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A German psychiatrist Alois Alzheimer first observed some strange behavioral symptoms, including short-term memory loss in his patient Auguste Deter. Upon her death, he carefully studied her brain and found some anomalies, of what later became known pathological hallmarks of Alzheimer’s disease. Alzheimer’s disease (AD) is a common form of dementia that is associated with progressive decline in memory, cognition and loss of thinking ability. Upon progression of the disease, it can be serious enough to interfere with activities of our daily life. AD accounts for up to 60-80% of total dementia cases. Patients diagnosed with AD lose their ability to be self-reliant, thereby needing support of their family as a care-taker or from healthcare providers. While the financial burden of providing a caretaker is significant, what affects the most is the emotional burden to the patient and their immediate family members of the deterioration of memories.
It is very stressful to know that someone in the world develops dementia every 3 seconds. There were an estimated 46.8 million people worldwide living with dementia in 2015, while it is believed to have touched 50 million in 2017 (Prince et al. 2015). In America alone, there were 5.7 million people diagnosed with Alzheimer’s dementia. By 2020, this number is projected to rise to nearly 14 million (Alzheimer Association 2018). The magnitude of the disease can be imagined when we think that between 2000 and 2015, the deaths from heart diseases have reduced by 11%, while the death from Alzheimer’s have increased by 123%. Currently, the caregivers provide an estimated 18.4 billion hours of care valued at over $232 billion. Early and accurate detection of this disease could save the taxpayers up to $7.9 trillion in medical care and costs (Alzheimer Association 2018). However, the current treatments available for Alzheimer’s type dementia cannot reverse the damage that has already been caused but is more focused on merely treating the symptoms. More about the current therapeutic strategy for Alzheimer’s will be mentioned in detail in the next section.
Currently, there are 5 therapies that have been approved for treatment of Alzheimer’s disease. Four of these, namely – tacrine, donepezil, rivastigmine and galantamine are classified as Cholinesterase inhibitors, while memantine is a N-methyl-D-Aspartate receptor (NMDARs) antagonist.
Acetyl choline is a chemical neurotransmitter released into the synaptic space by the pre-synaptic neurons. These neurotransmitters then bind to acetyl choline receptors on the post-synaptic neuron and is believed to help in cognition. To regulate this process, there is presence of acetylcholinesterase in the synaptic space, which degrades acetyl choline to acetyl CoA and Choline (Figure 1). The cholinergic hypothesis of AD states that in memory loss and deterioration of other cognitive and noncognitive functions can be attributed to impairment of cholinergic systems in the basal forebrain. This is due to the loss of acetylcholine neurons, loss of enzymatic function for acetylcholine synthesis, and degradation by the action of acetyl cholinesterase. Hence, using inhibitors of acetyl cholinesterase would enhance the cholinergic transmission by binding to acetyl cholinesterase in the synaptic space and blocking degradation of acetyl choline. This would lead to increase the availability of acetyl choline in the synaptic space, thereby helping neuronal transmission (Figure 1). These inhibitors have been approved by the FDA for mild to moderate AD and have been regarded as standard and first-line treatment for Alzheimer’s.
The only available medication for AD that affects the function of NMDA receptor (NMDAR) is Memantine. While excitotoxicity in mid-stage Alzheimer’s is believed to contribute to neurodegeneration, the exact role of glutamate in AD remains unclear. Memantine opposes the effect of glutamate in the brain and believed to halt the progression of neurodegeneration. Memantine binds to open channel of NMDAR’s and blocks the influx of Ca2+ into the cell. Memantine is believed to bind to the Mg2+ pore of NMDAR and is hence called trapping channel blockers of NMDARs (Figure 2). These inhibitors result in slight improvement in cognition and memory. Note, memantine has been approved by FDA only for severe AD.
It's often quoted that no drug comes without its own limitations. Using acetylcholinesterase inhibitors increases acetyl choline signaling in CNS. However, note that acetyl choline not just acts on the central nervous system (CNS), but also activates the peripheral nervous system (PNS). These medications can hence cause common side effects like nausea, gastrointestinal (GI) upset, and diarrhea. Some of the other less common side effects include muscular weakness, syncope, and significant weight loss on occasion. A drug with most adverse side effects is rivastigmine, where only a limited number of patients can tolerate the full dose of 6mg twice daily. (Refer paper for more limitations)
While memantine’s action on NMDAR is believed to halt the progression of neurodegeneration, we also know that NMDARs play a key role in controlling synaptic plasticity and memory function. Depending on specific NR2 sub-unit type of NMDAR is present (NR2A or NR2B), blocking NMDARs impair synaptic plasticity, and compromises learning and memory. Hence, it is important for memantine to not block all NMDARs and memantine meets this criterion since it only blocks NMDARs which are in open state or is overstimulated. The clinical significance is only seen in case of severe AD and the cost is also considerably high for this drug. Note that there are other trapping channel blockers like ketamine, which has strikingly similar channel blocking properties to memantine, but exhibit dissimilar clinical effects and hence not been approved for clinical use. Recent phase III trials have shown Memantine’s efficacy in moderate to severe AD.
Basic question for any family whose dear ones are diagnosed with Alzheimer’s in its early stage is how clinicians decide on the prognosis. It should be noted that there are no established guidelines on the prognosis for Alzheimer’s. If the patient is diagnosed with Alzheimer’s early enough, then they are put on acetyl cholinesterase inhibitors (ACheIs). Synergistic effect of ACheIs with Memantine has been observed in moderate to severe AD. In early stage AD, synergistic effect of drugs has not been observed.
To summarize, the existing drugs do not treat the underlying cause of the disease and only slow its progression modestly. Hence, many research groups have now been focused on finding a more efficient drug for treatment of Alzheimer’s that could treat the underlying symptoms. We know that neuroinflammation plays a key role in progression of Alzheimer’s disease, and molecular targeting of microglial proteins involved in neuroinflammation is crucial. To understand this, we need to carefully evaluate the signaling pathway involved in neuroinflammation, which is precisely what my project will be focused on.
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