Rodent Models of Alzheimer's Disease: Bridging the Translational Gap Through Systems-Level Integration

Area of Science:

• Neuroscience
• Pharmacology
• Gerontology

Background:

• Alzheimer's disease (AD) is a leading cause of dementia, with limited effective treatments.
• Rodent models are crucial for studying AD pathology but show poor translation to human clinical trials.
• Existing models often fail to replicate the multifactorial nature of sporadic AD and aging.

Purpose of the Study:

• To critically evaluate current rodent models of Alzheimer's disease (AD).
• To propose a systems-level framework for categorizing AD models based on pathological domains.
• To outline a roadmap for developing next-generation AD models with improved translational relevance.

Main Methods:

• Narrative review of various rodent models: transgenic, chemically induced, metabolic, inflammatory, and lesion-based.
• Categorization of models using a systems-level framework based on AD pathology domains (genetic, environmental, systemic).
• Identification of critical gaps and underrepresented factors in current AD modeling.

Main Results:

• Most existing rodent models focus on familial AD aspects and lack complexity, failing to model sporadic AD, aging, or vascular dysfunction.
• Key underrepresented factors in current models include glymphatic dysfunction, cerebral small vessel disease, and the microbiota-gut-brain axis.
• A significant gap exists between preclinical findings in rodent models and clinical efficacy in humans.

Conclusions:

• Next-generation rodent models must integrate underrepresented factors like aging, vascular health, and systemic interactions for better translational predictability.
• A systems-based approach and minimum criteria framework are essential for developing more physiologically relevant AD models.
• Improved rodent models are critical for bridging the gap between AD research and successful clinical therapies.