The standard practice in neuropathology is to diagnose Alzheimer's disease (AD) based on the distribution and abundance of neurofibrillary tangles and Aβ deposits. However, other significant abnormalities including neuroinflammation, gliosis, white matter degeneration, non-Aβ 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-Aβ 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.
Keywords: Alzheimer’s disease; Amyloid; Dementia; Insulin resistance; Microvascular disease; Neuroinflammation; White matter degeneration.