Hope emerges in the research world as scientists move closer towards finding a cure for Alzheimer’s disease (AD), a heart-rending and devastating disease currently affecting over 5 million Americans. Approximately one in nine people aged 65 and older has AD, and it is now the 6th leading cause of death in the United States. The neurodegenerative disorder is commonly known for its effects on memory, but it induces an array of adverse symptoms that impact the entire body. AD has confounded researchers for years, but a recent article published in Nature inspires hope for a cure as an antibody called aducanumab reduced the plaques and tangles that cause AD. Jeff Sevigny, Ping Chiao, Thierry Bussière & Paul H. Weinreb and colleagues report on their testing of aducanumab’s effect on reducing amyloid beta plaques and tangles and slowing the cognitive and functional decline that accompanies neurological degradation.
Alzheimer’s Disease is a form of dementia brought on by the gradual accumulation of insoluble plaques, composed of amyloid protein, and tangles. The plaques expand in between neurons and tangles build up in dead and dying cells where the system to transport essential nutrients has fallen apart. It is presumed that a mass of plaques and tangles leads to cell death and tissue loss, causing synaptic dysfunction and neurodegeneration. On that account, scientists have been investigating antibodies that can spark the clearance or mitigation of toxic amyloid-β (Aβ) plaques by binding to Aβ’s functional tissue. Prior to the development of aducanumab, antibody based immunotherapy has been unsuccessful; however, researchers observed significant reduction of Aβ plaques when inserting aducanumab into mice brains, prompting a clinical trial.
In preclinical studies in mice, researchers observed substantial, dose dependent decreases in Aβ plaques by up to 70%. Moreover, scientists were able to detect a possible mechanism for how the antibody clears the plaques. Presumably, aducanumab binds to and accumulates on the functional tissues of Aβ plaques and initiates the recruitment of microglia, which are connective cells in the brain that support and protect neurons. Microglia bind to the aducanumab antibody and display enhanced bacteria-eating activity (phagocytosis). It is suggested that phagocytosis by the microglia clears the existing neurotoxic plaques and prevents new plaques from forming.
Currently in phase one, the double blind PRIME study randomly selected patients with prodromal, an early form of the disease characterized only by memory impairment, or mild AD who have similar Aβ pathology in the brain. The primary purpose of the study is to find a successful treatment for AD, but phase one is specifically concerned with establishing the antibody’s safety, effectiveness, and how it is tolerated and moved through the body. In the study, 125 patients were given either a placebo or aducanumab doses of 1, 3, 6 or 10 mg kg−1 once a month for one year.
To monitor patient declines in Aβ plaques, researchers used PET imaging. The average PET standard uptake value ratio (SUVR), which is imaging employed for quantitative analysis, showed a significant decline from the original PET score in patients receiving the 3, 6 and 10 mg kg−1 doses after 54 weeks, indicating a decline in the plaques. The researchers observed a direct relationship between the dose of aducanumab and the amount the plaque decreased, seeing the greatest drop of plaque build-up in the people receiving a 10 mg kg−1 dose. The trial primarily focused on testing the drug’s safety, exploratory clinical tests were performed and it was determined that the drug was capable of improving mental aptitude. Patients were given the Mini Mental State Examination (MMSE), which is an eleven-question test with a maximum score of 30 that screens for mental capability by testing 5 areas of cognitive function — orientation, registration, attention and calculation, language, and recall. Results below 23 show clinical impairment. The study shows slowed progression in declining scores in those patients receiving a 3 mg kg−1 score and better scores in those receiving 10 mg kg−1, indicating improved mental capabilities.
The side effects were limited to amyloid-related imaging abnormalities (ARIA), headache, urinary tract infection, and upper respiratory tract infection. Out of those listed, only ARIA must be reported as a medically important serious adverse effect; brain inflammation has led to death in previous antibody trials. The swelling correlates to higher doses, especially in those who carried the APOE-E4 gene, which increases the risk of succumbing to AD. Looking at pharmacokinetics, how drugs move through the body, only three out of 118 patients developed an anti-aducanumab antibody; other potential antibody responses in the body were minimal.
Many other monoclonal antibodies like aducanumab have undergone testing, but none have had the same success, usually proving to be unsafe and ineffective. Aducanumab is the first monoclonal antibody to inspire hope for a future cure. The antibody successfully decreased Aβ plaque content as seen through the PET SUVR scores. Potentially the most critical finding is that the decreased Aβ plaque levels correlate to improved cognitive results. This essential discovery provides insight into how exactly aducanumab binds to plaques, most likely onto oligomer forms of Aβ, which are molecules that are too small in size to be detected by a PET scan but potentially have a profound effects on cognition. Dissolving these toxic forms of Aβ allows for recovery of neuronal function, but the process is time-sensitive–it takes the 54 weeks to view clinical improvement.
The antibody treatment is still moving through phase one, but recent results prove to be extremely optimistic given the mystery that surrounds the cause and inability to find a cure for Alzheimer’s disease. That being said, other antibody treatments have proved to be effective in early trial phases, and then transpired to be unsafe and unsuccessful. Aducanumab is more auspicious in the sense that the results have demonstrated significant declines in plaque as well as noteworthy slowing of clinical impairments. Improved mental capabilities after treatment are unique to the aducanumab antibody; an antibody known as solanezumab failed to slow cognitive decline in multiple clinical trials. Additionally, while other antibody therapies have been capable of reversing the burden of Aβ plaque buildup, none have done so to the same magnitude as aducanumab.
As initially promising therapies continuously surfaced and receded in the fight against Alzheimer’s disease, people living with the devastating effect of AD have learned to expect little hope. Year after year, the disease lays waste to the memories and lives of people suffering from AD with inescapable cruelty. Perhaps, finally, this new hope will emerge and endure, and offer millions of AD sufferers and their families the effective treatment so elusive and so desperately anticipated for so long.
Sevigny, J., Chiao, P., Bussière, T. Weinred, P. H. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, doi: 10.1038/nature19323
Other Information Gathered From
Netzer, W. J. (2015, March 31). Experimental Alzheimer’s Drug, Aducanumab, Slows Cognitive Decline in Early Trials. Retrieved October 03, 2016, from https://www.alzinfo.org/articles/diagnosis/experimental-alzheimers-drug-aducanumab-slows-cognitive-decline-in-early-trials/
Kurlowicz, L., & Wallace, M. (1999, January). Mini-Mental State Examination (MMSE) – Mount Sinai Hospital. Retrieved November 4, 2016, from https://www.mountsinai.on.ca/care/psych/on-call-resources/on-call-resources/mmse.pdf