Originally published April 2, 2015
There is a good chance that you personally know someone suffering from Alzheimer’s disease. This is unsurprising, as it is estimated that one out of every nine people over 65 is affected, making it the most common form of dementia. Initially, someone with Alzheimer’s will show signs of forgetfulness and disorientation which may not be immediately noticeable. A person might find themselves losing their keys more often or asking the same question multiple times in a conversation without realizing it. These symptoms gradually get worse over a period of three to nine years, leading to more severe memory loss, mental and physical impairment, and eventually resulting in death. According to the 2014 World Alzheimer Report, 44 million people are living with dementia worldwide, with the number set to double by 2030. Aside from the devastating emotional costs imposed upon the individuals and their care providers, usually family members, the economic impact of dementia is an imposing figure. In 2010, the cost of care for dementia was $604 billion, with costs expected to exceed $1 trillion by 2030.
Decades of research have revealed several risk factors for the disease, such as age, head trauma, heart disease, and sex (women may be more susceptible than men). Despite information about these risk factors and studies revealing the differences between the brains of people with Alzheimer’s relative to those of healthy people, the exact cause still remains a mystery. In recent years, researchers have discovered many clues that have gotten us closer to solving this mystery. One of the key findings is that the degeneration of the brain in Alzheimer’s is associated with the presence of protein fragments called amyloid beta peptides. Amyloid beta is present in healthy brains as well, but problems arise in Alzheimer’s when these peptides become folded in an incorrect way, causing them to associate with one another and form clumps, called plaques, which deposit in the brain.
Another major finding is that tau proteins, which normally help to stabilize the structural components of cells, can become defective in Alzheimer’s disease, causing them to get tangled up and deposit in the brain. Both amyloid beta plaques and tau protein tangles are quite toxic to nerve cells and eventually result in the death of the neurons that make up the brain. Despite these and a variety of other clues that have been discovered, Alzheimer’s is plagued by the classic chicken-or-egg question: which of the observed problems are causes of the disease, and which ones are a result of the disease process? So far, this question has been very difficult to answer. Only one form of Alzheimer’s, known as early onset familial Alzheimer’s disease, has a definite cause involving a mutation in specific genes that produce amyloid beta proteins. However, these mutations are the cause of only 1 to 5 percent of cases, while the origin of the rest of the cases remains unclear.
The field of Alzheimer’s research is rapidly advancing, with new discoveries made nearly every day. One intriguing recent discovery suggests that an immune response may be responsible for the progression of Alzheimer’s disease. In a March 2015 review published in Nature Immunology, a group led by Michael T. Heneka from the University of Bonn explained some of these recent findings. One of these hypotheses proposed explains that, because amyloid beta is found in several different viruses and bacteria, the body developed an immune system response to the peptide in order to fight off these pathogens. In some cases, the immune response can become misdirected and targets the amyloid beta found in human tissue instead of that of an invader, which is known as an autoimmune response. When the immune system attacks tissue within the brain, it causes damage to the local neurons and leads to destruction of brain tissue.
The immune response in the brain is controlled by cells called microglia. These cells act as the guard dogs of the central nervous system, both defending against infections and scavenging damaged cells and waste found around the brain. Much like certain dogs, they can have extremely strong reactions to even small disturbances. This sensitivity, while quite advantageous for quickly responding to threats, can also have major consequences if they become so sensitive that they start attacking human tissues. Once the microglia are activated, they release molecules that trigger inflammation in surrounding tissue. Inflammation is a process that normally helps to eliminate the initial cause of an injury and help with tissue repair, but persistent inflammation will result in significant cellular damage. Moreover, this response actually makes it more difficult for the body to clear beta amyloid plaques, causing a negative feedback loop that results in even more plaque deposition in the brain.
Adding more evidence to this theory, a new study published in the Journal of Alzheimer’s Disease on February 2015 by the Bieberich lab at Georgia Regents University demonstrated that an autoimmune response might be responsible for the progression of the disease. Researchers have discovered that a molecule called ceramide, mainly found in membranes surrounding cells throughout the body, can be targeted by the immune system. This immune response causes an increase in antibodies that destroy ceramide in the brain. The researchers found that when amyloid beta plaques start to build up in the brain, certain cells begin producing more ceramide. The ceramide is then targeted by the immune system, causing inflammation and increasing the amount of amyloid beta in the brain. These new studies suggest that our own immune response, then, may be what is ultimately responsible for the advancement of the disease.
While we may still not know the root cause behind the mystery of Alzheimer’s disease, these new findings have revealed another important clue, which is that autoimmune responses may play a significant role in the progression of the disease. One of the exciting aspects of this research is that it opens up a whole new set of opportunities to treat Alzheimer’s using therapeutics that target the microglia or reduce inflammation in the brain, which may be able to slow down the progression of the disease. More effective treatments are sure to significantly address the mounting healthcare costs associated with the growing population afflicted with this disease. More importantly, these new treatments have the potential to provide life-altering relief to those currently suffering from Alzheimer’s.