New Antibody Drug Clears Brain of Amyloid Plaques and Delays Onset of Alzheimer’s Disease Symptoms in Small Clinical Trial


An experimental drug called aducanumab seem to be able to remove the toxic proteins that build up and cause the onset of Alzheimer’s disease in the brain, according to findings from a small clinical trial. Because of the small size of this trial, I must stress that these results, though potentially exciting, should also elicit some caution.

The results of this small clinical trial were reported in the journal Nature on August, 31, 2016. In this trial, aducanumab dissolved amyloid-β proteins in patients suffering from early-stage Alzheimer’s disease. This was a Phase I clinical trial, and therefore, was designed mainly to test the safety of aducanumab in human patients. Thus, the final word on whether aducanumab works to mitigate the memory losses and cognitive decline associated with Alzheimer’s disease must be subjected to clinical trials specifically designed to test such things. Two larger phase III trials are presently in progress, and are planned to be completed approximately in 2020 (note: this is an estimate).

The latest study enrolled 165 subjects who were split into different groups; subjects in one group received aducanumab and subjects in the other group were administered a placebo. In the group that received aducanumab infusions, 103 patients were given the drug once a month for up to 54 weeks. These patients experienced a reduction in the amount of tangled amyloid-β in their brains. These clinical recapitulated the results of pre-clinical experiments in laboratory mice that were actually reported in the same paper. Aducanumab seems to clear amyloid-β plaques from the brains of laboratory mice and human patients.

“This drug had a more profound effect in reversing amyloid-plaque burden than we have seen to date,” says psychiatrist Eric Reiman, who serves as executive director of the Banner Alzheimer’s Institute in Phoenix, Arizona. Reiman and his colleagues are in the process of testing other approaches for Alzheimer’s prevention and treatment. “That is a very striking and encouraging finding and a major advance.” Reiman wrote a commentary accompanying the article.

“This is the best news we’ve had in my 25 years of doing Alzheimer’s research, and it brings hope to patients and families affected by the disease,” says neurologist Stephen Salloway of Butler Hospital in Providence, Rhode Island, who is a member of the clinical team that ran the trial.

Patients in those groups that received aducanumab were divided into different subgroups that were given one of four different doses. Those patients who received the highest doses also had the highest reductions in plaques, and a group of 91 patients who had been treated for 54 weeks saw slower cognitive declines than did those who received placebo infusions.

Neuroscientists have had a long-standing and often spirited debate over the significance of the accumulation of amyloid-β in the pathology of Alzheimer’s disease. The memory loss and other symptoms of Alzheimer’s disease almost certainly result from the die-off of neurons in the brain, but do the amyloid-β plaques form as a consequence of this massive neuronal die-off or are they the cause of it? This clinical trial seems to provide good evidence for the “amyloid hypothesis,” since the elimination of amyloid-β protein seems to ameliorate the symptoms of Alzheimer’s disease.

Reiman however, cautions, wisely I think, that this trial is too small to definitively demonstrate that aducanumab actually works. Several other drugs for Alzheimer’s disease have shown promising results in the early-stage of clinical trials only to end in failure, and even in the deaths of patients.

Aducanumab led to abnormalities on brain-imaging scans in less than one-third of the patients. Researchers must closely monitor these anomalies in Alzheimer’s trials, because some participants in previous Alzheimer’s antibody trials have died as a result of brain inflammation. Fortunately, all of the reported imaging abnormalities eventually disappeared in about 4 to 12 weeks, and none of the patients who showed such abnormalities were hospitalized. Curiously, some of the patients who showed imaging anomalies continued to take the drug despite these side effects. Patients who received higher doses of the drug, or who had genetic risk factors for Alzheimer’s, were more likely to develop the brain anomalies.

Biogen, the company that makes aducanumab, has adjusted the drug’s dosage and the monitoring schedule for patients who have an increased genetic risk for Alzheimer’s in its phase 3 trials. According to Reiman, drug makers, like Biogen, must determine if a particular dosage that hits a “sweet spot” that is strong enough to work without causing potentially lethal brain inflammation.

Aducanumab is a bright spot in the field of Alzheimer’s therapeutics after years of failed antibodies and other types of drug trials. The antibody drug solanezumab failed to slow cognitive decline in two large 2013 clinical trials.  However solanezumab may have a second life and is being tested in multiple other trials, one of which includes individuals with mild Alzheimer’s disease. Results from this trial might be reported as early as the end of 2016.

Other therapeutic strategies undergoing clinical trials include strategies that target enzymes called β-secretase 1 that processes amyloid proteins, antibodies that attack the so-called the microtubule-binding tau protein, which is found in high concentrations in the neurofibrillary tangles found in the brains of many Alzheimer’s disease patients.

“The fact that we now have an antibody that gets into the brain sufficiently enough to engage its target and remove plaques is an important development, and we look forward to seeing results from this and other phase 3 trials,” Reiman says.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).