Imagine waking up confused, unable to articulate your thoughts—functioning minimally as far as cognition goes. You are still however able to carry out your morning routine getting dressed and getting ready for the day ahead. As you step out of the house you slowly notice tell-tale signs of a break-in; opened kitchen drawers, rummaged cupboards, clothes in all sorts of places and alas, missing car keys. You swear you placed them on the key holder behind the basement door and for some reason they have mysteriously disappeared along with your wallet, bag and cellphone. As you rush to the kitchen phone to call the police you catch a glimpse of yourself in the mirror—your t-shirt is on backwards. As more confusion sets in, you hear the jangling of keys as the front door swings open. A lady walks in and quickly comes to your aid. She introduces herself and assures you will be fine. She asks you to sit down as she explains the situation—you have Alzheimer’s.
This description while fictional describes the life of most patients living with Alzheimer's disease. While able to stick to routines, Alzheimer’s patients have difficulty forming new memories making menial tasks seem impossible. They forget where they’ve placed their keys, how to use a telephone; they forget people, places and things. They even forget speech, self-identity, and in its later stages their body forgets how to stay alive as they forget how to eat, excrete waste, breath, and keep a heartbeat. As the disease progress, patients begin living their life moment-to-moment, with no memories of the past or expectations of the future. They become prisoners in their own minds as parts of their brain slowly shuts down until it turns off for good.
The Shrinking Brain
Alzheimer’s is a form of dementia which is a term describing general mental disorders associated with brain damage leading to memory loss, mood changes and personality disorders. Alzheimer’s affect approximately 40 million people worldwide and is prevalent in the aging population. While it is known that defects in neuronal protein structures contribute to the progression of the disease, its exact cause remain elusive.
The brain is made up of cells called neurons. Neurons are cells shaped like starfish with long tentacle-like projections termed ‘axons’ attached to a main body termed ‘soma’. Using their axons, neurons are able to form connections between neighboring neurons which facilitate communication throughout the brain. Neurons are responsible for creating thought and storing memories by means of electrical pulses. A neuron initiates an electrical pulse within the soma which they shoot down the length of their axons. At the end of the axon, the electrical pulse triggers the release of chemicals called neurotransmitters which bind to receptors on the surface of adjacent neurons (Figure 1). These neighboring neurons become activated and the electrical pulse continues. With this mechanism, neurons are able to form an electrical circuit capable of propagating communication between neighboring neuronal cells. It is estimated that ~100 billion neurons exists in our brains forming a staggering 100 trillion points of connection. Depending on the strength of the electrical charge and the different combinations of activated neurons, different thoughts and memories are created.
Figure 1. The anatomy of a neuron. Neurons are the medium for thoughts and memories. They form a vast network of electrical circuitry capable of interacting with one another via the ‘synapse’ or synaptic cleft.
In patients with Alzheimer’s, these neuronal interactions are compromised by a protein called the Amyloid-beta (AB) protein, a by-product of the parent amyloid precursor protein (APP). AB interferes with neurons by physically blocking neuronal connections called ‘synaptic clefts’—the space in which electrical impulses pass from one neuron to the next. APP is found on the surface of neurons which in healthy cells is cut by specific enzymes to produce by-products necessary in maintaining neuronal health. In Alzheimer’s, APP is processed differently—of which root cause remains unknown—resulting in the production of excessive AB proteins. AB is a protein with a characteristic ‘sticky’ spot enabling it to aggregate with other AB proteins (Figure 2). This aggregation result in the formation of AB plaques which is believed to block neuronal connections leading to neuronal death, brain shrinkage and ultimately, death.
Figure 2. The Amyloid-beat protein (AB) is made from its parent amyloid precursor protein (APP). Upon cleavage by specific proteins, APP gives off the AB protein as a by-product. AB clumps together with one another forming the Beta-Amyloid Plaque which can interfere with neuronal connections by blocking synapses.
