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AAN Debate: Neurologists Divided on Amyloid as Alzheimer Target

— Many attendees say the pathway is still worth exploring

MedpageToday

BOSTON -- The amyloid hypothesis is not dead yet, winning more support than anticipated during a head-to-head debate at the American Academy of Neurology meeting here, though a moderator called a marginal victory in favor of the anti-amyloid camp.

Reisa Sperling, MD, of Harvard, who is running the large-scale A4 trial that is widely thought to be the last hope for targeting amyloid, faced off during a "Controversies in Neurology" session against George Perry, PhD, of the University of Texas at San Antonio, who says the field should already be moving on.

Both agreed that trying to remove amyloid from the brain at too late a stage is futile -- but while Sperling insisted that investigating whether earlier removal of amyloid -- before patients are symptomatic -- is an essential question to answer, Perry said many basic science researchers are already trying to understand the "further complexity" of the disease, like teasing apart whether different oligomers of beta-amyloid behave differently.

"Can anti-amyloid agents improve cognition in Alzheimer's disease? I'll say yes, but with an asterisk," Sperling said. "I think it will depend on initiating therapy at the right stage of disease when beta-amyloid is still driving the pathology, and it has to be dosed at sufficient levels to combat the amyloid burden."

"We have to test the right drug at the right dose in the right stage of disease, which I don't think we've done yet," she said.

Sperling acknowledged the tough odds against her: no anti-amyloid drug has yet to succeed in a clinical trial, and there are a proportion of people who have amyloid pathology in the brain but show no signs of cognitive impairment. She argued that past trials have not started early enough to be effective, and they may not have used the right dose. Additionally, she said those with amyloid pathology and no cognitive symptoms may just be slowly progressing; studies have shown that patients with amyloid and mild cognitive impairment are five times more likely to progress to Alzheimer's than those without.

Tau certainly has a role to play, too, Sperling said, noting that amyloid might accelerate tau pathology. Ultimately, the proper treatment of symptomatic Alzheimer's will likely involve combination therapy, she added.

Perry said researchers started to question the amyloid cascade hypothesis 15 years ago, and many are convinced that they should be digging more deeply into the disease's complexity rather than focusing on amyloid-targeting agents.

"Amyloid and tau are much like inflammatory responses and are critical to the disease, yet the deposition we see during aging could be because [these proteins] are a critical response to an injury," he said. "Could amyloid be protective? Would removing it be harmful?"

That leads to the question of whether it's ethical to remove amyloid from the brains of people who wouldn't convert to Alzheimer's within a decade if it perhaps hastens disease, he said.

"With A4 or A3 [Sperling's early-stage amyloid removal trials], it's going to take years before you can see results as to whether these patients improved," he said. "To have a major effect we're going to need to design drugs that actually modify the course of the disease."

"I don't think we know enough about what amyloid or tau really does in the brain, even though these are probably some of the best-studied proteins," he added.

Sperling and Perry sparred over a cholesterol analogy: Sperling likened the amyloid hypothesis to the "cholesterol wars" of the 70s and 80s, when it wasn't clear if cholesterol was related to heart disease -- but subsequent secondary prevention trials showed large reductions in cardiac morbidity and mortality with statin treatment to lower LDL cholesterol.

Perry noted that some types of cholesterol are necessary for survival, arguing that some types of amyloid may be beneficial; but Sperling countered that cholesterol "is a problem when it clogs up your arteries. Amyloid is a problem when it clogs up your synapses."

After a show of hands from the hundreds of neurologists in the audience, moderator Joseph Jankovic, MD, of Baylor College of Medicine, called the debate in favor of Perry -- but his co-moderator, Aleksandar Videnovic, MD, of Massachusetts General Hospital, told Jankovic he needs an eye exam. The room appeared nearly evenly divided.

The "Controversies" plenary session included two other debates; one on deep brain stimulation versus focused ultrasound for Parkinsonism, and another on whether disease-modifying therapies should be stopped in progressive multiple sclerosis.

On the MS front, Robert Naismith, MD, of Washington University in St. Louis, eked out a small victory (about 60% versus 40%) over John Corboy, MD, of the University of Colorado, for suggesting that drugs for relapsing disease shouldn't be stopped when a patient moves into a progressive phase, because it's not clear if it's no longer useful to target inflammation at that point.

Michael Okun, MD, of the University of Florida, won a more obvious victory (about 90% versus 10%) over Paul Fishman, MD, PhD, of the University of Maryland, as the audience was unpersuaded that focused ultrasound is either safer or more effective than deep brain stimulation.