The complexity of dementia development and its comorbidities: The collaborative cross‐mouse population for multivarious tasks approach

Jan 13, 2026Animal models and experimental medicine

Understanding the complexity of dementia and related conditions using a diverse mouse population across multiple tasks

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Abstract

Emerging evidence suggests that autoimmune diseases and metabolic syndromes may play a significant role in the development of dementia.

Chronic inflammation, immune dysregulation, and metabolic dysfunction are associated with neurodegeneration.
Autoimmune conditions like rheumatoid arthritis and type 1 diabetes are linked to an increased risk of dementia through mechanisms such as immune activation and blood-brain barrier disruption.
Metabolic disorders, including diabesity, may accelerate cognitive decline by promoting insulin resistance and oxidative stress.
Glaucoma exhibits neurodegenerative features alongside autoimmune characteristics, indicating a need for revised classification and treatment strategies.
The Collaborative Cross mouse model shows variability in strain susceptibility to inflammation and cognitive impairment, suggesting differences in human responses.

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The rising incidence of dementia and associated neurodegenerative disorders poses a growing public health challenge. These conditions have traditionally been studied as isolated central nervous system disorders; however, emerging evidence suggests that broader systemic factors, including chronic inflammation, immune dysregulation, metabolic dysfunction, and genetic susceptibility, may also play a role. This review examines the interconnection between autoimmune diseases and metabolic syndromes in the pathogenesis and exacerbation of neurodegeneration. Conditions such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus have been associated with a heightened risk of developing dementia through chronic immune activation, blood-brain barrier disruption, and neuroinflammatory signaling. Similarly, metabolic disorders such as diabesity promote insulin resistance and oxidative stress, accelerating cognitive decline. The review also discusses glaucoma as a neurodegenerative condition with autoimmune features, underscoring the need for expanded classification and treatment strategies. A key focus is the utilization of the Collaborative Cross (CC) mouse model, which enables the study of gene-environment interactions across genetically diverse backgrounds. Findings from CC mice reveal strain-dependent susceptibility to inflammation, cognitive impairment, and gut-brain axis dysfunction, providing a translational bridge to human variability. This review highlights the importance of integrating precision-based approaches to dementia research that consider systemic influences. Advancing our understanding of these multiorgan interactions holds potential for designing precision-based therapeutic approaches to postpone the onset or reduce the incidence of neurodegenerative conditions.

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The complexity of dementia development and its comorbidities: The collaborative cross‐mouse population for multivarious tasks approach

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