Blood test may be key to Alzheimer’s treatment

Early warning may offer the best chance to treat Alzheimer’s disease, but that requires a reliable and affordable diagnosis. As Tim Dean and Elizabeth Finkel report, Australian scientists may have found one. 

A blood test would be an ideal way to diagnose Alzheimer's before memory loss sets in but development has been problematic. – iStock

Darn it – you’ve known that person for years and you just can’t remember their name! Is it just forgetfulness or the beginning of Alzheimer’s?

One in eight people over the age of 65 will develop Alzheimer’s disease (AD). By the time symptoms appear the disease can have been eating away at the brain for more than 20 years. But so far there has been no simple test to flag the havoc being wrought.

A new finding reported in Molecular Psychiatry last month offers a fresh lead. Testing the blood of symptom-free people, Andrew Hill and colleagues at the University of Melbourne discovered an early disease signature written in tiny molecules of RNA (ribonucleic acid). The researchers hope their finding, along with other tests now being developed will ultimately lead to a simple early-warning blood test for AD.

Despite decades of research and billions of dollars spent trying, no drug exists that can halt Alzheimer’s. The prime suspect behind the disease is “beta-amyloid” or Aβ – a sticky shard of protein that splinters off a larger protein and clogs up the brain cells of people with the disease. So far, drugs that remove it or prevent it from splintering off its mother protein in the first place have failed to halt any mental decline.

Perhaps that’s because treating patients once they have memory loss is too late and by then the damage is irreversible. “We may be trying to close the gate once the horse has bolted,” says Bryce Vissel, head of Neurodegenerative Diseases at Sydney’s Garvan Institute.

Indeed one recent trial of a drug that clears Aβ from the brain (solanezumab) hinted it might be helpful in less-severely affected patients. To test whether failed AD drugs can do better at prevention than cure researchers need a way to identify patients before they lose their memories.

The bloodstream is the dumping ground for everything that goes on in the body, making it hard to detect what is specifically coming from the brain.

An earlier Australian study has shown that’s possible. Known as the Australian Imaging Biomarkers and Lifestyle Group it tracked 200 people over the age of 55 monitoring the build-up of Aβ in their brains using PET scans. Some people who appeared normal, or had mild memory loss at the beginning, went on to develop AD. The ones with the fastest memory loss also showed the fastest increase of brain Aβ deposits.

The study, published in Lancet Neurology in 2013, estimated that PET scans should be able detect rising levels of Aβ in people 20 years before they display symptoms, perhaps in people in their late 30s. But a PET scan costs $2,000 and requires an injection of a radioactive tracer. So scans are not going to be helpful for widespread screening.

Membrane-wrapped particles in the blood called exosomes, the doughnut-shaped structures here, provide early evidence of Aβ build-up in the brain. – Kourembanas Laboratory, Boston Children's Hospital

A blood test is ideal but has been problematic. The bloodstream is the dumping ground for everything that goes on in the body, making it hard to detect what is specifically coming from the brain. However in recent years researchers have been intrigued to find the brain provides its own clean diagnostic package – exosomes. While all cells produce these membrane-wrapped particles, about the size of a virus, it is possible to identify those that are specifically freighted out of the brain into the bloodstream.

Seven years ago Hill found that exosomes carried proteins associated with Creutzfeld-Jacob Disease, the human form of mad cow disease. They also carried tinier molecules known as microRNA that control genes and have been associated with diseases such as cancer. That gave Hill the idea of seeing whether exosomes could be used to diagnose AD.

He wasn’t the only one. Last August, a team of US researchers showed that measuring protein fragments such as Aβ and tau – another protein marker of AD – in brain exosomes could provide a reliable early AD blood test.

Hill’s group decided to test the predictive power of the microRNAs in brain-derived exosomes. Using the blood of people enrolled in the Australian biomarkers study, Hill and his team identified a signature of 16 different microRNAs that correlated with people who had elevated Aβ levels in their brains. Some of these microRNAs appear to regulate genes involved in Aβ production. In the second stage of the study they tested another 60 people, this time without knowing their diagnosis beforehand, and cross-checked the results with the PET diagnosis.

The microRNA blood test agreed with the PET scan 77% of the time.

Hill suspects the microRNA test may actually detect the disease before it shows up on the scan, an idea that will be tested as people are followed up in the biomarkers study, which now has 1,000 recruits.

One problem for tests that rely on measuring levels of Aβ in the brain is that about a third of elderly people have high levels even when they don’t suffer from AD. Clearly there are other factors at play and the Australian biomarkers study has identified some of them. Diet plus physical and mental exercise can help a bit. But the main factor appears to be a person’s genetic make-up, particularly the genes APOE and BDNF. A paper published last October in Molecular Psychiatry found that inheriting a bad form of these genes accelerates the rate of memory loss.

“We’re right at the beginning,” says Colin Masters, Senior Deputy Director of the Florey Institute and co-author on both the recent Molecular Psychiatry papers. “Any future blood screening test will probably be a combination of the ones now being tested, and will serve to refer people for PET scanning.”

“It’s great work and extremely important. The AIBL study is an exceptional Australian contribution to worldwide understanding of this terrible disease.” says Vissel.

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