Glucose dysmetabolism is a critical predisposing factor for Alzheimer's disease (AD).
Hyperglycemia, hyperinsulinemia, and are independent risk factors for AD.
Disturbances in the blood-brain barrier and brain insulin resistance link glucose metabolism to AD.
Glucose-lowering interventions in patients with type 2 diabetes may reduce the risk of developing AD.
The American Diabetes Association now includes cognitive issues as a comorbidity in type 2 diabetes treatment.
Certain diabetes medications like metformin may help prevent cognitive declines, while sulfonylureas could worsen them.
Simplified
The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.
Key numbers
1.5 to 2×
Increased dementia risk
Type 2 diabetes increases the risk of developing dementia.
43%
Prediabetes dementia risk
Individuals with prediabetes have a 43% greater risk for dementia.
HR = 0.68
Lowered dementia risk with
Use of significantly lowers dementia risk compared to nonusers.
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