Little is known about the causes of Alzheimer’s disease (AD), despite it being the most common form of dementia (“Alzheimer’s disease,” 2016). AD is characterized by misfolded proteins in the brain. These proteins have an unknown function in their original form, amyloid precursor protein (APP). When APP degrades, one of its products is the amyloid beta protein (Aβ). While Aβ normally exists as soluble solo particles called monomers, it can misfold into an S-shape. These S-shaped particles fit together and form long chains called fibrils. The fibrils do not dissolve and instead build up to form plaques in the brain. Although these physiological changes are common to AD patients, it is not clear what actually causes dementia symptoms. One hypothesis is that either the fibrils or intermediate forms known as oligomers cause apoptosis (cell death), which leads to dementia as brain cells do not regenerate. (“Biochemistry of Alzheimer’s disease,” 2016)

A recent study, the results of which were published in Nature (Sevigny et al., 2016), sought to investigate this hypothesis by attempting to destroy Aβ fibrils and tracking patient progress on standard dementia tests. First they searched human memory cells until they found a monoclonal human antibody (mAb) known as aducanumab that attacks Aβ fibrils and oligomers. Pre-trial studies showed that aducanumab was able to cross into the brain and destroy Aβ plaques in mice. This led researchers to believe that aducanumab might be able to attack the plaques in human patients as well, instead of staying in the bloodstream as some previous potential treatments had.

Before going to human trials, the researchers wanted to ensure that only the harmful forms of Aβ would be destroyed. In the lab, they used a dot blot test in which they added the monomer, oligomer, and fibril forms of Aβ to aducanumab and other antibodies and found that aducanumab bound to the oligomers and fibrils but not the monomers. Aducanumab was the only molecule tested that got those desired results.

The human trial divided the patients into four groups. Three of the groups received monthly injections of aducanumab (either 3, 6, or 10 mg/kg, depending on the group), and one received a placebo as a control. PET scans of the patients’ brains showed a significant reduction after one year in amyloid plaques in the brains of the patients taking aducanumab, with greater reduction visible with higher doses. I felt their data was convincing that aducanumab binds to Aβ fibrils and destroys the plaques. However, as I mentioned earlier, the cause of AD is unknown, so the destruction of the plaques does not necessarily mean an improvement in symptoms.

The patients were given two standard cognitive tests of dementia, the MMSE and the CDR. The MMSE tests patients’ abilities to carry out various cognitive tasks. The results with the group under study were inconclusive. Groups with some doses of aducanumab performed better than the control group, while others did not. The CDR is a scale that measures the severity of dementia symptoms on a scale from 0 (none) to 3 (severe) (“Clinical Dementia Rating,” 2016). After 26 weeks, all patients had gotten worse at about the same rate as compared to baseline results from the start of the trial. However, at week 54, patients on aducanumab showed significant slowing in onset of dementia symptoms as compared to the control group, with those on the highest dose even showing slight improvement over their week 26 result. Considering that AD patients usually get progressively worse over time from the appearance of initial symptoms, this shows promise that the destruction of Aβ plaques can halt the progression of the disease.

Based on the results of this study, I think that this treatment has promise. However, it needs to undergo full-scale clinical trials before being released on the market. More data could clarify the MMSE results and help confirm the others. Additional cognitive tests might help as well, to be certain aducanumab actually treats dementia symptoms and not just the physical presence of Aβ plaques. A longer period of study with more patients will also help ensure that there are no side effects to treatment that would outweigh the potential benefits.

References

Alzheimer’s disease. (2016, October 10). Wikipedia, The Free Encyclopedia.  Retrieved from https://en.wikipedia.org/w/index.php?title=Alzheimer%27s_disease&oldid=743696317

Biochemistry of Alzheimer’s disease. (2016, September 29). Wikipedia, The Free Encyclopedia.  Retrieved from https://en.wikipedia.org/w/index.php?title=Biochemistry_of_Alzheimer%27s_disease&oldid=741725622

Clinical Dementia Rating. (2016, March 7). Wikipedia, The Free Encyclopedia.  Retrieved from https://en.wikipedia.org/w/index.php?title=Clinical_Dementia_Rating&oldid=708771069

Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., . . . Sandrock, A. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 537(7618), 50-56. doi:10.1038/nature19323

http://www.nature.com/nature/journal/v537/n7618/abs/nature19323.html#supplementary-information