Few clinical trials change a company's value by $10 billion before full results are even public. And yet, a pair of studies did that and more to Biogen twice in less than eight months.

The fate of Biogen and, to an extent, the most popular theory in Alzheimer's drug research rests on how regulators interpret those studies. If their view is positive, then Biogen's aducanumab will gain approval, offering Alzheimer's patients the first ever drug advertised to treat the underlying cause of the disease. That decision would likely bring the company billions of dollars in sales, and validate management's controversial decision to push for approval.

If regulators turn down aducanumab based on the EMERGE and ENGAGE studies, then Biogen would surely face another huge stock sell-off. It's also possible the company's board may seek a change in leadership. At the highest level, the rejection would provide further evidence that Alzheimer's drug developers should look beyond amyloid beta, a protein fragment long viewed as central to the disease's progression.

EMERGE and ENGAGE were identically designed studies testing aducanumab in patients with early stage Alzheimer's disease. Interim analyses made it look like neither would succeed, leading Biogen to halt them both in late March. But when more data became available, a very different narrative played out — by mid-October, Biogen was saying one of the trials actually hit its primary goal, which gave it confidence to file for approval.

Reversals like the one seen with aducanumab are rare. Before the drug has a chance to enter the market, however, Biogen faces several pressing questions. Why did patients in ENGAGE fare so much worse than those in EMERGE? Could the latter trial's results be a false positive? And, above all, what will the Food and Drug Administration make of all this seemingly confounding data?

Biogen provided new efficacy and safety data at a medical conference in early December, claiming the high dose of its drug in the EMERGE trial led to modest improvement on a cognitive test and side effects that, while noteworthy, were mostly mild and manageable. The company also pointed to a discrepancy in the number of patients who received high-dose aducanumab as the reason for why EMERGE and ENGAGE had different outcomes.

Researchers are still trying to make sense of the data themselves, leaving the field divided on whether aducanumab remains promising or over-sold. In either case, the data are poised to have lasting effects on Alzheimer's research efforts.

The prevailing theory thus far has been that sticky plaques formed by a fragmented protein known as amyloid beta are the root cause of Alzheimer's. Yet in clinical testing, amyloid-targeting drugs have consistently failed, with at least 10 high-profile failures over the last five years. The interim analyses of aducanumab provided arguably the greatest prod yet that the research community should move beyond amyloid.

"Every time there's an amyloid drug that is not successful at a given stage, there seems to be a new story about how you haven't targeted the right population," Constantine Lyketsos, associate director of the Alzheimer's Disease Research Center at the Johns Hopkins School of Medicine, said in a mid-October interview before aducanumab's surprise revival.

Though the track record has been poor for amyloid-targeting drugs, Lyketsos said he was still disappointed when the aducanumab trials were halted in March. "As with everybody else, we're hopeful that the amyloid hypothesis will take us to the promised land. But it is seeming less and less likely that we will get there."

Views on the amyloid hypothesis remain mixed. ​Eliezer Masliah, director of the neuroscience division at the National Institute of Aging, says it deserves further investigation — namely in pre-symptomatic patients.

But Richard Isaacson, director of the Alzheimer’s Prevention Clinic at Weill Cornell Medical College, disagrees with that strategy, arguing instead that precision medicine will be the best shot at a treatment.

"The field has been investing incorrectly and I hope that it corrects itself," Isaacson said.

"If someone keeps putting all of their time and effort and energy into amyloid, [thinking], 'It'll work, let's just go earlier.' Well, that's just a bunch of ridiculousness."

Despite the setbacks, amyloid drugs still receive considerable funding. Of the $1.7 billion government agencies and private organizations have spent on Alzheimer's translational research and clinical interventions since 2008, at least $384 million was directed at the amyloid-beta protein, according to the International Alzheimer's and Related Dementias Research Portfolio. Drugmakers like Biogen have spent even more, likely much more.

Other areas of research, such inflammation and neurostimulation, appear to have received much less investment. Another protein named tau, though, has attracted millions in research funding in the last several years.

"Investors are just exhausted right now of the amyloid-beta hypothesis," Evercore ISI analyst Mike DiFiore told BioPharma Dive ahead of Biogen's October announcement. "For companies to get rewarded, they have to just pivot to new targets."

Yet with aducanumab's reversal, it's unclear how strong investors will push back if it looks like the amyloid hypothesis can finally yield a potential drug.