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Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer's pathology and cognitive resilience

Tosoni, Giorgia LU orcid ; Ayyildiz, Dilara ; Snoeck, Sarah ; Moreno-Jiménez, Elena P ; Penning, Amber ; Santiago-Mujika, Estibaliz ; Ruiz Ormaechea, Olmo ; Lee, Hyunah ; Poovathingal, Suresh and Davie, Kristofer , et al. (2026) In Cell Stem Cell 33(5). p.9-783
Abstract

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,... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Humans, Alzheimer Disease/pathology, Hippocampus/pathology, Neurons/metabolism, Aged, Aging/pathology, Male, Aged, 80 and over, Female, Cognition, Transcriptome/genetics, Gene Expression Profiling, Neurogenesis
in
Cell Stem Cell
volume
33
issue
5
pages
9 - 783
publisher
Cell Press
external identifiers
  • pmid:42034060
  • scopus:105038603859
ISSN
1934-5909
DOI
10.1016/j.stem.2026.04.002
language
English
LU publication?
no
additional info
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.
id
8728f753-04df-462a-9bd8-330d4e9c7b72
date added to LUP
2026-09-25 10:22:53
date last changed
2026-09-26 04:00:34
@article{8728f753-04df-462a-9bd8-330d4e9c7b72,
  abstract     = {{<p>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.</p>}},
  author       = {{Tosoni, Giorgia and Ayyildiz, Dilara and Snoeck, Sarah and Moreno-Jiménez, Elena P and Penning, Amber and Santiago-Mujika, Estibaliz and Ruiz Ormaechea, Olmo and Lee, Hyunah and Poovathingal, Suresh and Davie, Kristofer and Bryois, Julien and Macnair, Will and Anink, Jasper and De Vries, Luuk E and Farmand, Sahand and Nutma, Erik and Swaab, Dick F and Aronica, Eleonora and Middeldorp, Jinte and Thuret, Sandrine and Roybon, Laurent and Basak, Onur and Fitzsimons, Carlos P and Lucassen, Paul J and Salta, Evgenia}},
  issn         = {{1934-5909}},
  keywords     = {{Humans; Alzheimer Disease/pathology; Hippocampus/pathology; Neurons/metabolism; Aged; Aging/pathology; Male; Aged, 80 and over; Female; Cognition; Transcriptome/genetics; Gene Expression Profiling; Neurogenesis}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{9--783}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer's pathology and cognitive resilience}},
  url          = {{http://dx.doi.org/10.1016/j.stem.2026.04.002}},
  doi          = {{10.1016/j.stem.2026.04.002}},
  volume       = {{33}},
  year         = {{2026}},
}