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    Two New Approaches To The Growing Alzheimer’s Disease Problem

    by Bradley van Paridon - March 27 , 2018


    Photo Credit: by Kristina Campbell
    Photo Credit: by Kristina Campbell

    Alzheimer’s disease is one of the leading causes of dementia in North America and health officials estimate that the number of cases will rise dramatically in the coming years. This chronic disease affects the cognitive functioning of patients, which causes a cascading effect of stress and suffering, not only for the patient, but also for their caregivers and family members. This dual cost to society is leading researchers to look not just for cures, but for ways in which we can slow down the progression of disease—lessening the need for constant care by restoring Alzheimer’s sufferers’ independence.

    The Sandwich Generation

    In Canada, Alzheimer’s disease was estimated to affect 564 000 people in 2016 and this number is expected to rise by 66% by 2031. For patients, the struggle begins with short term memory loss and trouble focusing. Soon, this progresses to all-out cognitive decline which results in difficulties completing common tasks and problem solving, changes in personality, confusion, and an inability to communicate via written or spoken word. Once started, this decline does not stop and continues until death.

    The consistent decline in cognitive ability leaves patients frustrated, depressed and filled with anxiety. Often patients undergo mood swings and may withdraw from family and friends. Like most chronic diseases, the decline in health requires that patients receive ever increasing amounts of care. This puts strain on health services—but more often than not the weight falls primarily on family members. Referred to as the “sandwich” generation, increasing numbers of adults struggle to balance commitments to their own kids and spouses while simultaneously caring for an elderly family member. Many of these people themselves report worsening physical and mental health. The reach of this disease beyond the patient reveals the importance of research towards both a cure, and (in the meantime) therapies that can slow down patient decline.

    How Does Alzheimer’s Reduce Brain Function

    Alzheimer’s is a form of dementia linked to a buildup in the brain of a molecule called beta-amyloid peptide. This buildup causes plaques to form, which are toxic to nerve cells. Peptides, referred to also as proteins, are naturally occurring products in the body. They consist of chains of amino acids and perform numerous functions in our bodies, as neurotransmitters or hormones for example. A single peptide can change shape in response to the conditions within our bodies and this allows them to perform different functions.

    One way the shape and functions of peptides are changed is by enzymes—biologically active molecules that cleave amino acids off of the peptide chains. When an amino acid has been removed, the chemical properties—such as the number of and strength of hydrogen bonds between atoms—are changed. The remaining amino acids adjust and new bonds between them are formed, causing a new folding of the chain. This folding then determines the structure and function of said peptide. The beta-amyloid peptide is created when the amyloid precursor protein (APP) is chopped down by one such enzyme. Beta-amyloid is therefore produced by our bodies and must have some function; unfortunately though, it becomes dangerous when it becomes “misfolded”.

    It turns out that there are multiple ways peptides can fold themselves and some of these formations are in fact harmful to the body because the body cannot clear them out. Thus, they form plaques by clumping together in large tangles of misfolded protein.

    Stopping the Formation of Plaque

    One current avenue of research is aimed at preventing the body from creating beta-amyloid altogether. This is a logical approach and focuses on eliminating the enzyme—known as BACE1—that cleaves APP into beta-amyloid. This avenue has been pursued since 2004 and numerous drugs are being tested that inhibit BACE1. Recently, though, a mouse model was developed to better understand the far-reaching consequences of shutting down BACE1 completely.

    Unfortunately, like most enzymes in the body, BACE1 has many functions, not just the role in beta-amyloid formation. Mice in which the gene producing BACE1 has been silenced suffer severe neurodevelopmental defects, indicating that BACE1 is essential to some developmental functions and putting into question the safety of eliminating it in humans as well. So, rather than eliminating BACE1 completely a team from the Cleveland Clinic Lerner Research Institute decide to try a gradual diminishing of the enzyme throughout the lives of mice susceptible to Alzheimer’s.

    To do this they bred mice modified to gradually lose BACE1 as they age, with mice that form amyloid plaques and Alzheimer’s when they are 75 days old. The offspring of this pairing developed normally and by day 75 they were producing 50% less BACE1 than normal and yet, they still began to develop plaques and disease. Shockingly, though, as they continued to age the plaques began to disappear and by ten months of age the mice had no plaques at all.

    According to the research team involved this was the first time such a dramatic decrease in plaques was achieved in the mouse models of Alzheimer’s. Along with the reduction in plaques, there was also a reduction in physical damage to the brain, known as neuritic dystrophy, along with improvements in cognitive function. Like all research in animal models, it must be cautioned that this is simply a first step and much work is left to be done, such as developing drugs that can safely cross the blood-brain barrier and act to inhibit BACE1. However, a few important milestones have been shown here.

    First, the reduction of the plaque and improvements in cognitive function are promising. Second, this research showed that a gradual decrease of the BACE1 protein was able to achieve this. There are still concerns about completely removing BACE1 because of its other functions in the body and any treatment for Alzheimer’s is going to be a long-term affair. But the gradual reduction method demonstrated here is promising for developing treatment of this chronic disease.

    However, while we wait for research like this that offers a chemical treatment and possible cure for Alzheimer’s, a completely different approach is being investigated to slow the progression of disease.

    A Pacemaker for the Brain

    Deep brain stimulation (DBS) is a treatment whereby a device is implanted into the brain which provides electrical stimulation to specific brain regions—much like a pacemaker for the brain. DBS is used to treat a number of neurological disorders like, Parkinson’s disease, tremors, depression and obsessive compulsive disorder. Evidence also exists showing that activating neurons using stimulation techniques, such as DBS, improves cognitive, behavioural and functional impairments. It is this line of evidence that makes DBS an intriguing treatment for Alzheimer’s. Even small improvements in the cognitive function of Alzheimer’s patients would restore some of their independence, reduce their need for care and lower the stress and anxiety levels of all involved.

    A small trial consisting of three patients recently used DBS and was recently conducted at Ohio State University. The DBS devices were implanted into a region of the patients’ brains called the ventral capsule/ventral striatum (VC/VS) in the hopes that they could improve their ability to perform tasks associated with everyday life. According to study co-author Dr. Douglas Scharre, “we have many memory aides, tools and pharmaceutical treatments to help Alzheimer’s patients with memory, but we don’t have anything to help with improving their judgments, making good decisions, or increasing their ability to selectively focus attention on the task at hand and avoid distractions”, all things required to function in everyday life. The goal is to give patients back the ability to do things like make the bed, choose what to eat or socialize with family and friends.

    Results of this pilot study showed that DBS did reduce the decline in cognitive ability normally experienced by those with mild or early stage Alzheimer’s. For one participant this meant she regained the ability to prepare simple meals for herself; something she was not doing prior to the trial. She also regained independence in choosing her clothing as well as planning and going out for day trips. This trial is not proposing a cure, per se, but rather a way to reduce the burden by slowing the rate of decline, something that could go a long way to improving the lives of Alzheimer’s patients and their families.

    The Desire For Cures And Treat

    Searching for cures to chronic diseases is necessary, but alleviating the need for chronic care is another important avenue with near equal value. Buying quality time at the end of life goes a long way to reducing physical and mental pain for elderly people and their families. As the population in western countries rapidly ages, both these streams of research increase in importance and governments and health officials should increase their urgency in supporting them.

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    Dr. Bradley van Paridon is a writer and science communicator who holds a PhD in Parasitology.


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