平特五不中

平特五不中-Gothenburg collaboration yields affordable test that could revolutionize the way AD is diagnosed, studied and treated

By Gillian Woodford

A simple blood test that can detect Alzheimer鈥檚 disease (AD) has been discovered and validated in a joint effort by a 平特五不中 team and researchers in Sweden. Their results are published in the May issue of聽The Lancet Neurology.聽An accompanying聽commentary聽calls the discovery 鈥渢ransformative.鈥�

The blood test accurately measures one of the proteins 鈥� P-tau181 鈥� implicated in AD. Blood P-tau181 indirectly measures tau hyperphosphorylation in the brain, which is one of the hallmarks of the disease along with the clumpy plaques caused by the protein amyloid 尾. Prior to this discovery, detecting the proteins and confirming an AD diagnosis was possible only through expensive PET scans, invasive lumbar punctures, or autopsy.

The search for an AD blood test has been years in the making, but a test sensitive enough to detect tau long eluded researchers. 鈥淚t was a challenge because these proteins are in very low amounts in the blood,鈥� explains neurologist Dr. Tharick Pascoal, who just completed his PhD in 平特五不中鈥檚 Integrated Program in Neuroscience (IPN) and who is co-first author with Thomas K Karikari who works with Kaj Blennow and Henrik Zetterberg at the University of Gothenburg. The new assay is sensitive enough to detect even the very low levels of the protein in blood in patients showing no signs of cognitive impairment. 鈥淚f you compare with the fancier tests, such as PET or cerebrospinal fluid (CSF), we saw that they are almost the same for several applications,鈥� adds Dr. Pascoal. 鈥淭he results were amazing. We were very surprised, to be honest, and very excited. We didn鈥檛 expect that a simple blood test could give very similar results to the PET technique.鈥�

Gold standard PET

鈥淭his is a game changer,鈥� agrees study co-author Dr. Serge Gauthier, Director of the Alzheimer鈥檚 Disease and Related Disorders Research Unit of the 平特五不中 Research Centre for Studies in Aging (MCSA)聽and Professor in the Departments of Neurology & Neurosurgery, Psychiatry, and Medicine at 平特五不中. Dr. Gauthier, Dr. Pedro Rosa-Neto, Associate Professor in the Departments聽of Neurology & Neurosurgery and Psychiatry, and Dr. Pascoal, who are world leaders in PET imaging in AD, which they conduct out of the MCSA鈥檚聽Translational Neuroimaging Laboratory, based at the聽Douglas Research Centre, and the聽Montreal Neurological Institute, were asked to join the huge, international study headed up by the renowned blood immunoassay group at the University of Gothenburg.

Using data collected as part of their Translational Biomarkers in Aging and Dementia (TRIAD) cohort, launched three years ago by Dr. Gauthier and Dr. Rosa-Neto, the 平特五不中 group鈥檚 role was to provide the primary care cohort to replicate the assay in vivo. The TRIAD cohort was designed for two purposes, explains Dr. Rosa-Neto: 鈥淥ne is to understand disease pathophysiology and the other is using the gold standard technology 鈥� PET scans 鈥� for benchmarking novel blood biomarkers. 聽That鈥檚 what makes our cohort really special and unique.鈥� 聽The blood was collected in Montreal from TRIAD participants and sent to Sweden where the assay was tested. The results were then replicated in Montreal by comparing against PET scan and CSF results.

Major clinical applications

The team is leading another trial to ascertain the clinical utility of this biomarker in clinical settings and test how the biomarker performs in real life. The test should be widely available in two to three years.

There are several important clinical applications for the test, including as a screening tool in the primary care setting; to monitor the disease progression; and as a way of ensuring that subjects enrolled in clinical trials indeed have Alzheimer鈥檚 disease and that the drugs they are testing are effective against AD. The assay could greatly reduce costs of diagnosing and studying the disease here and in the developing world. Says Dr. Gauthier, 鈥淐ountries that don鈥檛 have PET scanners now have hope for a more accurate diagnosis for Alzheimer鈥檚 disease.鈥� The test could also pave the way for better treatments that don鈥檛 just reduce cognitive impairment, but actually slow the progression of the disease, says Dr. Rosa-Neto. 鈥淲e can now dream of such a drug,鈥� adds Dr. Gauthier.

The test is also sensitive enough to differentiate Alzheimer鈥檚 patients from patients with other neurodegenerative disorders, including frontotemporal dementia. It will also be possible to rule out Alzheimer鈥檚 in MCI patients, indicating there is some other cause of their memory issues. Dr. Pascoal notes that about 30% of patients currently diagnosed with AD don鈥檛 actually have the disease. Adds Dr. Gauthier, 鈥淲e鈥檙e not talking about in 90year olds, we鈥檙e talking about 60 year olds where there鈥檚 uncertainty about the diagnosis when you鈥檙e that young.鈥�

Dr. Gauthier is quick to point out that the test, used at this early stage, will identify a risk factor, but is not a diagnosis. He compares it to a cholesterol test that can indicate a risk factor for heart disease. 鈥淭here is no treatment for mild cognitive impairment (MCI) except for lifestyle changes, especially lowering blood pressure, keeping the mind and body busy 鈥� all the good things you鈥檙e supposed to do,鈥� he says. 鈥淏ut people will be more motivated to do it if they know they have elevated proteins and are at risk.鈥�

Differentiating neurodegeneration

Dr. Rosa-Neto adds that the biomarker will be particularly useful to test younger patients displaying cognitive decline in order to rule out AD and look for other dementia causes, and also to pinpoint AD in patients with atypical symptoms, such as effortful speech, difficulty reading or writing, or certain behavioural problems. 鈥淎lzheimer鈥檚 has an important heterogeneity, and biomarkers allow physicians to identify which of these patients with atypical presentation has AD,鈥� he says. 鈥淭his is important because the main treatment for AD, cholinesterase inhibitors, can be harmful to those who don鈥檛 have the disease.鈥�

Dr. Pascoal adds that the assay will be important in helping clinicians stage Alzheimer鈥檚 disease, from early stages of MCI, when the tau levels are low, to later stage when the tau levels are much higher.

The clinician-scientists all acknowledge the immense contributions of volunteers from all over Montreal who gave their time for three PET scans per year, one lumbar puncture, one MRI, as well as blood and cognitive tests as part of the TRIAD cohort. 鈥淭hey knew that someday it would all pay off 鈥� well now it has,鈥� says Dr. Gauthier. Given the enormous costs involved (Dr. Rosa-Neto estimates that it costs in the range of $30,000 to study each participant), the team is also thankful for the support of their funders, the CIHR, the FRQS and the Weston Brain Institute.

The Lancet Neurology, Vol 19, May 2020, DOI:聽