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

TY - JOUR

T1 - Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer's pathology and cognitive resilience

AU - Tosoni, Giorgia

AU - Ayyildiz, Dilara

AU - Snoeck, Sarah

AU - Moreno-Jiménez, Elena P

AU - Penning, Amber

AU - Santiago-Mujika, Estibaliz

AU - Ruiz Ormaechea, Olmo

AU - Lee, Hyunah

AU - Poovathingal, Suresh

AU - Davie, Kristofer

AU - Bryois, Julien

AU - Macnair, Will

AU - Anink, Jasper

AU - De Vries, Luuk E

AU - Farmand, Sahand

AU - Nutma, Erik

AU - Swaab, Dick F

AU - Aronica, Eleonora

AU - Middeldorp, Jinte

AU - Thuret, Sandrine

AU - Roybon, Laurent

AU - Basak, Onur

AU - Fitzsimons, Carlos P

AU - Lucassen, Paul J

AU - Salta, Evgenia

N1 - Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2026/4/24

Y1 - 2026/4/24

N2 - 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.

AB - 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.

U2 - 10.1016/j.stem.2026.04.002

DO - 10.1016/j.stem.2026.04.002

M3 - Article

C2 - 42034060

SN - 1934-5909

VL - 33

SP - 763-783.e9

JO - Cell Stem Cell

JF - Cell Stem Cell

ER -