Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease.
Overview
- Department of Neurobiology, University of Chicago, Chicago, IL 60637
- California National Primate Research Center, University of California Davis, Davis, CA 95616
- Arizona State University - Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85281
- Department of Neurology, School of Medicine, University of California Davis, Sacramento, CA 95825
Abstract
Alzheimer’s disease and related dementias are typically described at two levels: the accumulation of molecular pathology and the emergence of cognitive impairment. Understanding the relationship between pathology, often studied in animal models, and human cognition will require measurements spanning intermediate scales, including single neurons, neuronal populations, and distributed networks. Here we combine longitudinal measurements of behavior and neuronal population activity with fluid and histological biomarkers in a macaque model of early-stage disease. We find in two animals that visually guided behavior becomes increasingly disorganized, with less consistent and more variable patterns of exploration, despite preserved performance on simple tasks. In parallel, coordinated activity within and between neuronal populations in visual and parietal cortex declines, even as single-neuron tuning and basic feature encoding remain stable. The magnitude of these physiological changes was broadly consistent with biomarker progression. These changes arise when pathology is largely confined to regions providing feedback to visual cortex, indicating that functional disruption extends beyond sites of prominent pathology. Together, these results show that early disease progression is not marked by the loss of individual functions at any single level, but by a selective disruption of coordination across levels, from neuronal populations to behavior. This disorganized state is measurable and modifiable: methylphenidate administration was associated with a transient restoration of behavioral organization. These findings identify disruption of neuronal population organization as a defining feature of early-stage Alzheimer’s disease and establish coordinated population activity as a candidate target for therapeutic intervention.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- figshare:32961443 — at figshare; found in “Data, Materials, and Software Availability”
Data, Materials, and Software Availability
Neuronal and behavioral data have been deposited in figshare (10.6084/
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 3 keywords, 9 MeSH terms, 7 funders, 83 references.
Cite
This paper
Ruff, D. A., Sheets, D. E. G., Srinath, R., Diniz, G. B., Griggs, D. J., Beckman, D., Ott, S., Schwartz, K., Erices, C. T., Muller, S., Kordower, J. H., Morrison, J. H., & Cohen, M. R. (2026). Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 123(35), e2614164123. https://
BibTeX
@article{ruff2026loss,
author = {Ruff, Douglas A and Sheets, Drew E G and Srinath, Ramanujan and Diniz, Giovanne B and Griggs, Devon J and Beckman, Danielle and Ott, Sean and Schwartz, Kayla and Erices, Carissa T and Muller, Scott and Kordower, Jeffrey H and Morrison, John H and Cohen, Marlene R},
title = {{Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = aug,
volume = {123},
number = {35},
pages = {e2614164123},
publisher = {National Academy of Sciences},
issn = {0027-8424},
doi = {10.1073/
url = {https://
pmid = {42640802},
pmcid = {PMC13534665}
}
RIS
TY - JOUR
AU - Ruff, Douglas A
AU - Sheets, Drew E G
AU - Srinath, Ramanujan
AU - Diniz, Giovanne B
AU - Griggs, Devon J
AU - Beckman, Danielle
AU - Ott, Sean
AU - Schwartz, Kayla
AU - Erices, Carissa T
AU - Muller, Scott
AU - Kordower, Jeffrey H
AU - Morrison, John H
AU - Cohen, Marlene R
TI - Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease
T2 - Proceedings of the National Academy of Sciences of the United States of America
J2 - Proc Natl Acad Sci U S A
PY - 2026
DA - 2026/
VL - 123
IS - 35
SP - e2614164123
SN - 0027-8424
PB - National Academy of Sciences
DO - 10.1073/
UR - https://
LA - en
ER -
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