Alzheimer’s disease neuropathological characterization of the dog brain and relationship to biofluid biomarkers and cognitive function
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting more than 55 million people worldwide and is characterized by cognitive decline, amyloid-beta (Aβ) plaques, and neurofibrillary tangles. Although transgenic rodent models have advanced understanding of AD, they do not fully replicate the spontaneous, age-related nature of human disease. Companion dogs naturally develop age-associated cognitive decline and AD-like neuropathology, making them a valuable translational model. This study characterized Aβ deposition, phosphorylated tau (pTau181) pathology, and neuritic plaque pathology in aged canine brains using neuropathologic assessment methods adapted from human AD frameworks (Thal, Braak, and CERAD), and examined associations with cognitive status and plasma biomarkers. Postmortem brain tissues from 24 client-owned senior dogs were evaluated and integrated with antemortem Canine Cognitive Dysfunction Rating (CCDR) scores and plasma biomarker measurements. Senior dogs exhibited Aβ deposition consistent with early Thal-like regional involvement, variable regionally restricted pTau181 pathology, and an absence of neuritic plaques. Quantitative analyses showed greater Aβ burden in cognitively impaired dogs, while age was the strongest predictor of regional Aβ accumulation. Plasma glial fibrillary acidic protein (GFAP) concentrations were positively correlated with Aβ plaque burden, whereas other biomarkers were not. These findings indicate that aged dogs develop early-stage AD-like pathology and support their utility as a naturally aging model for studying preclinical AD mechanisms and translational biomarkers.
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Authors: Abdullatif Alsulami, Marika Bogdani, Evan L. MacLean, C. Dirk Keene, Stephanie McGrath, Joshua M. Akey, Brooke Benton, Elhanan Borenstein, Marta G. Castelhano, Amanda Erickson Coleman, Kate E. Creevy, Kyle D. Crowder, Matthew D. Dunbar, Virginia R. Fajt, Annette L. Fitzpatrick, Unity Jeffery, Erica C. Jonlin, Matt R. Kaeberlein, Elinor K. Karlsson, Kathleen F. Kerr, Jonathan M. Levine, Jing Ma, Robyn L. McClelland, Daniel Promislow, Audrey Ruple, Stephen Mark Schwartz, Sandi Shrager, Noah Snyder‐Mackler, Mary Katherine Tolbert, Silvan R. Urfer, Benjamin S. Wilfond, Caitlin S. Latimer, Julie A. Moreno
Institutions: University of Washington, Tufts University, Cornell University, University of Massachusetts Chan Medical School, University of Arizona, University of Georgia, Arizona State University, Tel Aviv University, Broad Institute, Colorado State University, Texas A&M University, Princeton University, Virginia Tech, University of San Diego, Jean Mayer Human Nutrition Research Center on Aging, New York State College of Veterinary Medicine, Fred Hutch Cancer Center, Santa Fe Institute, Seattle Children's Research Institute, Treuman Katz Center for Pediatric Bioethics and Palliative Care