Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Pathology
• Biomarker Discovery

Background:

• Alzheimer's disease (AD) pathogenesis involves beta-amyloid and tau, with brain insulin resistance also a common feature.
• Elevated insulin receptor substrate-1 phosphorylated at serine-616 (IRS-1 pS616) is found in AD dementia (ADd) neurons.
• Semaglutide, an antidiabetic, is in clinical trials for AD, highlighting the therapeutic potential of targeting insulin resistance.

Purpose of the Study:

• To quantify IRS-1 pS616 in hippocampal neurons of normal and ADd cases.
• To investigate correlations between IRS-1 pS616, AD pathologies, and subject demographics.
• To explore IRS-1 pS616 as a potential biomarker for brain insulin resistance in AD.

Main Methods:

• Immunohistochemistry on hippocampal sections from 217 age- and sex-matched cases (NCI, preclinical, MCI, ADd).
• Quantification of beta-amyloid, phospho-tau, and IRS-1 pS616 using AI-based digital pathology (U-Net neural networks).
• Analysis of correlations between pathologies, age, and ApoE genotype.

Main Results:

• IRS-1 pS616 density increased with age in normal tissue but was elevated in ADd and decreased with age.
• IRS-1 pS616 pathology positively correlated with beta-amyloid, phospho-tau, and Braak stage.
• No significant differences in ADd pathologies were found across ApoE genotypes.

Conclusions:

• Brain insulin resistance, indicated by IRS-1 pS616, rises with age, peaks in ADd, and declines with neurodegeneration.
• Cytoplasmic IRS-1 pS616 accumulation in neurons is implicated in AD pathogenesis.
• IRS-1 pS616 may serve as a biomarker for brain insulin resistance and a target for AD therapies.