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Alzheimer's Researchers Propose Moving Towards Biological, Biomarker-Based Definition of Disease

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NEW YORK – As biomarker research into Alzheimer's disease continues to advance, it may be time to consider revising the definition of the disease, suggested several leaders in the field.

In an editorial published last month in Science Translational Medicine, Clifford Jack, a professor of radiology at Mayo Clinic; David Holtzman, chair of neurology at Washington University in St. Louis; and Reisa Sperling, a professor of neurology at Brigham and Women's Hospital, suggested that the "most scientifically productive way forward" for Alzheimer's research and treatment would be to "adopt a biological definition of AD."

Such a definition, which the authors proposed should be anchored in imaging and fluid biomarkers, would offer a variety of advantages over existing symptom-based diagnostics, including a better ability to distinguish between Alzheimer's and similarly presenting neurological conditions and the potential to detect the disease in the absence of classical symptoms and prior to the onset of symptoms—both of which they wrote could improve both drug development efforts and management and treatment of the disease.

The scientists' suggestions reflect both the current capacity of protein biomarkers to provide a reliable diagnosis of Alzheimer's and expectations within the field that blood-based biomarkers are poised to play a major role in diagnosing the condition in coming years, said Nicholas Seyfried, an associate professor of biochemistry at Emory University whose lab works on Alzheimer's and Alzheimer's biomarkers.

"I think what [the STM authors] were arguing, is that because these core pathologies, amyloid and tau in particular, can accumulate in the brain upwards of 20 to 30 years in advance of clinical symptoms, it's important to use the biomarkers," said Seyfried, who was not an author on the editorial.

He noted that the gold standard for diagnosing Alzheimer's disease post-mortem is the presence of amyloid plaques and tau neurofibrillary tangles in the brain, both of which can now be detected in living patients using PET imaging and measurement of tau and amyloid-β 42 in cerebrospinal fluid (CSF).

Classical Alzheimer's symptoms like dementia "can be caused by many different pathologies," said Henrik Zetterberg, a professor of neurochemistry at the University of Gothenburg, noting that this makes the notion of a biomarker-based definition appealing.

"But we also need to ask carefully if the biomarkers are good enough," he said.

In the case of Alzheimer's, they are, Zetterberg said. "We now have extremely good imaging and fluid-based biomarkers. Amyloid PET, for example, is very well established and approved by [the US Food and Drug Administration] for use in evaluating a person with early signs of Alzheimer's disease."

CSF measures of tau and amyloid-β 42 have not been cleared by FDA for use in diagnosing Alzheimer's, but Zetterberg said that they are widely used, especially in Europe, for determining if a patient's symptoms stem from Alzheimer's or another cause like cerebral vascular disease or depression.

"The [STM article] is a very timely, editorial, I think," Zetterberg said.

But while the current state of Alzheimer's biomarkers provides reason to think moving to a biological definition of the disease could be advantageous, perhaps the larger potential is in blood-based biomarkers for the disease, an area where researchers have made significant headway in recent years.

While PET imaging can detect the amyloid plaques and tau tangles characteristic of the condition, the procedure is expensive and primarily used only in patients suspected of having Alzheimer's. CSF-based biomarkers are easier to access, but measuring them still requires a lumbar puncture, which many patients, particularly asymptomatic patients, are reluctant to undergo.

The STM authors noted that proponents of a symptom-based diagnosis often point to these facts as limitations of the biomarker-based approach, however, they added, "these limitations may be rendered moot by the development of blood-based markers," which "would make biologically based AD diagnosis widely accessible and much less costly."

Researchers have been looking for effective blood-based markers for Alzheimer's for more than a decade, but these efforts have recently begun to bear fruit.

For instance, C2N Diagnostics, a company co-founded by Holtzman, has developed a blood-based test for amyloid called APTUS-Aβ that it has demonstrated predicts the presence or absence of brain amyloid.

The firm presented results from a clinical study of the test at the Clinical Trials in Alzheimer's Disease annual meeting in December, showing that in 415 blood samples collected at six sites across the US the test predicted the presence of amyloid in the brain with an area under the receiver operator curve of .86 and an AUC of .90 when the test results were combined with age and ApoE4 status.

The company has also launched a second study, its Plasma Test for Amyloid Risk Screening (PARIS) study, which it said it plans to use to support an FDA submission covering the test. Last year the test received Breakthrough Device Designation from the agency. Prior to receiving FDA clearance, C2N plans to offer APTUS-Aβ as a laboratory-developed test.

Meanwhile, last year researchers from King's College London published on a panel of 12 blood proteins that could identify asymptomatic patients positive for amyloid-β brain pathology with a sensitivity of .78 and specificity of .77.

Zetterberg said that a pair of publications were soon forthcoming in Nature Medicine that would demonstrate that plasma measurements of phosphorylated tau, which has also been used as a CSF marker, showed strong correlation with amyloid of tau PET measurements.

"I think what we will see in the next few months are suggestions for diagnostic algorithms that will start with blood tests," he said. "A general practitioner could have a patient seeking medical advice because of memory problems, they would take a blood test to see if phospho-tau is elevated or not, and if it is elevated you could refer that patient to a memory clinic for CSF analysis or PET."

Another development that could further intensify interest in blood-based markers is the decision by Biogen to apply for FDA approval of its anti-Alzheimer's drug aducanumab, which an analysis presented at the CTAD meeting indicated could be help slow progression of the disease.

"If they do get FDA approval, how are they going to screen the population [to determine who should receive the drug]?" Seyfried said. "I think it would be a blood-based test. Blood is much easier to take than [CSF], and so you could screen en masse. I think that is going to be the next frontier of [Alzheimer's] biomarkers, plasma."

"When we get the first disease-modifying therapy approved it will really be imperative that we figure out an effective way of diagnosing patients with Alzheimer's disease pathology," Zetterberg said. "If aducanumab is approved this spring or autumn, who should we treat? There are so many patients who will ask for the treatment, and it will be extremely important to create a diagnostic algorithm… and I think we will see [that] algorithm starting with a blood test."

Seyfried said that while much of the work in blood has revolved around detecting surrogates for the established brain markers amyloid and tau, he believes additional blood markers could improve their utility.

"What other markers could be used that might reflect, for instance, neurovascular disease, neuroinflammation," he said. "The question is how can we identify those people who are the most susceptible [to developing Alzheimer's] who would most benefit from a drug treatment. And I think it will take markers beyond amyloid and tau to really get at that question."

Zetterberg also noted that while a biological, biomarker-based definition of Alzheimer's had clear advantages, doctors will still need to carefully consider factors like clinical symptoms and patient history.

"You might have a patient who seeks medical advice because of memory problems who turns out to be amyloid positive," he said. "You as a doctor then have to figure out if this patient is having memory problems based on Alzheimer's or if their problem is depression and they just happen to have amyloid positivity that won't start causing Alzheimer's symptoms for another 10 years."

"It's a complicated field, but it has seen dramatic advances," he said.