Neuropathological Insights Into the Link Between Type 2 Diabetes and Dementia

Type 2 diabetes (T2D) is recognized as being associated with pathological changes in the aged human brain, but the precise nature, extent, and underlying mechanisms involved in these changes are incompletely understood. Research groups have reported an increased risk for cognitive impairment and all-cause dementia, and vascular dementia in particular, but also clinical Alzheimer's disease (AD) among persons with T2D compared with those without it. In line with the clinical data and the fact that the most common cause of dementia is mixed pathology, two leading hypotheses that may explain how T2D contributes to dementia relate to cerebrovascular disease (CVD) and AD neuropathological changes (ADNC). Published data have shed light on these two hypotheses. On the one hand, clinicopathological studies have consistently demonstrated that T2D is associated with brain infarcts, especially small subcortical cerebral infarcts, which supports a role for CVD in relating T2D to dementia. On the other hand, the scientific literature to date does not clearly support a link between T2D and ADNC, which argues against a role for AD. This dissociation underscores emerging themes: the imprecision of clinical diagnoses, the impact of CVD on aging, and the importance of considering treatable conditions such as T2D in patients with cognitive impairment. Furthermore, other T2D-associated changes in the brain, even unrelated to AD or CVD, are possible mechanisms, and further research is needed.