The Full Spectrum of Alzheimer's Disease Is Rooted in Metabolic Derangements That Drive Type 3 Diabetes

The standard practice in neuropathology is to diagnose Alzheimer's disease (AD) based on the distribution and abundance of neurofibrillary tangles and A beta deposits. However, other significant abnormalities including neuroinflammation, gliosis, white matter degeneration, non-A beta microvascular disease, and insulin-related metabolic dysfunction require further study to understand how they could be targeted to more effectively remediate AD. This review addresses non-A beta and non-pTau AD-associated pathologies, highlighting their major features, roles in neurodegeneration, and etiopathic links to deficits in brain insulin and insulin-like growth factor signaling and cognitive impairment. The discussion delineates why AD with its most characteristic clinical and pathological phenotypic profiles should be regarded as a brain form of diabetes, i.e., type 3 diabetes, and entertains the hypothesis that type 3 diabetes is just one of the categories of insulin resistance diseases that can occur independently or overlap with one or more of the others, including type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease.