Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach

Abstract

IN BRIEF There has been a concurrent dramatic rise in type 2 diabetes and dementia in the United States, and type 2 diabetes shares common genetic and environmental risk factors and underlying pathology with both vascular and Alzheimer’s dementias. Given the ability to identify this at-risk population and a variety of potential targeted treatments, type 2 diabetes represents a promising focus for a precision health approach to reduce the impact of cognitive decline and dementia in older adults.

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

“…Under physiological conditions when insulin binds to the IR, a cascade regulates key downstream serine/threonine kinases such as, protein kinases B (AKT/PKB), mechanistic target of rapamycin (mTOR), and extracellular signal-regulated kinases (ERK), that eventually phosphorylate serine/threonine residues of the insulin receptor substrates (IRS), inhibiting insulin signalling in a negative feedback regulation ( Figure 1 ) [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 44 , 45 , 46 ]. In neurons, the phosphoinositide 3-kinase (PI3K), AKT, glycogen synthase kinase 3β (GSK3β), BCL-2 agonist of cell death (BAD), fork-head box (FOX), mTOR and the mitogen activated protein kinase (MAPK) pathways are critical for cell survival signalling and are regulated by the activity of the IR [ 43 , 47 , 48 ]. Therefore, alteration of the physiological activity on these pathways might be the source of alteration in normal neuronal performance, supporting the hypothesis that brain insulin resistance could promote LOAD, precisely by inhibition of these pathways [ 39 , 41 , 45 ].…”

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

“…In particular, brain levels of insulin and insulin receptors (IRs) are reduced in AD patients and in experimental models of AD [5][6][7][8][9][10]. Such molecular links between deregulated insulin signaling in AD and 86 AF Batista et al diabetes have raised the prospect for novel therapeutic strategies based on anti-diabetic agents [11][12][13][14][15].…”

Association of glycated haemoglobin (HbA1C) level with working memory on type-2 diabetes mellitus and prediabetic patients

“…11 Some mechanisms may underlie these associations, including the consequences of chronic hyperglycemic conditions, peripheral metabolic disorders due to insulin resistance or type-2 DM that indirectly damage the brain, vascular brain injury due to insulin resistance vasculopathy and type-2 DM, impaired insulin ability to perform tasks normally in the brain in patients with type-2 DM, or due to a combination of these things. 12 In type 2 diabetes, the gradual erosion of beta cell function causes hyperglycemia to increase while resistance to insulin action can cause hyperinsulinemia. The combination of beta cell dysfunction and/or insulin resistance can cause chronic hyperglycemia and glucose toxicity which has profound implications for the body, including the brain in this case cognitive function.…”

“…8 The central nervous system is rich in insulin receptors, which are most prominent in important areas for learning and memory, including the hippocampus, amygdala, parahippocampal gyrus, thalamus, and caudate-putamen. 12 The mechanism by which insulin affects memory may be related to a number of pathways. First is the role of insulin in brain energy metabolism.…”