Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease.

Authors

Douglas A Ruff, Drew E G Sheets, Ramanujan Srinath, Giovanne B Diniz, Devon J Griggs, Danielle Beckman, Sean Ott, Kayla Schwartz, Carissa T Erices, Scott Muller, Jeffrey H Kordower, John H Morrison, Marlene R Cohen

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2614164123. Epub Aug 25, 2026.

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.

PMID:
42640802
Bibliographic data and abstract were imported from PubMed on 26 Aug 2026.

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