What is Alzheimer’s disease?
Alzheimer’s disease is an irreversible and progressive neurological disorder in which the degeneration and death of brain cells result in memory loss and cognitive decline. It is the most common type of dementia (the ongoing decline of brain function). One in six people over the age of 80 in the United Kingdom suffer from this condition.
Alzheimer’s disease was first reported in 1906 by German psychiatrist Alois Alzheimer in a patient (Auguste D.) suffering from memory loss, progressive sleep, and paranoia. Through the autopsy of the patient, he described “a peculiar severe disease process of the cerebral cortex” and also recognized plaques, neurofibrillary tangles, and shrinkage in and around brain nerve cells.
Figure 1: A human brain before and after being Alzheimer’s disease. There is an evident shrinkage in the size of the brain as the cerebral cortex shrunk as well as the hippocampus. Shrinkage can reduce cognitive function, reducing the brain’s ability to carry out simple tasks.
According to the World Health Organization (WHO), Alzheimer’s disease and other dementias are the 5th global cause of death in 2016 and the 3rd leading cause of death in high-income countries during the same year. Moreover, alarmingly, Alzheimer’s cases are rising steeply every year.
The life expectancy for Alzheimer’s disease varies depending on age. Older adults usually live three to four years whilst younger generations may live for more than ten years.
In this article, we will look into the stages of development of the disease, the assumed effect of Alzheimer’s on the brain, the main contributing factors to this disease, as well as present and possible future research options. We will also look into risk factors for the disease and ways to reduce your risk of developing Alzheimer’s.
The impact of Alzheimer’s on the human brain
As we age, our brain begins to shrink in size, losing small numbers of neurons (brain cells). However, with Alzheimer’s disease, a significant number of neurons die, disrupting communication between neurons and impairing body processes such as metabolism, tissue repair, and memory storage.
As we previously mentioned in the introduction, Alzheimer’s disease is a neurodegenerative disease, in other words, it is caused by the degeneration of brain tissue. The main reason for this deterioration is associated with the build-up of toxic proteins such as an overbuild-up of tau proteins (this will be explained further along this section).
Figure 2: Schematic representation of a neuron, including dendrites, axon terminals and glial cells.
A functioning brain uses the glymphatic system to get rid of toxins and other waste products accumulated on the brain throughout the day. The glymphatic system is very important to avoid an accumulation of toxins in the brain. During sleep, the glymphatic system is involved in clearing the brain from these toxins produced from metabolic waste. This system is managed by the glial cells of the brain (refer to Figure 3), hence the name glymphatic, and involves the travel of cerebrospinal fluid around the brain. In addition, cerebrospinal fluid is found around the brain and spinal cord and provides a mechanical barrier against injuries by acting as a cushion distributing the impact. Additionally, cerebrospinal fluid is also in charge of transporting metabolic waste products, antibodies, and chemicals from the brain to the spinal cord and then into the bloodstream.
As we age, our ability to clear our brain from toxins declines, and thus toxic proteins begin to build up. These toxic aggregates can damage neurons, playing a key role in brain degeneration. Toxic aggregates also disturb brain synapses, thus disturbing brain cell communication and normal body functioning.
There are three key factors in Alzheimer’s disease that interact with each other: amyloid-ß peptides, tau proteins, and chronic inflammation.
Amyloid-ß (Aß) peptide is a product of the cellular metabolism resulting from the amyloid precursor protein (APP). APP is found on the plasma membrane of neurons and generates amyloid-ß through enzymatic action, which can then be released into the extracellular space, where it can cause toxic build-ups and block neural receptors. Neurons, particularly those in the cortex and hippocampus, can create amyloid-ß. Even though the exact role of amyloid-ß is still under research, it has been linked to memory, brain synapses (chemical transfer of information between neurons) and neurogenesis (formation of neurons).
Nonetheless, an accumulation of amyloid-ß in the brain has been linked to Alzheimer’s disease even though the clear process by which this happens is still unclear. A build-up of amyloid-ß in the brain can form plaques around neurons, enveloping dendrites and interfering with brain synapses. The current amyloid hypothesis suggest that a misfolding of extracellular Aß protein found in senile plaques (extracellular deposits of amyloid-ß in the brain’s grey matter also known as amyloid plaques) can cause initial memory loss and cognitive decline over time. This is accompanied by the intracellular deposit of tau proteins in neurofibrillary tangles (insoluble fiber “tangles” inside neurons).
Tau proteins are proteins found in the axon of neurons (where signal transmission occurs). They are involved in maintaining the structure of the axon as well as transporting nutrients and other substances from different parts of nerve cells through their microtubule conformation. When an overaccumulation takes place, such as the one found in dementia patients, neurofibrillary tangles form. These tangles form due to hyperphosphorylation (adding an extra phosphate molecule) of tau proteins of neurons, a process in which Aß proteins are believed to be involved. This hyperphosphorylation causes the tau proteins to aggregate in an insoluble form resulting in the curling and tangling of neuron axons as well as collapsing the microtubule structures needed for transport.
