Insulin resistance and reduced brain glucose metabolism in the aetiology of Alzheimer’s disease

Abstract

Significant epidemiological and clinical evidence has emerged that suggests Alzheimer’s disease (AD) can be added to the list of chronic illnesses that are primarily caused by modern diets and lifestyles at odds with human physiology. High intakes of refined carbohydrates insufficient physical activity, suboptimal sleep quantity and quality, and other factors that may contribute to insulin resistance combine to create a perfect storm of glycation and oxidative stress in the brain. Specific neurons lose the ability to metabolise and harness energy from glucose, ultimately resulting in neuronal degeneration and death. Simultaneously, chronic peripheral hyperinsulinaemia prevents ketogenesis, thus depriving struggling neurons of a highly efficient alternative fuel substrate. The intimate association between type 2 diabetes and AD suggests that they have common underlying causes, namely insulin resistance and perturbed glucose metabolism. Preclinical evidence of AD is detectable decades before over symptoms appear, indicating that AD progresses over time, with observable signs manifesting only after the brain’s compensatory mechanisms have failed and widespread neuronal atrophy begins to interfere with cognition and performance of daily life tasks. That dietary and environmental triggers play pivotal roles in causing AD suggests that nutrition and lifestyle based interventions may hold the key to ameliorating or preventing this debilitating condition for which conventional pharmaceutical treatments are largely ineffective. Results from small scale clinical studies indicate that dietary and lifestyle strategies may be effective for reversing dementia and cognitive impairment. Increased research efforts should be dedicated towards this promising avenue in the future.

Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers

“…Alterations in the gut microbiota and an increase in gut permeability may lead to dysfunction in the hippocampus [63, 64] and the development of insulin resistance, which correlates with AD pathogenesis. [65–67] It has been hypothesized that increased gut permeability allows bacteria-derived amyloids from the gastrointestinal tract to accumulate at the systemic and brain level [68]. This in turn could lead to the upregulation of pro-inflammatory microRNA-34a and as a consequence, downregulation of TREM2 leading to the accumulation of Aβ 42.…”

Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers

“…Alterations in the gut microbiota and an increase in gut permeability may lead to dysfunction in the hippocampus [57,58] and the development of insulin resistance, which correlates with AD pathogenesis. [59][60][61] It has been hypothesized that increased gut permeability allows bacteria-derived amyloids from the gastrointestinal tract to accumulate at the systemic and brain level [62]. This in turn could lead to the upregulation of pro-inflammatory microRNA-34a and as a consequence, downregulation of TREM2, leading to the accumulation of Aβ42.…”

Evaluation of dietary and lifestyle changes as modifiers of S100β levels in Alzheimer’s disease

“…Research on AD and insulin resistance, particularly the role of brain insulin resistance which has been notionally defined as "type 3 diabetes", has recently been received with considerable interest (139)(140)(141)(142).…”

“…As CSF S100β may be increased in AD, and the KD appears to reduce CSF S100β in mice, it is possible that a ketogenic diet (KD) or low carbohydrate diet may promote healthy brain insulin signalling by means of limiting chronic elevation of S100β. Several reviews have discussed the potential application of the KD and KB in the treatment and prevention of neurodegenerative conditions including AD, through the management of dysfunctional insulin signalling and glucose metabolism (140,(188)(189)(190)(191). The reduced S100β levels observed in mice consuming a KD (134,137) is partly attributed to the production of BHB that can cross the BBB and provide energy to the brain as a safe alternative in the presence of impaired glucose metabolism (192).…”