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Publication
bioRxiv

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

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  • March 18, 2026
  • Marlene Cohen, et al., University of Chicago
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
NHP-CSF, Plasma-NHP

Abstract

Alzheimer’s disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.

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Authors & Affiliations

Douglas A. Ruff¹, Drew E.G. Sheets¹, Ramanujan Srinath¹, Giovanne B. Diniz², Devon J. Griggs², Danielle Beckman², Sean Ott², Kayla Schwartz², Carissa Erices², Scott Muller³, Jeffrey H. Kordower³, John H. Morrison²⁴, and Marlene R. Cohen¹

¹ Department of Neurobiology, University of Chicago, IL, USA
² California National Primate Research Center, University of California Davis, Davis, California, USA
³ ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, USA
⁴ Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, USA

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.