Neurofibrillary tangles form within the neuron and interfere with the creation and recycling of proteins, killing the cell. The build-up of tau proteins is believed to be caused by the accumulation of amyloid-ß, but this theory is still to be proven as tau proteins are also believed to influence the toxic effects of amyloid-ß. Moreover, non-toxic amounts of amyloid-ß utilize tau proteins, turning into toxic amyloid-ß likely through the NMDA neurotransmitter receptor. What is for certain is that amyloid-ß and tau proteins are both involved together when forming toxic accumulations.
Another factor that is now believed to contribute to Alzheimer’s is inflammation. Inflammation is an immune system response to disease and a side effect of dementias. Until recently, inflammation was believed to help the body fight the disease, but recent studies have shown that inflammation does in fact contribute to the disease progression. This was first observed in patients with arthritis (pain and inflammation in joints) that receive anti-inflammatory drugs have a lower Alzheimer’s incidence. In Alzheimer’s patients, whilst reduced inflammation has a neuroprotective role, chronic inflammation and its consequent immune response have been proven to aggravate both amyloid-ß and tau proteins accumulation as well as being possibly linked to the initial accumulation of amyloid-ß.
When inflammation occurs, toxic products are produced such as nitric oxide. It has been shown that in patients who recently died from head trauma (injury in the brain that produces an inflammatory response), there were increased levels of interleukin 1 (IL-1), a type of cytokine (proteins that regulate immunity). IL-1 cytokines are responsible for APP production and thus amyloid-ß as well as an increase in amyloid-ß deposits. Moreover, high levels of IL-1 triggers the production of other cytokines, such as IL-6. High IL-6 levels trigger the activation of a kinase enzyme (CDK5) which is in charge of the hyperphosphorylation of tau proteins, resulting in neurofibrillary tangles. In other words, an overtime constant inflammatory immune response has been linked to a higher production of amyloid-ß and to the coiling of tau proteins.
Aside from toxic build-ups inside and outside of neurons, vascular issues have a significant impact on brain function and prompt Alzheimer’s disease. Vascular issues include strokes, atherosclerosis (build-up of fats and cholesterol on artery walls, hardening arteries and restricting blood flow.), and amyloid-ß deposits on arteries. These restrict blood flow and with it, oxygen transport to the brain as well as harming the blood-brain barrier. The blood-brain barrier helps protect against incoming toxins getting inside the brain as well as facilitating the entrance of nutrients and glucose needed for brain function. In a patient with Alzheimer’s, the blood-brain barrier is damaged and nutrients aren’t able to go in as well, preventing the clearing of amyloid-ß plaques and neurofibrillary tangles. In turn, this then leads to inflammation, resulting in the three main triggers for neuronal decay that we previously mentioned as well as aggravating vascular issues.
Figure 3: The different parts of the brain.
The stages and symptoms
Alzheimer’s disease can be classified into different stages based on brain tissue degradation and cognitive function decline.
Preclinical Alzheimer’s disease: This stage is the one that precedes any symptoms. It is usually only recognised during research studies. This stage is mainly identified by initial deposits of amyloid-ß peptides (please refer to the section “brain and Alzheimer’s” for a more detailed explanation). Research is now being carried to utilize these early signs to stop the disease.
Mild cognitive impairment (MCI): This stage is characterized by mild changes in thinking and memory capabilities such as having trouble recalling recent (less than a year ago) events and having trouble judging the length of a task or how many steps it involves. It is also important to point out that not all cases of MCI lead to Alzheimer’s disease.
Mild dementia: This is the stage where Alzheimer’s is usually diagnosed and it is when daily tasks start to become challenging for the patient. Examples of characteristic behaviours of this stage include getting lost easily, taking a longer time to perform daily tasks, or behavioural changes. It is here that dementia affects neurons in the entorhinal cortex and hippocampus involved with memory (refer to Figure 3).
Moderate dementia: It is at this stage that the patient requires assistance to complete daily tasks. Here, the disease has affected the cerebral cortex (refer to Figure 3) that is responsible for social behaviour, language, and reasoning. Symptoms include greater memory loss, inability to learn new things, impulsive behaviour, hallucinations, and difficulty recognizing family members and friends.
Severe dementia: Here, amyloid-ß plaques and neurofibrillary tangles are present throughout the brain. The brain shrinks in size considerably (refer to Figure 1) and it leads to absolute dependency on others, inability to communicate coherently, and decline in physical abilities.
Risk factors
Although risk factors related to Alzheimer’s disease are widely studied, there are a lot of inconsistent and unknown ideas surrounding Alzheimer’s research in science today.
