Non-transgenic rodent models associated with Alzheimer's disease: applications, evaluations, and perspectives

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Familial AD accounts for less than 1% of cases, while sporadic AD (SAD) accounts for over 95%. Mild cognitive impairment (MCI) is the critical transition phase from normal aging to AD dementia. Understanding the pathological progression from MCI to AD and the mechanisms underlying SAD is essential. Rodent models, including transgenic and non-transgenic models, are vital tools for developing effective AD therapies. However, transgenic models primarily mimic familial AD and poorly replicate MCI and the complex pathological features of SAD. Non-transgenic models address these limitations by incorporating genetic, environmental, and aging factors, thereby better simulating SAD complexity. In addition, non-transgenic models are valuable for studying the compensatory mechanisms within neural networks that preserve cognitive function despite early pathology during MCI. In this review, we provide a comprehensive summary of non-transgenic rodent models used in AD and MCI research. First, we detail modeling strategies, including agents, administration routes, and dosages. Next, we discuss evaluation methods, such as behavioral and molecular assessments. We emphasize the importance of electrophysiological data, such as long-term potentiation, for evaluating cognition. Finally, we discuss the advantages and limitations of these non-transgenic models. This review may serve as a reference for selecting models to study the progression from MCI to AD and to develop related therapeutics. Combining non-transgenic and transgenic models more accurately replicates the complex, multifactorial pathology of the disease.