Are researchers on the wrong track?

(HealthDay) – Amyloid beta has long been a major suspect in Alzheimer's disease, as abnormal levels of protein form disruptive plaques between patients' brain cells.

But drug trials aimed at reducing amyloid levels have repeatedly failed to save people's brains, and some researchers now believe that it's necessary to focus on other potential culprits. .

The researchers quickly ended the last failed clinical trial, after the patients' brains continued to decline, even though the amyloid beta-blocker, verubecestat, had managed to lower amyloid levels in the body. brain and cerebrospinal fluid.

The disappointing results of the verubecestat appear in the April 11 issue of New England Journal of Medicine, along with a research letter announcing equally negative preliminary results from the clinical trial of another inhibitor of the amyloid substance called atabecestat.

These negative results are consistent with those of previous trials and present "fairly strong evidence that amyloid reduction is not the right target," said Dr. David Knopman. He is a professor of neurology at the Mayo Clinic and has written an editorial accompanying the new reports.

Knopman noted that the verubecestat trial showed that amyloid levels had decreased slightly in the brain and quite significantly in the cerebrospinal fluid after treatment with the drug, but that the brain structure of patients was deteriorating and their ability to reason and remember always diminished.

"They have reached their target and yet, people have gotten worse, still worse, both in terms of brain structure and brain cognition," said Knopman.

The strange thing is that amyloid beta plaques remain a "very good marker of cognitive impairment related to Alzheimer's disease," Knopman said. When these plaques are found, it is very likely that the person is suffering from Alzheimer's disease.

For this reason, it is very important that research focused on beta amyloid continues, said Rebecca Edelmayer, director of scientific engagement at the Alzheimer's Association.

"There is still a preponderance of evidence that beta-amyloid is an essential protein of the disease and I think we need to continue to understand the role it plays in the disease," said Edelmayer, who n & # 39; 39, did not participate in the studies.

"The ongoing trials on part of the amyloid signaling cascade need to be completed so that we can learn from each of these trials, whether there are positive or negative results," she said. .

At the same time, the Alzheimer's Association has already expanded the scope of its research funding to focus on other ways to treat or prevent the disease, Edelmayer said.

The results of clinical trials on amyloid are now on the rise, as one of the main symptoms of Alzheimer's disease, amyloid beta-plaques were one of the first therapeutic targets to pursue, she said.

"It makes sense that we most often see amyloid in the news because these are the ideas that were launched 10 to 15-20 years ago," it took about as much of time it takes science to explore these pathways, said Edelmayer.

In the years that followed, many other potential treatment processes and targets began to be pursued in the quest for curative treatment.

Research teams are still studying the role of the other major feature of Alzheimer's disease: entanglements of tau proteins that accumulate in neurons and potentially interfere with communication between synapses.

"We know that these two features of the disease are present and help us define some of these clinical symptoms, but we still do not know why these healthy proteins in our brain are turning into something that becomes aberrant, pathological or destructive in the brain, "Edelmayer said.

The other therapeutic targets under study are chronic inflammation in the brain, the health of cerebral blood vessels, the role of the immune system and the contribution of genetics, said Edelmayer and Knopman.

"We are studying a wide variety of therapeutic mechanisms," said Knopman. "We will not neglect anything with this disease."

Some researchers are also arguing that viruses or bacteria may be the cause.

A study presented last week at the annual meeting of the American Association of Anatomists showed that the bacteria P. gingivalis, which causes gum disease, could be badociated with Alzheimer's disease. Other previous research has established a similar potential link with the herpes simplex virus.

The theory of "infection" of Alzheimer's disease is still in its infancy, however pointed out Knopman.

"I do not think that the evidence currently provides any treatment other than the obvious pill of administering antivirals to Alzheimer's patients, which is barely justified given the paucity of data." Knopman said.

The verubecestat trial ended in February 2018, a year before the completion of its first phase, after the enrollment of 1,454 patients, the new report said. A data and safety monitoring committee concluded that the drug would not surpbad the placebo at either of the two doses tested.

The atabecestat trial was also completed early, in May 2018, due to adverse events related to liver health. The 557 participants are still being monitored as part of a security follow-up.

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