Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications Cognitive dysfunction is increasingly recognized as a significant comorbidity of diabetes. Different stages of diabetes-associated cognitive dysfunction vary in severity, affected age groups, prognosis, and underlying mechanisms. Subtle cognitive decrements occur in all age groups, while more severe stages, such as mild cognitive impairment (MCI) and dementia, primarily affect older individuals. Studies on risk factors, brain imaging, and neuropathology provide insights into mechanisms. Although both Alzheimer's disease and vascular dementia risks are increased in diabetes, the burden of Alzheimer's pathologies is not. Identifying mechanisms affecting the brain and contributing to dementia beyond Alzheimer's pathologies is a major challenge. Experimental models can help, but require better synergy between experimental and clinical scientists. Worldwide, diabetes prevalence is increasing, particularly type 2 diabetes (T2DM), due to lifestyle changes and aging populations. Similar trends are seen in dementia, leading to increased co-occurrence. Epidemiological studies show increased dementia risk in individuals with diabetes. Diabetes is also linked to less severe cognitive dysfunction, with important implications for patient management. This review addresses different manifestations of diabetes-associated cognitive dysfunction, focusing on dementia and pre-dementia stages in T2DM. Studies on risk factors and neuroimaging provide clues on mechanisms, though many questions remain. Experimental models may help unravel etiology and identify treatment targets. A key strength is their ability to isolate individual causative pathways. Diabetes-associated cognitive decrements, the mildest stage, can occur in all age groups. Further cognitive decline is generally slow, affecting the group as a whole. Dementia, characterized by poor cognitive performance, is more severe and primarily affects older individuals. While diabetes may increase young-onset dementia risk, most dementia cases in diabetes occur in those over 65. Mechanisms of cognitive dysfunction include vascular brain injury, insulin resistance, and inflammation. Risk factors include poor glycaemic control, vascular risk factors, insulin resistance, and inflammation. Brain imaging studies show brain atrophy and white matter changes in T2DM. Etiological markers and neuropathology indicate increased lacunes and white matter hyperintensities in T2DM. AD is not more common in T2DM, but T2DM is associated with higher levels of MRI and PET biomarkers of neurodegeneration, suggesting non-AD mechanisms. Cerebral insulin resistance and amylin dyshomeostasis are emerging concepts. Experimental models show that diabetes can accelerate neurodegeneration via non-AD mechanisms. Cognitive dysfunction in diabetes affects daily clinical care. Current guidelines suggest detecting and managing cognitive impairment in T2DM. Different stages require different approaches. MCI and dementia warrant more intensive management. Prevention strategies include vascular risk factor management and lifestyle modifications. Future research should focus on improving diagnostic constructs and developing effective strategies for detecting undiagnosed cognitive impairment. The review highlights the need for further research to understandCognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications Cognitive dysfunction is increasingly recognized as a significant comorbidity of diabetes. Different stages of diabetes-associated cognitive dysfunction vary in severity, affected age groups, prognosis, and underlying mechanisms. Subtle cognitive decrements occur in all age groups, while more severe stages, such as mild cognitive impairment (MCI) and dementia, primarily affect older individuals. Studies on risk factors, brain imaging, and neuropathology provide insights into mechanisms. Although both Alzheimer's disease and vascular dementia risks are increased in diabetes, the burden of Alzheimer's pathologies is not. Identifying mechanisms affecting the brain and contributing to dementia beyond Alzheimer's pathologies is a major challenge. Experimental models can help, but require better synergy between experimental and clinical scientists. Worldwide, diabetes prevalence is increasing, particularly type 2 diabetes (T2DM), due to lifestyle changes and aging populations. Similar trends are seen in dementia, leading to increased co-occurrence. Epidemiological studies show increased dementia risk in individuals with diabetes. Diabetes is also linked to less severe cognitive dysfunction, with important implications for patient management. This review addresses different manifestations of diabetes-associated cognitive dysfunction, focusing on dementia and pre-dementia stages in T2DM. Studies on risk factors and neuroimaging provide clues on mechanisms, though many questions remain. Experimental models may help unravel etiology and identify treatment targets. A key strength is their ability to isolate individual causative pathways. Diabetes-associated cognitive decrements, the mildest stage, can occur in all age groups. Further cognitive decline is generally slow, affecting the group as a whole. Dementia, characterized by poor cognitive performance, is more severe and primarily affects older individuals. While diabetes may increase young-onset dementia risk, most dementia cases in diabetes occur in those over 65. Mechanisms of cognitive dysfunction include vascular brain injury, insulin resistance, and inflammation. Risk factors include poor glycaemic control, vascular risk factors, insulin resistance, and inflammation. Brain imaging studies show brain atrophy and white matter changes in T2DM. Etiological markers and neuropathology indicate increased lacunes and white matter hyperintensities in T2DM. AD is not more common in T2DM, but T2DM is associated with higher levels of MRI and PET biomarkers of neurodegeneration, suggesting non-AD mechanisms. Cerebral insulin resistance and amylin dyshomeostasis are emerging concepts. Experimental models show that diabetes can accelerate neurodegeneration via non-AD mechanisms. Cognitive dysfunction in diabetes affects daily clinical care. Current guidelines suggest detecting and managing cognitive impairment in T2DM. Different stages require different approaches. MCI and dementia warrant more intensive management. Prevention strategies include vascular risk factor management and lifestyle modifications. Future research should focus on improving diagnostic constructs and developing effective strategies for detecting undiagnosed cognitive impairment. The review highlights the need for further research to understand