Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages

Abstract

Metabolic dysfunction is a well-established feature of Alzheimer’s disease (AD), evidenced by brain glucose hypometabolism that can be observed potentially decades prior to the development of AD symptoms. Furthermore, there is mounting support for an association between metabolic disease and the development of AD and related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D), hyperlipidemia, obesity, or other metabolic disease may have increased risk for the development of AD and similar conditions, such as vascular dementia. This association may in part be due to the systemic mitochondrial dysfunction that is common to these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis. In fact, aging itself presents a unique challenge due to inherent mitochondrial dysfunction and prevalence of chronic metabolic disease. Despite the progress made in understanding the pathogenesis of AD and in the development of potential therapies, at present we remain without a disease-modifying treatment. In this review, we will discuss insulin resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic and bioenergetic disruptions linking insulin resistance and AD. We will also focus on potential neuroimaging tools for the study of the metabolic dysfunction commonly seen in AD with hopes of developing therapeutic and preventative targets.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Insulin resistance is characterized by elevated fasting blood insulin and glucose levels, and is a major risk factor for diabetes, cardiovascular disease, and stroke. Peripheral insulin resistance is also associated with poorer cognitive function during aging (Thambisetty et al, 2013) and may be a risk factor for AD (Neth and Craft, 2017). Neurons may exhibit insulin resistance and impaired glucose transport in aging as suggested by progressive reductions in glucose utilization demonstrated by PET imaging of radiolabeled glucose uptake; this impaired glucose metabolism is particularly prominent in the temporal, parietal, and frontal lobes, and motor cortex (Goyal et al, 2017).…”

Protective effect of daidzein against streptozotocin‐induced Alzheimer's disease via improving cognitive dysfunction and oxidative stress in rat model

“…Alzheimer's disease (AD) exhibits weakening of cognitive functions in the patients like memory deficits and behavioral impairments that is related to pathological accumulations of amyloid β (Aβ) peptide as well as neurofibrillary tangles of accumulated hyperphosphorylated tau protein that are found in the brain cells . Various reports suggested that in initial developmental stage of the disease, instabilities observed in numerous phases of cellular metabolism appeared to be clinically important in AD, such as increase in the brain insulin resistance, decline in utilization of glucose and energy metabolism . Even though the exact etiology is unknown for the AD, a number of existing evidence indicated that excessive free radical production may lead to triggering of neuronal deterioration in case of AD .…”

Ketones, omega-3 fatty acids and the Yin-Yang balance in the brain: insights from infant development and Alzheimer’s disease, and implications for human brain evolution

“…However, brain glucose uptake depends on brain activity not plasma glucose. Furthermore, chronic hyperglycemia actually contributes more to Alzheimer's rather than alleviating it because it contributes to insulin resistance, which is already fairly prevalent in older people and is a major risk factor for Alzheimer's disease (Mullins et al, 2017;Neth and Craft, 2017). If brain cells are taking up less glucose because they are dying then brain ketone uptake should also be defective in Alzheimer's disease.…”