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It is likely that most of us, especially if we are hopeless romantics, had heard about the book or movie called „The Notebook“. In this two-hour romantic drama we are led through a wonderful and a bit painful story of a young couple who, against all ods, managed to grow old together. However, „The Notebook“ shows us much more than just a romantic love story – it also shows us the tragic lives of some 50 million people around the world whose memories and families fade away due to dementia.
A bit of statistics, numbers and pathophysiology
Although there are multiple types of dementia, Alzheimer’s disease (AD) is the most common one by occupying 60-70% of all dementia cases. Depending on the lateness of its appearance, AD is divided into either sporadic or familial. According to current information only 5-15% of Alzheimer cases are genetically conditioned, being the early type of familial AD which sets in around the age of 40. The rest of the cases are made up of sporadic Alzheimer’s which usually sets off after the age of 65 with an unclear etiology.
The oldest theory about the progression of Alzheimer’s is based on extracellular deposits of amyloid β proteins and intracellular clusters of neurofibrillary strands of tau protein. Sadly those clusters of strands are still only observable in the brain tissue of post-mortem patients, while reliable methods for early detection still do not exist. A significant loss of brain mass is also observable upon death, primarily in the hypothalamus area whose primary task is keeping memories. The decline of cholinergic neurons and the cessation of cholinergic communication is the actual cause of memory loss which is only noticeable once those neurons and memories are lost permanently.
Differential diagnosis and mental status estimation are the two main diagnostic tools for Alzheimer’s with imaging techniques such as MRI, CT and PET being introduced much later along with different genetic tests to serve as a supplement to differential diagnosis. Even though such techniques are far more advanced than clinical tests or a doctors diagnosis, we are still unable to confirm Alzheimer’s on time.
What about therapy?
As far as therapy goes, things don’t seem much brighter than diagnostics. Out of only 6 currently registered medications, 5 serve to suppress symptoms such as memory loss, disorientation and insomnia while only one of them is capable of actually slowing down the diseases’ progression.
The larger group of medication is made up of cholinesterase inhibitors. As their name suggests, they inhibit certain enzymes responsible for decomposing acetylcholine – the main cholinergic messenger responsible for communication between neurons and information transfer. The idea is to stop any further cholinergic neuron loss, thus also putting a stop to memory loss, speech impediment or disorientation. This group is made up of three medications: donepezil which is approved for all stages of Alzheimer’s, rivastigmin and galantamin approved for mild to medium stages.
Memantin is a modulator of glutamate receptors and is used to treat medium and late stages of AD. Although glutamate on its own as a neurotransmitter doesn’t play a role in forming and processing new information, it is key to shaping memories and their repeated activation, in other words remembering. The most common clinical practice is starting therapy with memantin or one of the cholinesterase inhibitors, but usually it is necessary to combine them quite soon.
One of the symptoms of Alzheimer’s is insomnia, causing patients to wander around during the night which can significantly affect their safety. For this reason suvorexant, a selective antagonist for orexin receptors, is often introduced aswell. Orexin is a neuropeptide responsible for maintaining wakefulness and appetite, and inhibiting its receptors causes the opposite – sleep. Thus, its primary indication is narcolepsy.
The only so far registered medicine known to affect the course of the illness is a monoclonal antibody – aducanumab. It is an anti-amyloid β antibody administered intravenously and its effectiveness compared to the other medications still remains questionable.
New ideas, new approaches
Owing to shortages of effective therapy it has become evident that we require new ideas and different approaches to treating Alzheimer’s disease. As such it has been discovered about fifteen years ago that a key role in the pathophysiology of AD is played by insulin resistence present locally in the brain. Alzheimer’s disease has since in scientific circles taken on the name of „type 3 diabetes“, which opened up new paths of treatment.
One of the more recent groups of medications used in therapy of diabetes consists of GLP-1 receptor agonists. GLP-1, that is glucagon-like peptide 1, is incretin whose physiological role activates after and during a meal. GLP-1 is excreted in the intestines, and through circulation reaches peripheral organs such as the stomach, pancreas, liver and muscles. Although a part of peripheral GLP-1 hormone also reaches the brain, the majority of this incretin required for the brain is also synthesized within it. Since the birth of this idea and theory until today, many pre-clinical trials have proven the role of the GLP-1 signalization pathway in proliferation and survival of neurons, especially in the regions of hypothalamus and hippocampus which happen to be the focal point in the pathophysiology of Alzheimer’s. Activation of GLP-1 receptor sets off intracellular signalization pathway which in the end inhibits apoptosis and encourages cell survival and proliferation.
What’s interesting, some research has shown that the activation of GLP-1 receptor could have a role in coactivation of insulin receptor in the brain, thus maintaining neuronal sensitivity to insulin. Why is this important? Decreased peripheral tissue sensitivity to insulin is present in type 2 diabetes. Essentially, this means that the cell is “blind” to food and does not recognize glucose. At the brain level, this means that neurons are “starving” and gradually dying out and GLP-1 agonists seem to prevent that from happening.
This interesting link between the two seemingly unrelated diseases has also triggered clinical trials of the efficacy of intranasally administered insulin and GLP-1 receptor agonists in the early stages of AD. Unfortunately, the results so far are not promising, so there are still no official guidelines and recommendations. At the same time, an attempt is being made to find a bypass pathway by which we could activate the GLP-1 receptor signaling pathway, without its direct activation. One idea is administrating galactose. Yes, that’s right, simple galactose which seems to activate GLP-1 signaling pathway via glucose receptor activation. Oral and intravenous administration of galactose in animal models of AD is currently being investigated in preclinical studies.
Alzheimer’s disease is a silent killer that takes the lives of the living, and there is still no effective therapy. All that is available for now are just straws of hope and salvation. Every new, fresh look at AD is therefore valuable and appreciated, but fortunately, there have been quite a few ideas lately. What is even more important than therapy is timely diagnosis, but this is a separate topic that we will discuss some other time, hopefully in a bit more optimistic tone.
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