World-first research at Macquarie University has paved the way to a low-cost blood test that could diagnose Alzheimer's disease up to 20 years before the onset of symptoms.
Head start: New research offers the prospect of a blood test that could detect Alzheimer's – suffered by more than 300,000 Australians – long before symptoms appear.
Macquarie University Department of Biomedical Sciences Research Fellow Dr Pratishtha Chatterjee is the lead author on a groundbreaking new study published this week in the journal Alzheimer's & Dementia.
The study is the first to show higher blood levels of Alzheimer's-related proteins in cognitively-normal older adults whose brain scans showed pre-clinical Alzheimer's, than in otherwise similar adults with normal brain tissue.
The researchers also found rising levels of these proteins in the blood of affected subjects over time.
These findings will allow more cost-effective screening and prognosis in clinical trials.
"Our findings highlight promising biomarkers for use in early diagnostic and prognostic blood tests for Alzheimer's disease, prior to symptoms," Chatterjee says. "These findings will allow more cost-effective screening and prognosis in clinical trials."
The research involves an international, multi-disciplinary team from around Australia, the UK, the USA, Sweden and Belgium headed by neurobiologist Professor Ralph Martins from Macquarie University's Department of Biomedical Sciences, who is also Foundation Chair of Ageing and Alzheimer's Disease at Edith Cowan University in Western Australia.
Alzheimer's is a degenerative brain disease that affects more than 300,000 Australians, and is more common with advancing age.
How Alzheimer's is diagnosed
The current clinical diagnosis of Alzheimer's relies on cognitive tests which are not sensitive enough to detect changes in the brain before a person already shows symptoms.
Long road: Identifying Alzheimer's in living patients currently involves specialised brain imaging and cerebrospinal fluid (CSF) tests.
"Sometimes these memory-based tests are accompanied by an MRI to see if certain regions of the brain have shrunk, and then these tests are followed up a few months later to see if the disease is progressing and to confirm a clinical Alzheimer's diagnosis," Martins says.
The brain changes from Alzheimer's disease – called brain amyloidosis – include deposits of the protein beta-amyloid forming 'plaques' outside the brain cells, and accumulation of the tau protein in 'neurofibrillary tangles' inside brain cells.
This abnormal protein build-up damages connections between brain cells and causes eventual cell death, shrinking brain volume. These changes occur gradually, and it can be more than 15 years before the accumulated damage is noticeable through behavioural change.
Until around a decade ago, the abnormal protein build-up characteristic of Alzheimer's disease could only be confirmed by a post-mortem examination, says Martins.
However, scientists can now use a specialised brain imaging technique called positron emission tomography (PET) amyloid imaging, along with cerebrospinal fluid (CSF) tests, to identify these abnormal brain tissue changes in living patients.
These specialised tests are expensive and/or invasive, so they are not suitable for widespread screening.
Pinpointing the proteins
Martins says that this is the first study to compare the blood proteins associated with Alzheimer's disease in a group of older people who had no behavioural signs of Alzheimer's, but where some subjects had the early build-up of amyloid in the brain associated with the disease.
New hope: Being able to use blood tests to more easily identify people with early signs of Alzheimer's disease is a game-changer, says Professor Ralph Martins.
it will allow clinical trials that are much more robust and potentially identify earlier interventions
The study included 100 volunteers aged from 65 to 90 from the Kerr Anglican Retirement Village (co-established and co-ordinated by study co-author Associate Professor Kathryn Goozee), who were screened to exclude those with signs of cognitive impairment or other significant health factors.
All of the volunteers also had their brains scanned using a PET amyloid analysis, and researchers identified those with pre-clinical Alzheimer's based on the presence of abnormal protein deposits, or brain amyloidosis.
The researchers assessed other risk factors for Alzheimer's disease, including age, sex and a higher genetic predisposition through the presence of the Apolipoprotein E allele.
The blood proteins of all subjects were compared, and the results showed that people with pre-clinical Alzheimer's also showed higher blood levels of three proteins: GFAP, p-tau181 and p-tau231.
The researchers assessed other risk factors for Alzheimer's disease, including age, sex and a higher genetic predisposition through the presence of the Apolipoprotein E allele. They found that using GFAP in a statistical model with these risk factors gave a high accuracy of 86 per cent, in distinguishing between people with pre-clinical Alzheimer's disease and cognitively normal older people without Alzheimer's-specific abnormal brain tissue changes.
"We also found for the first time, that levels of GFAP and p-tau181 levels increased in pre-clinical Alzheimer's patients over 12 months, but these didn't increase in cognitively normal older people without Alzheimer's-specific abnormal brain tissue changes," says Martins.
A game-changer for clinical trials
Martins and his colleagues have done extensive work with the longitudinal Alzheimer's study titled the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study, involving regular data collection of blood samples, neuroimaging and cognitive testing of more than 2000 people, some since 2006.
"We found that we could identify beta-amyloid in the brains of people up to 20 years before the onset of symptoms," he says.
"Clinical trials are now starting much earlier, because we think the reason so many fail, is that people's brains have been severely compromised by the time drug treatments were being attempted."
The controversial new drug aducanumab is a case in point: despite objections by an advisory panel, it became the first new drug approved by the US FDA to treat Alzheimer's in more than a decade.
While aducanumab was shown to clear amyloid plaque, critics questioned its effectiveness in later disease and the risk of common side-effects involving brain bleeds.
Martins says that a PET brain amyloid scan can cost upwards of $2000 in Australia, and up to five times more in the US, so running clinical trials with hundreds or thousands of people would be prohibitively expensive – whereas blood tests would likely be under $50 each, at scale, he says.
"Being able to more easily identify people with very early signs of Alzheimer's disease is a real game-changer, it will allow clinical trials that are much more robust and potentially identify earlier interventions," says Martins.
Professor Ralph Martins is a Professor in the Department of Biomedical Sciences and the Centre for Ageing, Cognition, and Wellbeing at Macquarie University.
Dr Pratishtha Chatterjee is a Research Fellow in the Department of Biomedical Sciences and the Centre for Ageing, Cognition, and Wellbeing at Macquarie University.
