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Early diagnosis good, but good targets better in Alzheimer's

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By Anette Breindl
Senior Science Editor

BOSTON – At the presidential plenary session of the 2017 annual meeting of the American Academy of Neurology, Ronald Petersen freely admitted that "I'm biased."

But Petersen, a faculty member and practicing neurologist at the Mayo Clinic, was hardly voicing an isolated opinion when he called Alzheimer's disease (AD) "the disease of our profession," one whose importance is rapidly increasing as the population ages.

Though the topic of Petersen's talk was "How early can we diagnose Alzheimer's disease?" a good part of the talk focused on how to diagnose AD more accurately.

Historically, AD was diagnosed by its clinical symptoms, and the definitive diagnosis of Alzheimer's disease was made postmortem, by the amyloid plaques as well as tau tangles and degeneration that are AD's pathological calling cards.

Advances in brain imaging have allowed researchers and clinicians to look at all three of those biological changes without waiting for the patient's demise.

"We now have pretty good measures of looking at these pathologic indices in life, and that has given us a tremendous advantage," Petersen said.

It has also complicated the picture.

Amyloid plaque accumulation precedes cognitive impairment by decades. "Abeta is perhaps the initiating event, but note that it begins very early in the disease process, when people are still normal," he said.

Clinical symptoms come only after Abeta, tau and structural changes have all occurred.

At the same time, there is a significant number of people who have neurodegeneration and cognitive symptoms, but no amyloid pathology. That group goes by the acronym SNAP, for suspected non-Alzheimer's pathology.

As part of the Mayo Clinic Study on Aging, Petersen and his colleagues have now recruited more than 5,000 people, 80 percent of whom are cognitively normal, 18 percent with mild cognitive impairment, and 2 percent with outright dementia.

The researchers are looking at amyloid pathology, tau pathology and metabolic abnormalities that indicate neurodegeneration. They have also collected cerebrospinal fluid from more than 1,000 of their subjects to look for amyloid and tau.

The goal of all that work is to gain a better understanding of mild cognitive impairment, the stage preceding dementia that is characterized by memory and cognitive impairment but a continued ability to function, with the goal of being able to predict who will go on to develop dementia and, possibly, to intervene.

For now, such intervention is hampered as much by the lack of good therapeutic options as by the inability to predict who will go on to dementia.

Lawrence Friedhoff was the developer of Aricept (donepezil, Pfizer Inc.), the only drug that is approved for the treatment of AD. Currently, he is the chief development officer of Axovant Inc., which is testing intepirdine (RVT-101) in the phase III MINDSET trial. The trial is designed as a confirmatory trial for an earlier trial in which adding intepirdine to donepezil significantly improved the cognitive abilities in patients with mild to moderate Alzheimer's disease. If the trial is successful, Axovant plans to submit an NDA by the end of 2017.

Friedhoff is an outspoken critic of the idea that being able to identify individuals that are on the road to Alzheimer's will lead to success as long as the industry's target of choice remains beta-amyloid, an approach exemplified in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study, a public-private partnership involving the National Institute on Aging, Eli Lilly and Co. and several philanthropic organizations.

There are several reasons the approach is not viable in his opinion. First, because such trials are longer, they are expensive even compared to other phase III trials – in a system that is already straining under the cost of drug development.

The fact that more than a dozen trials aimed at lowering amyloid beta levels in the brain have failed – Friedhoff succinctly summed up the history of amyloid beta-targeting clinical trials as "a total disaster" – also suggests that if there is an effect, it is likely to be small. And small effects need large clinical trials to uncover them, further adding to the cost.

Finally, even if there is such an effect when amyloid beta-targeting agents are used early enough, such a drug may still not get FDA approval, because "if you're treating patients who don't have Alzheimer's disease, who are just likely to get it many years from now, then the criteria for approval are very different," he told BioWorld Today. "If you have people who are basically healthy, and they just may get dementia, then I would think the FDA will not approve a drug unless it is incredibly safe. . . . Because most of those patients will never get Alzheimer's disease," succumbing instead to cancer or other diseases beforehand.

Jim Summers, vice president of neuroscience discovery research at Abbvie Inc., called the ability to diagnose early and treat effectively "interlinked."

The way to conduct successful trials in early stage disease, Summers told BioWorld Today, is to use biomarkers. "Trials over the past five to seven years have not made great use of biomarkers," he acknowledged. But good biomarkers could be used as surrogate endpoints, enabling early intervention without the need for decade-spanning trials.

Abbvie's efforts in Alzheimer's disease are not focused on amyloid beta. The company has the anti-tau antibody ABBV-8E12 in clinical trials,

The Foundational Neuroscience Center is also looking at proteostasis, which Eric Karran, vice president of Abbvie's Foundational Neuroscience Center, called "a hallmark of neurodegenerative disease," and aberrant immune activation.

In one sense, failure is not an option. As the population ages, Summers said, Alzheimer's disease "is a tsunami that's coming."