Ines Moreno-Gonzalez ^1,2,3 Jesus Garcia-Martin ¹ Roberta Marongiu ^4,5,6*

• ¹ Department of Cellular Biology, Genetics and Physiology, University of Málaga, Malaga, Andalusia, Spain
• ² Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Madrid, Spain
• ³ Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States
• ⁴ Department of Genetic Medicine, Weill Cornell Medicine, Cornell University, New York, New York, United States
• ⁵ Brain Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, New York, United States
• ⁶ Department of Neurological Surgery, Weill Cornell Medicine, Cornell University, New York, New York, United States

Neurodegenerative diseases, particularly Alzheimer's disease and related dementias (AD/ADRD), represent a significant global health challenge. As of 2019, dementia affected over 57 million individuals worldwide, with projections suggesting this number could exceed 150 million by 2050 (GBD 2019Dementia Forecasting Collaborators, 2022). This growing prevalence underscores the need for effective treatments and a deeper understanding of these diseases. Animal models are essential for elucidating the pathology of ADRD, offering valuable insights into disease mechanisms and enabling the evaluation of therapeutic strategies under controlled conditions. Specifically, transgenic models that overexpress human genes linked to familial AD have been instrumental for replicating hallmark features of AD, including the formation of extracellular amyloid-β plaques and intracellular tau neurofibrillary tangles, closely mirroring human neuropathology (Sanchez-Varo, 2022) neuroinflammatory processes associated with cerebrovascular dementia. In their study, accelerated ovarian failure was pharmacologically induced in transgenic SWDI mice, which express a human amyloid-β precursor protein with vasculotropic mutations (Davis et al., 2004). Their findings revealed dysfunction in key components of the neurovascular unit within hippocampal regions at early stages of pathology, suggesting that the perimenopausal period may represent a particularly vulnerable window for the development of dementia.As models evolve to better capture the complex risk factors associated with dementia, human stem cell transplantation models offer a promising alternative to address the longstanding challenge of limited translatability from animal studies to clinical applications. In this issue, Ifediora et al. introduce human induced pluripotent stem cell (iPSC) transplantation models as a significant advancement in AD research. By transplanting iPSC-derived neurons, astrocytes, and microglia into animal brains, these models enable the study of human cell interactions within a living brain environment, offering a closer approximation of human disease conditions than traditional isolated cell cultures. This innovative approach, as described by the authors, holds promise for preclinical studies focused on testing and optimizing therapeutic strategies. However, challenges such as replicating long-term aging processes and ensuring stable cell integration remain in these chimeric transplantation systems. Future models emphasizing prolonged observation periods and enhanced cell integration may better capture the chronic and progressive nature of AD and related dementias.Recent Through these models, the authors delve into the mechanisms linking elevated blood pressure to neurodegeneration. While pathogenic pathways vary among these models, the authors highlight several shared, key processes underlying hypertension-induced brain damage, demonstrating the versatility of animal models presented in this mini review.Beyond hypertension, sleep disturbances are also gaining recognition as a significant risk factor for dementia (Shi et al., 2018). The rising global impact of neurodegenerative diseases, especially AD, highlights the urgent need to develop improved treatments and deepen our understanding of disease neuropathophysiology. Traditional animal models have been invaluable for studying dementia.InNew and refined animal models that incorporate genetic and environmental risk factorsalong with human stem cell and advanced computational approaches -are bridging the gap between animal and human studies. This integrated approach presents a promising future where advanced tools converge offering new opportunities to develop precise and effective interventions for dementia and address this critical public health challenge. IM-G, JG-M and RM have contributed to manuscript writing and editing. All authors have made a substantial intellectual contribution to this manuscript and approved it for publication.