Animal models of multi-infarct dementia: Methodological approaches, neuropathology, functional outcomes, and translational relevance.

Multi-infarct dementia (MID) is a major subtype of vascular cognitive impairment, second only to Alzheimer's disease as a leading cause of dementia worldwide. Unlike neurodegenerative dementias, MID results from recurrent vascular insults, producing stepwise cognitive decline. Animal models have become indispensable for understanding MID mechanisms and testing therapies, yet no single model fully captures human disease complexity. This review synthesizes current knowledge of embolic, chronic cerebral hypoperfusion, hypertensive, and large animal models of MID. We compare methodological strategies, neuropathological features (including white matter injury, neuroinflammation, and blood-brain barrier disruption), and behavioral outcomes. Key limitations include poor replication of infarct heterogeneity, absence of comorbidities, and translational failures. Emerging directions such as multi-hit paradigms and mixed dementia models are discussed. We conclude that integrative, multifactorial models are essential for improving translational relevance and developing effective therapies.