Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease

Abstract

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) commonly cooccur. T2DM increases the risk for AD by approximately twofold. Animal models provide one means of interrogating the relationship of T2DM to AD and investigating brain insulin resistance in the pathophysiology of AD. Animal models show that persistent hyperglycaemia results in chronic low-grade inflammation that may contribute to the development of neuroinflammation and accelerate the pathobiology of AD. Epidemiological studies suggest that patients with T2DM who received treatment with specific anti-diabetic agents have a decreased risk for the occurrence of AD and allcause dementia. Agents such as metformin ameliorate T2DM and may have other important systemic effects that lower the risk of AD. Glucagon-like peptide 1 (GLP-1) agonists have been associated with a decreased risk for AD in patients with T2DM. Both insulin and non-insulin anti-diabetic treatments have been evaluated for the treatment of AD in clinical trials. In most cases, patients included in the trials have clinical features of AD but do not have

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

“…Diabetes and insulin resistance are other known risk factors for neurodegenerative diseases, mainly because they exacerbate inflammatory processes. Therefore, insulin and antidiabetic medications have been studied, especially in AD, but their positive effects were proven only in dementia patients with concomitant diabetes [ 98 ]. However, one antidiabetic drug, namely pioglitazone, demonstrated a particularly good neuroprotective effect in animal models of dementia.…”

“…However, one antidiabetic drug, namely pioglitazone, demonstrated a particularly good neuroprotective effect in animal models of dementia. According to current knowledge, this is provided by the ability of pioglitazone to bind to peroxisome proliferator-activated receptor gamma receptor (PPAR-γ) and thus inhibit proinflammatory NF-κB signaling [ 17 , 74 , 98 ]. Surprisingly, pioglitazone turned out not to be effective in the AD clinical trials [ 17 ], but its efficacy in animal models, including LPS-induced neuroinflammation, may be utilized as a reference point.…”

Alzheimer’s Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer’s Disease and Type 2 Diabetes

“…Brain lesions that occur in AD are accompanied by synaptic dysfunction, neurodegeneration and neuronal disorders, while the disease is characterized by extracellular plaques of insoluble β-amyloid protein and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein [ 3 ]. The exact cause of AD is not fully understood; there is therefore currently no effective treatment despite the large number of clinical studies that have been performed [ 4 ]. The strongest genetic risk factor for AD is the e4 allele of apolipoprotein E (APOE4) relative to the e3 allele and the protective e2 allele [ 5 , 6 ].…”

Alzheimer's disease and related dementias: From risk factors to disease pathogenesis

“…Cummings et al report that foundational science, animal models and epidemiological studies all link T2DM with acceleration of the pathobiology of AD and conversely clinical trials with antidiabetic agents such as insulin, metformin and glucagon‐like peptide 1 (GLP‐1) agonist may lower risk of AD. Ongoing trials will provide insight into the therapeutic utility of this approach (Cummings et al, 2022).…”