Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?

Oct 18, 2024Journal of Alzheimer's disease : JAD

Current Understanding of Insulin Network Problems in Alzheimer's Disease

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Abstract

Functional impairments in insulin and insulin-like growth factor signaling are associated with energy metabolism disruptions that contribute to Alzheimer's disease neurodegeneration.

Dysregulated insulin and IGF signaling may mimic conditions seen in diabetes and impact all brain cell types.
Insulin and IGF pathway dysfunctions are linked to cortical atrophy and neuroinflammation, contributing to Alzheimer's pathology.
Cognitive impairments in other conditions, such as type 2 diabetes and Parkinson's disease, share similar neuropathological processes.
Clinical trials have explored repurposing diabetes medications, including intranasal insulin and insulin sensitizers, for cognitive impairment.
There is a need for multi-targeted therapeutic strategies to address the complex signaling abnormalities in Alzheimer's and related neurodegenerative diseases.

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Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.

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Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?

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