by Jalwa Afroz

The antibody aducanumab reduces amyloid-β plaques, helping to prevent the cognitive decline of Alzheimer’s disease.

Alzheimer’s disease (AD) is a chronic type of dementia that affects a person’s memory and behavior. Ultimately, cognitive decline and behavioral disturbances lead to a person’s inability to perform daily activity. Through pathophysiological evidence, researchers have shown that amyloid-β (Aβ) plaque buildup in the brain causes neurotoxicity. This typically occurs years before symptoms of AD appear and are diagnosed. So far, therapeutic attempts have been unsuccessful. Trials involving antibody-based immunotherapy targeting Aβ have failed because of the antibody’s failure in engaging the proper brain target or because of poor selection of study participants.

In a recent study led by Dr. Jeff Sevigny, a human monoclonal antibody, named aducanumab, was generated to selectively target Aβ buildup in the brain. Aducanumab was constructed through recombination, cloning, and then sequencing of human memory B cells that reacted against Aβ buildup. In preclinical studies, researchers observed that the mouse analog of aducanumab crossed the blood-brain barrier, engaged the target, and cleared Aβ from Aβ-aggregated transgenic mouse brains. As a result, researchers started clinical trials with aducanumab and tested it on human patients with mild AD.

The researchers enrolled 165 participants, 50 to 90 years old, who either had mild AD or asymptomatic buildup of Aβ plaques in order to determine the dosage of aducanumab that would be both safe and effective. After splitting the participants into groups, scientists administered different dosage concentrations of aducanumab through monthly intravenous infusions once every four weeks for 52 weeks. To determine how the participants were responding to treatment, the team scanned their brains and quantified their plaques with PET and a radioscope ¹⁸F-florbetapir that the amyloid plaque absorbed. The researchers observed reduced brain Aβ in a dose and time-dependent manner, meaning the higher the dosage of aducanumab, the better the Aβ plaque was cleared. Patients who received the placebo showed no change in their Aβ.

The preclinical and clinical data allow for continued development of aducanumab as a treatment for AD. Interestingly, it may have taken up to 20 years for Aβ to accumulate to the levels in patients at the start of the study. Yet the removal of Aβ within a 12-month period shows promising results for this disease-modifying treatment of AD. For further research, the clinical effects of aducanumab would have to be corroborated in larger studies.

References:

1. Sevigny, et al., The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature537, 50-56 (2016). doi:10.1038/nature19323.
2. Image retrieved from: http://www.lipennysaver.com/spsect/living50-plus/article0004.html