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Publication
Alzheimer’s & Dementia

Sex-specific acceleration of Alzheimer’s pathogenesis by chronic sleep-deprivation

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  • January 30, 2026
  • Wai Haung Yu, Darcy Wear, et al., University of Toronto
Topic/Product:
Mouse Panel 120
Disease Area:
Alzheimer's Disease
Sample Type:
Hippocampal Homogenate

Abstract

INTRODUCTION

Sleep impairments likely contribute to Alzheimer’s pathology, though specific contributions to disease progression are incompletely understood. We propose that autophagic impairment is associated with chronic sleep disruption and examine how sleep loss and stress influence disease development, including having impacts on proteostasis, cognition, and neural circuitry.

METHODS

We sleep-disrupted 6-month-old APPNL-G-F mice for 2 weeks and behaviorally assessed sleep recovery, nesting, stress, and cognition. Subsequently, we analyzed markers of Alzheimer’s pathology, stress, neuroinflammation, and proteostasis in hippocampal and subcortical brain regions.

RESULTS

Sleep-deprived mice had altered sleep-related behaviors, increased stress, and signs of disease-acceleration including sex-dependent neurodegeneration, proteinopathy, and changes to autophagy and the neuroinflammatory response.

DISCUSSION

Chronic sleep disruption accelerates the pathological cascade of Alzheimer’s, including cognitive impairment and Alzheimer’s pathology in a sex-dependent manner. This work enhances our understanding of the sleep–stress–Alzheimer’s relationship, including sex-based differences, and may point to a novel therapeutic avenue to limit Alzheimer’s progression.

Highlights

  • Chronic SD accelerates hippocampal AD pathology.
  • Hypothalamic orexin production increases with SD in APPNL-G-F mice.
  • SD induces autophagic deficits and neurodegeneration in the locus coeruleus.
  • Sex-dependent impairments to the autophagic-lysosomal pathway follow SD.
  • Female-specific stress and neuroinflammatory responses occur with SD.
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Authors & Affiliations

Darcy Wear¹², Christopher Daniel Morrone², Dominic Simpson², Fang Liu¹²³⁴⁵, Syed Abid Hussaini⁶, and Wai Haung Yu¹

¹ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
² Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
³ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
⁴ Department of Physiology, University of Toronto, Toronto, Ontario, Canada
⁵ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
⁶ Burke Neurological Institute, Weill Cornell Medicine, White Plains, New York, 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.