org/0000-0002-9198-8020)
- Julien Bryois (ORCID: https://orcid.org/0000-0002-4747-2166)
- Giorgia Tosoni (ORCID: https://orcid.org/0000-0003-0787-8556)
- Evgenia Salta (ORCID: https://orcid.org/0000-0003-3151-9369)
- Onur Başak (ORCID: https://orcid.org/0000-0002-6864-3403)
- Elena P. Moreno‐Jiménez (ORCID: https://orcid.org/0000-0002-9865-4875)
- Hyunah Lee (ORCID: https://orcid.org/0000-0003-2188-9729)
- Olmo Ruiz Ormaechea
- Sahand Farmand
- Amber Penning
- Eleonora Aronica
- Dick F. Swaab
- Luuk E. De Vries
- Paul J. Lucassen
Institutions
- Roche (Switzerland) (CH)
- Netherlands Institute for Neuroscience (NL)
- Van Andel Institute (US)
- King's College London (GB)
- Utrecht University (NL)
- Biomedical Primate Research Centre (NL)
- University Medical Center Utrecht (NL)
- Amsterdam Neuroscience (NL)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University of Amsterdam (NL)
Publication Details
- Journal
- Cell stem cell
- Published
- 2026-04-24
- DOI
- https://doi.org/10.1016/j.stem.2026.04.002
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer Nederland