MULTIMODAL CHARACTERIZATION OF CANINE COGNITIVE DYSFUNCTION: INTEGRATING NEUROPATHOLOGY, NEUROINFLAMMATION AND BIOMARKERS TO MODEL ALZHEIMER’S DISEASE

Abstract

ABSTRACTMULTIMODAL CHARACTERIZATION OF CANINE COGNITIVE DYSFUNCTION: INTEGRATING NEUROPATHOLOGY, NEUROINFLAMMATION AND BIOMARKERS TO MODEL ALZHEIMER’S DISEASE Canine cognitive dysfunction syndrome (CCD) is a naturally occurring, age-associated neurodegenerative disorder in companion dogs that shares clinical and pathological features with Alzheimer’s disease (AD), amyloid-beta (Aβ) deposition, tau-related pathology, and neuroinflammation. This dissertation aimed to characterize CCD as a translational model of AD by integrating fluid biomarkers, cognitive assessments, neuropathology, glial morphology, and spatial analysis. First, biomarkers relevant to human AD, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and Aβ, were assessed in aged dogs. Age and cognitive decline were associated with biomarker alterations, particularly increased NfL and reduced Aβ1-42/1-40 ratios, supporting their potential use alongside behavioral assessment for CCD detection. Second, human AD neuropathological criteria were applied to aged canine brains. Dogs showed early to intermediate Aβ deposition, limited regional tau pathology, and absence of neuritic plaques, supporting the canine model as a representation of early AD-like pathology. In a larger cohort, cognitively impaired dogs showed higher Aβ burden and more widespread glial activation compared with cognitively intact aged dogs. Multivariate analysis identified distinct pathological dimensions, including an amyloid-inflammatory axis and tau-associated axes, while clustering revealed heterogeneous pathological subgroups. Finally, Aβ plaques relationship to glial cells were examined using morphological and spatial analyses. Astrocytes showed increased association with plaques, while microglial cells were more related to cognitive status Overall, this dissertation demonstrates that CCD reflects a heterogeneous neurodegenerative syndrome that resembles critical features of AD, such as Aβ pathology, neurofibrillary tangles, biomarker changes, and prominent neuroinflammation. These findings support the companion dog as a valuable naturally aging translational model for studying AD-related cognitive decline, identifying biomarker signatures, and evaluating therapeutic strategies targeting amyloid pathology and neuroinflammation.