Early neuronal reprogramming and cell cycle reentry shape Alzheimer’s disease progression
Open accessAbstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by hallmark pathologies, synaptic dysfunction, neuronal loss, gliosis and cognitive decline-dementia. Recent large-scale cell atlases of human AD brains exposed vulnerability of specific neuronal subtypes and highlighted early, coordinated glial responses, suggesting glial involvement in disease progression. However, the timing and nature of neuronal changes, differences between neuronal subtypes, and their coordination with glia remain unclear. Here, we used non-negative matrix factorization to identify co-expression gene programs in single-nucleus RNA profiles from the prefrontal cortex of 437 samples from donors whose clinical symptoms ranged between no cognitive impairment and AD dementia. This approach identified early coordinated transcriptional changes across all neuronal subtypes, preceding clinical symptoms of cognitive decline, and validated in independent snRNA-seq, proteomics, and ELISA datasets. We found neurons in AD undergo rapid modulation of synaptic genes, accompanied by convergence of neurons into two distinct programs: An oxidative stress and apoptosis program abundant in vulnerable neuronal subtypes, and a DNA damage and cell-cycle reentry program associated with resilient subtypes. Moreover, neuronal reprogramming was closely tied to glial responses, and diverged between AD to non-AD brain aging, suggesting neuro-glial coordinated reprogramming shapes the AD cascade and influences disease outcomes.
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A prior study reported a 3- to 4-fold increase in the number of neurons expressing cell cycle reentry programs in advanced AD patients compared to healthy individuals.
“Additionally, a prior study reported a 3‐ to 4‐fold increase in the number of neurons expressing cell cycle reentry programs in advanced AD patients compared to healthy individuals. 69”
From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [69]
The section ‘Neurons converge to distinct programs of stress/apoptosis or cell-cycle reentry’ reports a 3- to 4-fold increase in advanced AD compared with healthy individuals. It specifies that the increase occurred in inhibitory and deep-layer (L4–6) excitatory neurons, but not L2–3 neurons; the citing sentence omits that limitation. (LLM, conf=0.88)
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References 53 · Cited by 3
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- Authors
- Meir, R., Schwartz, G., Adam, M., Lapidot, A. A., Cain, A., Green, G. S., Menon, V., Bennett, D. A., De Jager, P. L., & Habib, N.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Columbia University Irving Medical Center (US)
- Rush University Medical Center (US)
- Center for Translational & Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA
- Corresponding author
- Habib, Naomi
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2025-06-06
- PMC
- PMC12157441
- OpenAlex
- W4411081439
- Cited by
- 3
- References
- 53
- Citations by year
- 2026: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Rush University
- Israel Science Foundation
- National Institutes of Health (AG015819)
- National Institute on Aging (R01AG017917, U01AG046152, R01AG015819, P30AG010161, U01AG061356, RF1AG057473, U01AG072572, P30AG072975)
- H2020 European Research Council (853409)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, neuronal reprogramming, cell cycle re-entry, neuronal cell types, prefrontal cortex, single-nucleus RNA sequencing, oxidative stress, apoptosis, DNA damage, brain aging, synaptic dysfunction, disease progression, cognitive decline
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