A dysfunctionally phosphorylated neuronal protein, insulin receptor substrate-1 (IRS-1), is able to "near-perfectly" differentiate patients with Alzheimer's disease from cognitively normal elderly adults, adults with diabetes, and those with frontotemporal dementia, according to researchers.
It is known that brain insulin resistance occurs in patients with Alzheimer's disease (AD), even in the absence of peripheral insulin resistance, but clinicians had no biomarker to detect this development until now.
Dimitrios Kapogiannis, PhD, from the National Institute on Aging in Baltimore, Maryland, and colleagues assessed whether the IRS-1 protein, which plays a key role in insulin signaling in the brain, could predict Alzheimer's disease (AD) in two small studies. They reported the findings at the Society for Neuroscience 2014 Annual Meeting.
In the first study, Kapogiannis and colleagues examined levels of IRS-1 and its state of phosphorylation in neural-derived plasma exosomes. The cross-sectional study involved 48 patients with AD without diabetes, 20 elderly cognitively normal participants with diabetes, 16 patients with frontotemporal dementia, and 84 cognitively normal control participants.
Patients with AD had significantly higher p-Ser312-IRS-1 and Ser312/p-panY ratios and lower p-panY-IRS-1 than all other patient groups, the researchers found.
In a separate longitudinal analysis that involved 22 patients with AD, who had blood samples available one to 10 years prior to AD diagnosis, levels of IRS-1 proteins were indistinguishable in the preclinical and clinical stages of AD and differed significantly from patients with out the disease.
Although the findings are relatively "clear-cut" and reached high levels of statistical significance, Kapogiannis emphasized the need for larger studies to replicate and validate the findings due to the relatively small sample sizes and case control design.
A novel biomarker of brain insulin resistance defective in Alzheimer’s and detectable in blood shows promise for early preclinical diagnosis.
The protein, insulin receptor substrate-1 (IRS-1), plays a key role in insulin signaling in the brain. Brain insulin resistance occurs in AD even in the absence of peripheral insulin resistance, but until now, no brain biomarker of brain insulin resistance has been discovered.