# Canine Cognitive Dysfunction and Alzheimer’s Disease: Pathophysiological Relationships and the Impact of Glymphatic System Impairment on Neurodegeneration

## TL;DR

Canine cognitive dysfunction shares similarities with Alzheimer's disease, including amyloid accumulation and impaired brain clearance systems, making dogs a useful model for studying neurodegeneration.

## Contribution

The paper highlights the glymphatic system's role in both canine cognitive dysfunction and Alzheimer's disease, emphasizing CCD as an Aβ-predominant condition and a partial analog of AD.

## Key findings

- Both CCD and AD involve β-amyloid accumulation and impaired glymphatic clearance, leading to cognitive decline.
- CCD exhibits less pronounced tau pathology compared to AD, suggesting it is an Aβ-predominant condition.
- CCD serves as a valuable large-animal model for studying neurodegenerative mechanisms and clearance-related therapies.

## Abstract

Canine cognitive dysfunction (CCD) is a common age-related neurodegenerative disorder in dogs and shares several pathological and clinical characteristics with human Alzheimer’s disease (AD). In both species, β-amyloid (Aβ) accumulates in the brain parenchyma and along cerebral blood vessel walls, where it is associated with synaptic loss, oxidative stress, mitochondrial dysfunction, and persistent neuroinflammatory processes, leading to a progressive decline in cognitive function. Growing evidence suggests that impairment of the glymphatic system is a key pathogenic mechanism in both CCD and AD. This glia-dependent perivascular network is involved in the clearance of Aβ and other metabolic by-products from the brain, and its function is reduced by aging, vascular disease, and astrocytic alterations, including changes in aquaporin-4 distribution. Reduced glymphatic and periarterial drainage promotes the retention and aggregation of Aβ and tau proteins. Compared with AD, tau pathology in CCD is typically less pronounced, supporting the interpretation of CCD as an Aβ-predominant condition and a partial pathological counterpart of Alzheimer’s disease. Clinically, CCD manifests as a spectrum of behavioral changes, including disorientation, altered social interactions, sleep–wake cycle disturbances, a loss of housetraining, changes in activity patterns, and increased anxiety, commonly summarized by the DISHAA acronym.

Canine cognitive dysfunction (CCD) is a common age-related neurodegenerative disorder in dogs that shares several pathological and clinical features with human Alzheimer’s disease (AD). In both species, β-amyloid (Aβ) accumulates within the brain parenchyma and cerebral vessel walls and is associated with synaptic loss, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, ultimately leading to progressive cognitive decline. Increasing evidence indicates that impairment of brain clearance mechanisms, particularly the glymphatic system, represents a central pathogenic mechanism in both CCD and AD. The glymphatic system is a glia-dependent perivascular network involved in the clearance of Aβ and other metabolic waste products from the brain. Its function declines with aging, vascular disease, and astrocytic alterations, including changes in aquaporin-4 distribution. Reduced glymphatic and periarterial drainage promotes the retention and aggregation of Aβ and tau proteins. Compared with AD, tau pathology in CCD is generally less extensive, supporting the interpretation of CCD as an Aβ-predominant condition and a partial pathological analog of Alzheimer’s disease. Clinically, CCD is characterized by a constellation of behavioral changes including, disorientation, altered social interactions, sleep–wake cycle disturbances, a loss of housetraining, changes in activity levels, and increased anxiety, commonly summarized by the DISHAA acronym. Overall, CCD represents a valuable spontaneous large-animal model for investigating neurodegenerative mechanisms and clearance-related therapeutic targets relevant to both veterinary and human medicine.