Cellular Garbage Aids Quest for Alzheimer’s Blood Test

Experimental Approach Predicts Future Alzheimer’s Diagnoses

By Brandon Levy

Tuesday, October 15, 2019

If you looked through my garbage, you would probably find a litany of apple cores (my favorite fruit) and a couple fundraising requests from my alma mater. Similarly, scientists can learn a lot about what is going on in cells by examining their trash. IRP researchers recently developed a blood test that may be able to predict Alzheimer’s disease years before the onset of symptoms by examining packages of waste products from neurons.¹

Just like people, cells are constantly discarding a variety of materials. This cellular trash is packaged into tiny capsules called exosomes and shipped out of cells into the bloodstream.

Recently, researchers like IRP investigator Dimitrios Kapogiannis, M.D., have become interested in how exosomes expelled from neurons into the bloodstream differ between healthy people and those with brain illnesses like Alzheimer’s disease. Eventually, this work could allow clinicians not only to easily and noninvasively diagnose Alzheimer’s disease in individuals currently experiencing cognitive difficulties, but also to predict the onset of the illness years in advance during the ‘preclinical’ phase when changes to the brain have begun but there are no apparent symptoms.

“This is a phase of disease when we think we have to intervene to stop it from progressing because, by the time there are symptoms, the disease may already be too advanced to treat effectively,” says Dr. Kapogiannis. “To find a way of diagnosing Alzheimer’s disease in the preclinical phase has been kind of the ‘holy grail’ for the field. We think it is a necessary step towards finding a treatment for Alzheimer’s disease.”

Dr. Kapogiannis’ team began by isolating neuronal exosomes from nearly 900 blood samples taken over the course of several years from 350 healthy individuals participating in the Baltimore Longitudinal Study of Aging (BLSA). Some of these participants were eventually diagnosed with Alzheimer’s disease, and the IRP researchers compared these individuals’ neuronal exosomes to those from BLSA participants who did not later develop Alzheimer’s disease. The groups were matched based on age and gender to ensure that differences in their exosomes were not due to those factors.

The team’s statistical analysis used samples from two-thirds of the BLSA participants and produced a mathematical model that was nearly 90 percent accurate in its ability to classify individuals who would later develop Alzheimer’s disease versus those who would not. When the researchers subsequently analyzed samples from the remaining one third more of the BLSA participants, the model correctly determined which participants later developed Alzheimer’s with 80 percent accuracy.

BLSA participants who eventually developed Alzheimer’s disease had higher levels of certain proteins in their neuronal exosomes. Even before their diagnoses, when they were still considered healthy, the neuronal exosomes of those future patients contained more of two types of the tau protein that has long been linked to Alzheimer’s disease. Their neuronal exosomes also had more of two forms of a molecule called insulin receptor substrate 1 (IRS-1), a marker of a syndrome known as insulin resistance in which cells don’t respond as strongly to the hormone insulin, which helps control blood sugar levels and provide energy to neurons.

“It’s possible that the development of insulin resistance in the brain is an early event in the Alzheimer’s process,” Dr. Kapogiannis explains. “There’s a lot of data from other studies showing that the brain in Alzheimer’s doesn’t respond well to insulin and doesn’t process blood sugar normally.”

The IRP team also conducted a validation study using blood samples from a different set of individuals comprised of healthy individuals and Alzheimer’s patients who had been diagnosed before their samples were taken. This analysis confirmed the results of the first, finding higher levels of those tau and IRS-1 proteins in neuronal exosomes from people with Alzheimer’s disease compared to healthy controls.

Dr. Kapogiannis hopes to replicate his results in an even more diverse set of participants, as well as boost the blood test’s accuracy by incorporating measurements of additional molecules found in exosomes from neurons and other brain cells. Once that is done, the test will likely be used at first to screen individuals for participation in clinical trials of Alzheimer’s treatments. This would considerably speed up the drug development process, and once an effective therapy is found, clinicians could use the test to identify people who may benefit from treatment before they experience irreversible cognitive and neurological changes.

“If we could identify those seemingly healthy people in whom the Alzheimer’s disease process is active, perhaps we could give them something that will decrease their chances of developing clinically detectable symptoms or slow down the disease’s progression,” says Dr. Kapogiannis. “It’s the same thing we do with cholesterol: people with high cholesterol take statins to decrease their cholesterol, which decreases their risk for a heart attack. That’s kind of the approach that we hope to be able to take in the future.”

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References:

[1] Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging. Kapogiannis D, Mustapic M, Shardell MD, Berkowitz ST, Diehl TC, Spangler RD, Tran J, Lazaropoulos MP, Chawla S, Gulyani S, Eitan E, An Y, Huang CW, Oh ES, Lyketsos CG, Resnick SM, Goetzl EJ, Ferrucci L. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.2462. [Epub ahead of print]

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