The promise of Immunotherapy
Amongst the several approaches in treating Alzheimer’s, immunotherapy proves most promising. Immunotherapy exploits the body's own immune system by provoking an immune response to attack the beta amyloid plaques. Researchers are able to provoke an immune response by creating antibody tags which specifically bind to AB proteins. These tags decorate AB proteins making them visible to the immune system, inducing clearance of pre-existing amyloid plaques. Dr. Yednock’s group first demonstrated this feat in 2000 when his team immunized PDAPP mice (mouse model engineered to overproduce AB proteins and hence plaques) with the antibody tags. They found that mice administrated with the antibodies showed significant reduction in plaque formation compared to those non-treated1. This also translates in a very rapid reversion of memory impairment in certain learning and memory tasks as demonstrated by Paul’s group in 2002.
Despite these findings, immunotherapy has been met with uncertainties as clinical trials performed last year on AB antibody drugs such as Bapineuzumab failed to predict clinical efficacy3. Similarly, a drug which binds individual AB proteins called Solanezumab has also failed clinical trials in the same year4. A study by Busche et al., 2015 further highlights the intricacies of immunotherapy in treating Alzheimer’s. His team found that while effective in reducing AB plaque formation, structural neuronal abnormalities and at instances behavioral deficits in mice, antibodies used in immunotherapy was ineffective in treating neuronal dysfunction and instead worsened it5.
The current promise of Immunotherapy
Although unsuccessful in previous clinical trials, new AB drugs and their mode of administration are currently being improved and are entering their initial clinical trial phases. The drug Solanezumab initially failed an 18-month trial and was deemed ineffective in treating Alzheimer’s. The trial however was continued for two more years at which point its therapeutic effects became evident. Solanezumab has since attracted a lot of attention due to its ability in slowing brain deterioration in patients. Results presented at the Alzheimer’s Association International Conference in 2015 showed that patients treated with the drug experienced cognitive benefits which improved with longer treatment durations. The drug is currently in clinical trials and is expected to have its final patient visit on October 20166. Other drugs such as Aducanumab has also been created which unlike Solanezumab can target the plaques itself and not just individual BA proteins. Similarly, despite flopping in its initial trials, Aducanumab provides robust cognitive benefits and is planned to enter a larger clinical trial in the near future7. Drugs such as Azeliragon is also being investigated which is currently in its phase 3 trial in the United states and in Toronto, expected to run until 2018. Azeliragon addresses issues with brain inflammation which is also a known causative agent of the disease8.
We are nearing the new frontier in our fight against Alzheimer’s. It is however important to remember that nothing is ever clear cut where disease is concerned. Half the battle with immunotherapy lies with detection as amyloid beta deposition and accumulation probably occurs many years before the onset of symptoms, at which point neurological damages may be too severe to reverse3. Thus, investment in prevention rather than treatment is the prime target. As well, no single treatment is ever effective against one particular disease as it is complicated by external factors including genetics, lifestyle, exercise and diet. A multi-target therapeutic approach is more likely to improve disease prognosis as seen in other treatment regimens including HIV and cancer.
Contrary to the popular belief, Alzheimer’s is not part of the ‘normal aging’ process despite the fact that 1 in 2 people over 85 are affected9. Rather, it is a disease which like other diseases, have causes and thus potential cures. It’s surprising to note that since it’s discovery in 1901, progress in treating Alzheimer’s has not significantly advanced in comparison with diseases such as HIV and cancer10. Alzheimer’s is the 6th leading cause of death in the United States and between 2000 and 2008, the number of deaths associated with the disease increased 66% while cancer and HIV have significantly decreased9. As well in 2012, it is estimated that $200 billion USD was spent treating/caring for the disease in the United States—compared to $88.7 billion USD for cancer11. With these terrifying statistics, awareness of the disease is of prime importance in fueling research and eventual alleviation of Alzheimer’s.