Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Abstract

Objective To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. Methods This clinical–pathologic study was derived from a community‐based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme‐linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. Results Brain insulin receptor substrate‐1 (IRS1) phosphorylation (pS307IRS1/total IRS1) and serine/threonine‐protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308AKT1 was associated with a lower level of global cognitive function (estimate = −0.212, standard error = 0.097; p = 0.031). Interpretation Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function. ANN NEUROL 2020;88:513–525

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

“…Therefore, the combined effect of Ang II and hyperglycemia may exacerbate oxidative stress damage in diabetic tissue (Chen et al, 2007;Fukumoto et al, 2008). Separately, abnormalities in brain insulin signaling pathways are associated with cognitive impairment and AD pathology (Arvanitakis et al, 2020).…”

“…Interestingly, there is a relationship between AD and diabetes mellitus type 2, which are both age-associated diseases (Denver and McClean, 2018). IR increases the risk of developing cognitive decline, and IR has been shown in postmortem brain tissue of AD patients without diabetes (Talbot et al, 2012;Arvanitakis et al, 2020). Also, impaired neuronal insulin signaling was demonstrated in the AD brain (Denver and McClean, 2018).…”

Exploiting Common Aspects of Obesity and Alzheimer’s Disease

“…Insulin mediates metabolic homeostasis by regulating glucose, lipids, and energy (Cheng et al, 2010b ). The role of insulin in AD is currently of major interest (Arvanitakis et al, 2020 ; Selles et al, 2020 ). Insulin regulates glucose metabolism, both directly and indirectly.…”

Genetic Variants behind Cardiovascular Diseases and Dementia

“…In the degenerating population, rs391300 polymorphism of the Serine Racemase ( SRR ) gene was associated with T2D and the progression of mild cognitive impairment (MCI) to AD [ 18 ]. In addition, the insulin resistance pathway, such as serine/threonine-protein kinase (AKT) phosphorylation, also plays an important role in dementia risk [ 19 ]. AKT1 rs2498786 CC genotype was a risk variant to insulin resistance and AD [ 20 ].…”