Abstract
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a major global health challenge affecting more than 55 million people worldwide. AD is clinically defined by progressive cognitive decline and neuropathologically characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs). While transgenic rodent models have provided valuable mechanistic insights, they do not fully capture the spontaneous, age-related nature of human AD. In contrast, the companion dog develops naturally occurring age-associated cognitive decline and AD-like neuropathological features, including Aβ deposition and tau pathology, and behavioral impairments measurable by the validated cognitive scales, Canine Cognitive Dysfunction Rating (CCDR). However, the systematic application of human AD neuropathological criteria to canine brains has been limited. OBJECTIVE: The objective of this study was to apply established human neuropathological criteria (Thal, Braak, and CERAD) to aged canine brains and examine relationships among neuropathology, cognitive status, and plasma biomarkers. METHODS: Postmortem brain tissues from 24 client-owned senior dogs were evaluated using Thal phases for Aβ deposition, Braak-based regional assessment of tau pathology, and CERAD criteria for neuritic plaques. Neuropathological findings were integrated with antemortem owner-reported cognitive assessments and plasma biomarker measurements to evaluate the clinico-pathologic and biomarker associations. RESULTS: Senior dogs exhibited Aβ deposition consistent with early to intermediate Thal phases, variable and regionally restricted tau pathology, and an absence of neuritic plaques. Quantitative analysis demonstrated greater Aβ burden in cognitively impaired dogs compared with cognitively intact dogs, while age, but not cognitive score, was strongly associated with regional Aβ burden. Further, plasma glial fibrillary acidic protein (GFAP) levels showed a significant positive correlation with Aβ plaque burden, whereas the other plasma biomarkers assessed did not. CONCLUSION: Senior dogs exhibit neuropathologic features consistent with early-stage AD-like pathology, characterized by Aβ deposition and limited tau pathology in the absence of neuritic plaques. These findings support the utility of the companion dog as a naturally aging model for investigating early ADrelated pathological processes and evaluating translational biomarkers during preclinical disease.