State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease

Abstract

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer’s disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.

Cerebrospinal fluid soluble insulin receptor levels in Alzheimer's disease

“…This is more likely the dominant function of the sIR in this case, as in AD, brain insulin signaling is reduced. 1,27 In our study, we observed cohort differences between some of the associations with sIR. Specifically, we observed a significant association between MoCA score and CSF sIR levels in the CIMA-Q cohort.…”

“…Brain insulin resistance and deficiency is now considered a consistent feature of Alzheimer's disease (AD). 1 Patients with AD have a decreased insulin cerebrospinal fluid (CSF)/serum ratio (indicating decreased availability), impaired brain insulin receptor (IR) signaling (indicating insulin resistance), and when insulin is delivered to the brain, cognition is improved. 1,2 Brain insulin resistance and deficiency is also being pursued as a therapeutic target for pre-clinical AD by multiple mechanisms including intranasal insulin administration 3−5 or incretin receptor agonist (IRA) treatment, 6 based on cognitive improvement after treatment.…”

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

“…For instance, obesity has been previously associated with age-related neurodegenerative processes, such as mild cognitive impairment and Alzheimer's disease (AD) [1][2][3][4]. Insulin receptors are present in several neural cell types, including glia and neurons [5], suggesting that AD might be related to insulin resistance [6,7]. Obesity-induced insulin resistance could fuel some of the culprits of age-related neurodegeneration, such as mitochondrial dysfunction, amyloid-beta deposit, protein aggregation, and neuroinflammation, to name a few.…”

Brain Insulin Signaling is Associated with Late-Life Cognitive Decline

“…AKT1 links this pathway to the signature pathologies of AD. Activated AKT1 inhibits glycogen synthesis kinase 3 (GSK3β), a constitutively active kinase promoting tau phosphorylation and also regulating the expression of βsite amyloid precursor protein cleaving enzyme 1 (BACE1) and insulin-degrading enzyme (IDE) [14]. Thus, abnormal interactions between AKT1 and GSK3β may promote the accumulation of paired-helical filament tau and amyloid-β plaque pathologies [14].…”

“…Activated AKT1 inhibits glycogen synthesis kinase 3 (GSK3β), a constitutively active kinase promoting tau phosphorylation and also regulating the expression of βsite amyloid precursor protein cleaving enzyme 1 (BACE1) and insulin-degrading enzyme (IDE) [14]. Thus, abnormal interactions between AKT1 and GSK3β may promote the accumulation of paired-helical filament tau and amyloid-β plaque pathologies [14]. Sustained AKT1 activation also indirectly activates mammalian target of rapamycin complex 1 (mTORC1), which inhibits IRS1 and further contributes to insulin resistance in a vicious cycle [15,16].…”