Brain Insulin Resistance Marker May Diagnose Alzheimer's

Megan Brooks

November 25, 2014

A neuronal protein that is defective in Alzheimer's disease (AD) and detectable in blood may be able to predict the disease up to 10 years before clinical symptoms appear, early research hints.

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.

The new research suggests that dysfunctionally phosphorylated IRS-1 in neural-derived blood exosomes may be a specific biomarker of brain insulin resistance in AD.

Dimitrios Kapogiannis, PhD, from the National Institute on Aging in Baltimore, Maryland, reported the findings at the Society for Neuroscience 2014 Annual Meeting.

"Near Perfect"

The researchers assessed the level of IRS-1 and its state of phosphorylation in neural-derived plasma exosomes in a cross-sectional study involving 48 patients with AD without diabetes, 20 elderly cognitively normal participants with diabetes, 16 patients with frontotemporal dementia, and 84 cognitively normal control participants.

They found that patients with AD had several-fold higher p-Ser312-IRS-1 and Ser312/p-panY ratios and lower p-panY-IRS-1 than all other patient groups. The Ser312/p-panY ratio achieved a 0.99 receiver operating characteristic area under the curve.

These markers "near-perfectly discriminate" patients with AD from cognitively normal elderly adults, adults with diabetes, and those with frontotemporal dementia, the researchers report in a conference abstract.

In a longitudinal analysis of 22 patients with AD who provided blood samples 1 to 10 years before diagnosis, preclinical and clinical levels of these proteins were indistinguishable; preclinical levels of all three differed significantly from those of control participants (P < .001).

"By measuring these proteins in the bloodstream, we were able to differentiate patients with AD from controls with almost 100% accuracy, and there is good hope that we may be able to predict the disease before clinical symptoms begin because these proteins are already abnormal when you look at them up to 10 years in advance," Dr Kapogiannis said in an interview with Medscape Medical News.

"That is the hope: diagnose the disease and predict it at a preclinical stage," he added.

Active Area of Research

The exosome-based technology used in the study will be further developed by NanoSomiX, a California-based biotechnology company that develops blood assays for neurodegenerative diseases and that is supporting the research.

Dr Kapogiannis emphasized that a blood test for AD is not around the corner.

"The emphasis should be on down the road because these are findings from case-control studies in a small number of patients and the findings need to be replicated and validated in larger studies, but still the findings are very clear cut and reached very high levels of statistical significance," he said.

Simon Lovestone, PhD, from King's College London and the Institute of Psychiatry, United Kingdom, who is not involved in the research, said it's "interesting for two reasons: the link to insulin signaling and the use of exosomes. There are plenty of other studies to make one think both these elements are real and worth pursuing in AD. Combining both makes this a potentially exciting study."

Asked for comment on these findings, Dean M. Hartley, PhD, director of science initiatives at the Alzheimer's Association, told Medscape Medical News that the search for preclinical biomarkers of AD to facilitate early diagnosis is a "very active" area of research.

"A simple blood test that is performed in a doctor's office is certainly something we see as a direction of the future, but this is very much still in the research phase," he said.

The study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, and NanoSomiX. The authors have disclosed no relevant financial relationships.

Society for Neuroscience 2014 Annual Meeting: Poster 197.03. Presented November 16, 2014.

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