Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Some findings in human and animal models have linked T2DM to AD-type dementia. Despite epidemiological associations between the T2DM and cognitive impairment, the inter-relational mechanisms are unclear. The preponderance of evidence in longitudinal studies with autopsy confirmation have indicated that vascular mechanisms, rather than classic AD-type pathologies, underlie the cognitive decline often seen in self-reported T2DM. T2DM is a known risk factor for cardiovascular and cerebrovascular disease (CVD), including increased risk of infarcts and small vessel disease in the brain and other organs. Furthermore, neuropathological examinations of post-mortem brains demonstrated evidence of cerebrovascular disease and little to no correlation between T2DM and β-amyloid deposits or neurofibrillary tangles. Nevertheless, the mechanisms upstream of early AD-specific pathology remain obscure. In this regard, there may indeed be overlap between the pathologic mechanisms of T2DM/”metabolic syndrome”, and AD. More specifically, cerebral insulin processing, glucose metabolism, mitochondrial function, and/or lipid metabolism could be altered in patients in early AD and directly influence symptomatology and/or neuropathology.