Review: Relationship of type 2 diabetes to human brain pathology

Abstract

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high-mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially nonvascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms. The clinicopathological studies to date demonstrate T2D to be consistently associated with infarcts, particularly subcortical lacunar infarcts, but not ADNC, suggesting the association of T2D with dementia may largely be mediated through CVD. Furthermore, growing interest exists in insulin resistance (IR), particularly IR within the brain itself, which may be an associated but distinct phenomenon from T2D, and possibly itself associated with ADNC. Other mechanisms largely related to protein processing and efflux in the central nervous system with altered function in T2D may also be involved. Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta-amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels. Medical research is ongoing to further disentangle the relationship of T2D to dementia in the ageing human brain.

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

“…This was followed by brain neuroglia (astrocyte and microglia) inflammation with the production of a host of toxic cytokines to induce neuronal BIR and endoplasmic reticulum stress with synaptic dysfunction and/or loss and its association with neuronal dysfunction and neurodegeneration in age-related LOAD. However, it is currently becoming more and more evident that there exists a primary BIR in LOAD [25][26][27][28][29].…”

A neural signature of metabolic syndrome

“…Although there are numerous mechanistic hypotheses as to how these degenerative changes occur, several have gained particular notoriety. The hypothesis of AD-related central nervous system (CNS) insulin resistance, coupled with observations that T2DM is associated with an increased risk of developing AD (Ott et al, 1996;Stranahan, 2015), has led researchers ask whether peripheral metabolic biomarkers could be used to predict neurological decline (Chatterjee & Mudher, 2018;Pruzin, Nelson, Abner, & Arvanitakis, 2018). Impaired insulin receptor binding in the hippocampus, a structure known to express high levels of insulin receptors, is presumed to influence the development of AD (De Felice, Lourenco, & Ferreira, 2014).…”

“…Impaired insulin receptor binding in the hippocampus, a structure known to express high levels of insulin receptors, is presumed to influence the development of AD (De Felice, Lourenco, & Ferreira, 2014). The hypothesis of AD-related central nervous system (CNS) insulin resistance, coupled with observations that T2DM is associated with an increased risk of developing AD (Ott et al, 1996;Stranahan, 2015), has led researchers ask whether peripheral metabolic biomarkers could be used to predict neurological decline (Chatterjee & Mudher, 2018;Pruzin, Nelson, Abner, & Arvanitakis, 2018). Besides brain insulin resistance, other mechanisms such as neuroinflammation, oxidative stress, and abnormal brain lipid metabolism have been proposed as pathophysiological contributors to neurocognitive decline in the MetS brain (Yates et al, 2012).…”

Links Between Adiponectin and Dementia: From Risk Factors to Pathophysiology

“…Another potential pathology is neurodegenerative change including deposits of neurotic NP and NFTs, which may be attributed to brain IR and altered insulin signaling (Verdile et al, 2015). In addition, disruption of the BBB, dysregulation of lymphatics, and activation of the hypothalamic-pituitary-adrenal (HPA) axis are also proposed in many published articles (Ng and Chan, 2017;Pruzin et al, 2018). In conclusion, present data indicate that the relationship between T2DM and dementia is probably multifactorial in etiology.…”

“…In several different studies, T2DM was consistently associated with an increased risk of pathologically verified infarcts at autopsy (Arvanitakis et al, 2006;Pruzin et al, 2017). These macroscopic brain infarcts may contribute to insidious ischemia of the brainrelated impaired cognitive function (Pruzin et al, 2018). Another potential pathology is neurodegenerative change including deposits of neurotic NP and NFTs, which may be attributed to brain IR and altered insulin signaling (Verdile et al, 2015).…”