Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms

Abstract

Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60–70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid β-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.

Oligomer-Targeting Prevention of Neurodegenerative Dementia by Intranasal Rifampicin and Resveratrol Combination – A Preclinical Study in Model Mice

“…Insulin has been shown to function in synaptic remodeling and neurogenesis ( Mainardi et al, 2015 ) and protects neurons from Aβ oligomers ( De Felice et al, 2009 ). Insulin resistance and type 2 diabetes are suggested as risk factors for AD ( Wei et al, 2021 ). Intranasal insulin is now undergoing clinical trials in AD, mild cognitive impairment, PD, and multiple system atrophy (Alzforum website 2 ).…”

Disentangling Mitochondria in Alzheimer’s Disease

“…Furthermore, in early or intermediate stages of AD, brain and CSF levels of insulin are also decreased [ 114 , 115 , 116 ]. Thus, in the early stages, AD is marked by deficits in cerebral glucose utilization and energy metabolism, and as AD progresses, impairments in insulin signaling, insulin-responsive gene expression, glucose utilization, and metabolism worsen [ 85 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 ].…”

Insulin and α-Tocopherol Enhance the Protective Effect of Each Other on Brain Cortical Neurons under Oxidative Stress Conditions and in Rat Two-Vessel Forebrain Ischemia/Reperfusion Injury

“…Among the compounds that may enhance the neuroprotective effect of insulin, α-tocopherol (α-T), the main and most active component of vitamin E, one of the natural components of various brain cells, is of particular interest (see, for example, [ 30 , 31 , 32 ]). In one of the recent mini-reviews [ 32 ] it is emphasized that targeting insulin resistance may be a breakthrough strategy to treat Alzheimer’s disease. It is of interest that vitamin E and C are considered to be able to decrease insulin resistance due to their antioxidant effects [ 32 ].…”

“…In one of the recent mini-reviews [ 32 ] it is emphasized that targeting insulin resistance may be a breakthrough strategy to treat Alzheimer’s disease. It is of interest that vitamin E and C are considered to be able to decrease insulin resistance due to their antioxidant effects [ 32 ]. High doses of α-T or vitamin E are usually used in clinical trials to improve cognitive function in Alzheimer’s patients.…”