It has been widely studied whether other types of genetic conditions such as having Down syndrome impact the risk of developing dementia and later Alzheimer’s disease. Down syndrome also causes an amyloid build-up in and around the brain and this is what may cause Alzheimer’s in some individuals. Additionally, age is a risk factor widely accepted to be the most significant one. According to the NHS, the chances of developing Alzheimer’s doubles every five years after reaching the age of 65 years. This is not to be confused with Alzheimer’s only impacting older individuals as around one in 20 people who have the condition develop symptoms at ages less than 65 – called early – or young-onset Alzheimer’s (for individuals around the age of 40 years). As with many other conditions, genes can be a factor influencing the onset of Alzheimer’s in people. Although not thought to be significant, our family histories can impact the risk of developing the condition. In a small number of generational families, Alzheimer’s could be linked to a single gene, which, in turn, allows for a significantly larger risk of developing the condition later on in life.
There are also some genetic risk factors to consider:
Heritable amyloid precursor protein (APP) gene mutation, which results in amyloid-ß and thus in the formation of amyloid-ß plaques.
Presenilin gene mutation. Presenilin is a protein involved in the conversion of APP into amyloid-ß.
Apolipoprotein E4 (ApoE4) gene mutation, linked to increased cardiovascular risk. As we previously mentioned, heart disease has been linked to a higher risk of Alzheimer’s. We all have two copies of the ApoE gene that we inherit from our parents. This ApoE gene has three variants that can be possibly inherited: ApoE2 gene which helps protect against Alzheimer’s (rare gene), ApoE3 gene which plays a neutral role for Alzheimer’s, and ApoE4 gene which increases the risk of Alzheimer’s by three-fold.
Even our everyday habits may influence the risk of developing Alzheimer’s in the future. Aspects of cardiovascular disease have been linked to this. This is nearly directly correlated with our everyday lives. Helping to reduce the risk of developing the disease includes stopping smoking, living a physically, mentally, and socially healthy life, and drinking less alcohol. Loneliness and depression have been linked to this as well, as they usually result in lack of sleep, physical inactivity, and increased blood pressure, all of them referred to above as drivers for cognitive decline.
Therefore, it is important to realise that it is not only our physical bodies and the learning of new information that lowers the risk of this, but it is also the deeper conditions and actions we expose ourselves to every day.
Treatment
There is currently no drug nor cure available to stop or reverse the action of Alzheimer’s disease but there are treatments to manage its symptoms. Some of the current solutions include:
Immunotherapy is being utilized as an alternative therapy for dementia. Immunotherapy uses the body’s own immune system to create antibodies that can target amyloid-ß and tau protein aggregates.
Ultrasound is also being explored. As the brain is of difficult access from the outside due to the skull and the blood-brain barrier, ultrasounds allow for the temporary opening of the blood-brain barrier and drugs can access, generating a different way to deliver drugs to the brain with higher bioavailability. A team at the University of Queensland led by Professor Jürgen Götz has recognised ultrasounds as a possible method to clear the amyloid-ß deposits on the brain, restoring memory. They have also found that scanning ultrasound also helps deliver antibodies that could be effective against tau protein accumulations.
Recently in 2019, a research team from Forschungszentrum Jülich and Heinrich Heine University Düsseldorf, have developed a drug that could help treat Alzheimer’s. The drug has been named PRI-002 and it has passed the first phase of human testing.
PRI-002 has been shown to eliminate toxic amyloid-ß plaques. During the human trial, patients took daily dosages of the drug for 4 weeks and are safe for use. The drug has now moved into the second phase of clinical trials.
There has also been research into other ways to clear out or dissolve amyloid-ß plaques such as the study carried by Dr. Matthew Campbell where they temporarily disrupted the blood-brain barrier to dispose of existing amyloid-ß plaques. By disrupting the blood-brain barrier, larger molecules, such as amyloid-ß plaques, can leave the brain to be excreted, reducing the build-up within the brain. Nonetheless, it has been found that clearing out amyloid-ß plaques alone is not sufficient to tackle Alzheimer’s disease.
Other treatments to alleviate symptoms and to allow patients to carry on with their day-to-day lives include medication against common symptoms like aggression or sleepiness as well as maintaining mental function.
Aside from these, it is of good practice to follow these behaviours to delay Alzheimer’s and other dementias:
Looking after your heart and having balanced levels of cholesterol, blood pressure or avoiding obesity as they can turn into vascular issues.
Exercise and follow a healthy diet to stimulate new neuron production, reducing cognitive decline.
Engage your brain through reading, studying or games such as sudoku to strengthen memory pathways through social engagement.
Why you should care?
Alzheimer’s disease is one of the leading causes of death worldwide and affects the lives of millions of people. Throughout this article, we have presented the assumed effects of Alzheimer’s on the brain and body as well as present treatments and how to reduce your risk of having it. The brain is one of the most complex systems in the body, and the majority of its function is still being studied. Many novel treatments for Alzheimer’s disease as well as other dementias are under research, and some very exciting advances are being made.
Author
Covadonga Piquero Lanciego
BSc Biological and Biomedical Sciences
University of Dundee