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Jack Zhong Neuroscience

A Promising Cure for Alzheimer’s Disease?

By: Jack Zhong
Edited By: Josephine McGowan

Alzheimer’s disease is the 6th leading cause of death in the US, and yet, it has no known cures, prevention methods, or approaches to slow down the progression of disease. Causing degeneration in the brain (Figure 1), Alzheimer’s disease has common symptoms that include: dementia, memory loss, decline in speech, and confusion. The disease pathology is gradual, with seven major stages. Its victims include former president Ronald Reagan and Nobel laureate physicist Charles Kao, and the disease mainly affects people 65 years and older. Recently, a new drug, Aducanumab (BIIB037), has yielded promising results in clinical trials.

 (Figure 1: Degeneration of the brain as a result of Alzheimer’s diseasedreamstime/a>)
Figure 1: Degeneration of the brain as a result of Alzheimer’s disease (via dreamstime)

In attempting to treat Alzheimer’s disease and other neurodegenerative disorders, neuroscientists and doctors struggle with a wide gap of knowledge in neuroscience. Neuroscientists understand well how a neuron works on a cellular level, and psychologists have to a certain extent clarified how humans behave. Yet, we do not understand well how the signals of millions of individual neurons throughout the brain integrate together to cause behavior. Similarly, we do not know what goes awry in neural circuitry to cause neurodegenerative diseases, even if we could detect abnormalities in individual neurons. Sometimes, a part of the brain can be removed with little consequence, but a slight mutation in the genes can cause devastating diseases. We simply don’t understand exactly how changes in neurons lead to changes in behavior or brain functions. Given our lack of knowledge in this respect, attempting to treat neurodegenerative diseases is like attempting to treat infectious diseases without knowing how viruses alter organ functions.

Though there are many hypotheses on the causes of Alzheimer’s disease, scientists are still debating what the definitive cause might be. Most of today’s treatments are based on the Cholinergic Hypothesis, which proposes that Alzheimer’s disease is caused by a reduction in acetylcholine, a molecule used in signaling between neurons. However, most drugs used to treat acetylcholine deficiency have not yet been proven to be effective in treating Alzheimer’s. Alternatively, the Amyloid Hypothesis suggests that amyloid beta (Aβ) deposits on the outside of neurons cause the disease (Figure 2). In support of the Amyloid Hypothesis, scientists note that the gene for the amyloid precursor protein (APP) is on chromosome 21, and many Down syndrome patients (with an extra chromosome 21) exhibit Alzheimer’s disease by age 40. Mice with mutated APP genes exhibit amyloid plaques and Alzheimer’s like symptoms. Also, APOE4 is a defective form of a protein that normally breaks down, and people with APOE4 gene are at risk of Alzheimer’s disease. There are still many other hypotheses on the causes of Alzheimer’s disease not mentioned here.

Figure 2: Amyloid beta (Aβ) plaques in Alzheimer’s disease. (via alzhyme)
Figure 2: Amyloid beta (Aβ) plaques in Alzheimer’s disease (via alzhyme)

When scientists at the biotech company Neurimmune developed Aducanumab, they sought to tackle the disease based on the Amyloid Hypothesis. Aducanumab is an antibody derived from healthy, aged donors without Alzheimer’s disease. The scientists figured that since the donors’ immune systems were resistant to Alzheimer’s disease, antibodies from these healthy patients could be turned into treatments. This process of turning antibodies from healthy individuals into therapeutics is called “reverse translational medicine.”

When determining the mechanism of these antibodies, the scientists found that Aducanumab targets a special recognizable region on the Aβ. Antibodies work by selectively binding to recognizable regions of pathogens called epitopes, and they trigger an immune response to destroy the pathogen (Figure 3). Once in the brain, Aducanumb binds to Aβ that forms aggregates, which is believed to cause Alzheimer’s disease, but the drug leaves single Aβ untouched.

Figure 3: Basic diagram of how antibodies function (via whfoods)
Figure 3: Basic diagram of how antibodies function (via whfoods)

Scientists testing the effectiveness of Aducanumab were greeted with promising results. There are many stages before drugs are released onto the market (Figure 4). Before human testing, scientists dosed mice with mutant APP genes with Aducanumab for thirteen weeks, and all sizes of the Aβ plaques were reduced. After the drug was found to be safe for human use, Biogen Idec started PRIME, a 2012 multi-dose study involving 166 people with Alzheimer’s disease. On March 20, 2015, analysis of the first data was presented. Aducanumab reduced amyloid deposits in 6 regions of the cerebral cortex of the brain. Large effects were observed after 1 year of dosage. The highest dose seems to reduce cortical amyloid close to normal detected levels. Further, cognitive tests administered to patients suggest that Aducanumab reduce cognitive decline in a dose-dependent fashion. PRIME is an ongoing study that will last until 2016.

Figure 4: Stages of clinical trials (via ipmglobal)
Figure 4: Stages of clinical trials (via ipmglobal)

The cure for Alzheimer’s disease may be around the corner if Aducanumab continues to yield encouraging results. Regardless of the eventual conclusion on Aducanumab, neuroscientists must continue to hunt down the cause of Alzheimer’s. Most importantly, neuroscientists need to work slowly to close this gap of knowledge in Alzheimer’s on a neuron-level, which can lead to a revolution in our understanding of the brain and treatments of neurological disorders. To achieve this hypothetical goal would mean eventually elucidating the etiology of this disease, as well as finding ways to prevent its progressive damage.

1 comment on “A Promising Cure for Alzheimer’s Disease?

  1. Reblogged this on stained glass memories and commented:
    Always hope.

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