Human hippocampal neurogenesis in adulthood, ageing and Alzheimer's disease

Ahmed Disouky; Mark A Sanborn; K R Sabitha; Mostafa M Mostafa; Ivan Alejandro Ayala; David A Bennett; Yisha Lu; Yi Zhou; C Dirk Keene; Sandra Weintraub; Tamar Gefen; M-Marsel Mesulam; Changiz Geula; Mark Maienschein-Cline; Jalees Rehman; Orly Lazarov

doi:10.1038/s41586-026-10169-4

Human hippocampal neurogenesis in adulthood, ageing and Alzheimer's disease

Nature. 2026 Feb 25. doi: 10.1038/s41586-026-10169-4. Online ahead of print.

Authors

Ahmed Disouky¹, Mark A Sanborn², K R Sabitha¹, Mostafa M Mostafa¹, Ivan Alejandro Ayala³, David A Bennett⁴, Yisha Lu^{5

6}, Yi Zhou^{5

6}, C Dirk Keene⁷, Sandra Weintraub³, Tamar Gefen³, M-Marsel Mesulam³, Changiz Geula³, Mark Maienschein-Cline⁸, Jalees Rehman⁹, Orly Lazarov¹⁰

Affiliations

¹ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
² Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
³ Mesulam Center for Cognitive Neurology and Alzheimer's disease, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
⁴ Rush Alzheimer's Disease Center, Chicago, IL, USA.
⁵ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
⁶ University of Chinese Academy of Sciences, Shanghai, China.
⁷ UW Biorepository and Integrated Neuropathology (BRaIN) Lab, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
⁸ Research Informatics Core, University of Illinois Chicago, Chicago, IL, USA.
⁹ Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA. jalees@uic.edu.
¹⁰ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA. olazarov@uic.edu.

PMID: 41741649
DOI: 10.1038/s41586-026-10169-4

Abstract

The existence of human hippocampal neurogenesis has long been disputed^1-12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD)^11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)^14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

Abstract

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