{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:42:48Z","timestamp":1791855768472,"version":"4.3.4"},"reference-count":185,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,9,29]],"date-time":"2019-09-29T00:00:00Z","timestamp":1569715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer\u2019s disease\u2013dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db\/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain\u2019s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. Aging (chronic age-related diseases); ii. metabolic (hyperglycemia advanced glycation end products and its receptor (AGE\/RAGE) interactions and hyperinsulinemia-insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen\u2013nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis\u2014vascular stiffening and microvascular NVU\/neuroglial remodeling) with resulting impaired cerebral blood flow.<\/jats:p>","DOI":"10.3390\/brainsci9100262","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T05:58:33Z","timestamp":1569823113000},"page":"262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Type 2 Diabetes Mellitus Increases the Risk of Late-Onset Alzheimer\u2019s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy"],"prefix":"10.3390","volume":"9","author":[{"given":"Melvin R.","family":"Hayden","sequence":"first","affiliation":[{"name":"Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO 65212, USA"},{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,29]]},"reference":[{"key":"ref_1","first-page":"31","article-title":"The Human Brain in Numbers: A Linearly Scaled-up Primate Brain","volume":"3","year":"2009","journal-title":"Front. 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