Alzheimer disease research: progressing forward and giving hope
When Dr. Alois Alzheimer presented his initial findings on Alzheimer disease in 1906, his colleagues were less than impressed. Fast-forward over a century and Alzheimer disease research received $2.8 billion in funding this year from the National Institutes of Health. So, what have we learned over the past century?
In 1906, a former patient of Dr. Alzheimer died of an unknown mental illness. Although he had not been her doctor for several years, Dr. Alzheimer remained interested in her case because of how quickly the fifty-year-old patient’s symptoms of memory loss, language problems, and unpredictable behavior had progressed. Because of Alzheimer’s interest in her case, his former boss sent him the patient’s medical files and samples of her brain tissue after her death.
It was while examining her brain tissue that Dr. Alzheimer found many abnormal clumps and tangled bundles of fibers that he later linked to brain damage and the progression of the patient’s misdiagnosed illness. We now know these abnormalities, referred to as amyloid plaques and neurofibrillary (or tau) tangles, as hallmarks of the devastating neurodegenerative disease, Alzheimer disease.
Alzheimer Disease: Signs, Symptoms, and Pathology
Alzheimer disease is a progressive disease that affects a person’s memory, thinking, and behavior. Since its discovery in the early 1900s, it has become the most commonly diagnosed form of dementia, with more than five million Americans presently living with the disease. At its current rate, this number will triple by 2050.
The healthy human brain contains tens of billions of neurons, or brain cells, that send messages between different parts of the brain, and from the brain to the muscles and organs of the body. Toxic changes in the brain, such as the clumps and tangles of protein that Dr. Alzheimer first saw in his late patient’s brain, disrupt the communication between neurons, ultimately resulting in their loss of function and death.
Amyloid plaques are caused by a buildup of the naturally occurring protein beta-amyloid outside of and between neurons in the brain. These protein bundles disrupt the communication between brain cells, and can eventually kill the neurons.
Neurofibrillary tangles are accumulations of misfolded tau protein inside of neurons. In healthy neurons, tau functions to stabilize microtubules within the neurons which aid in transporting nutrients throughout the neuron. In Alzheimer disease, changes in tau cause it to detach from microtubules and stick to other tau molecules, forming the characteristic tangles in the brain. By disrupting the nutrient supply in neurons, tangles ultimately lead to neuronal cell death.
Neural damage from Alzheimer disease is typically first observed in parts of the brain involved in memory. Consequently, early signs of Alzheimer disease usually involve mild memory loss such as difficulty remembering names or recent events. The damage then spreads to the cerebral cortex, the area of the brain involved in language, reasoning, and social behavior. As the damage progresses, the person’s cognitive impairment increases, leading to more severe memory loss, confusion, difficulty with language, behavioral changes, mood swings, and eventually an inability to care for themselves.
What Causes Alzheimer Disease?
To date, researchers cannot point to one singular causative factor that causes Alzehimer disease. Although it is clear that amyloid plaques and neurofibrillary tangles cause a lot of the damage to the brain, it is still unclear what causes the abnormalities in beta-amyloid and tau protein function.
While researchers have not found a magic bullet to beat Alzheimer disease, they have narrowed in on several risk factors that increase a person’s likelihood of developing the disease. Older age is an important risk factor, with the number of people with Alzheimer disease doubling every five years beyond the age of 65. Age-related changes such as shrinking of parts of the brain, inflammation, vascular damage, and the production of damaging molecules called free radicals, may harm neurons and contribute to brain damage.
Genetics also serve as a risk factor for Alzheimer disease, meaning a family history of the disease increases a person’s likelihood of developing the disease. In addition, researchers have discovered several genetic variants that increase a person’s risk for Alzheimer disease. For example, having a certain form of apolipoprotein E (APOE) gene increases a person’s risk of developing Alzheimer disease and it is also associated with an earlier onset of the disease.
Advances in Alzheimer Disease Research
Although much progress has been made in Alzheimer disease research since the landmark discovery by its namesake in the early 1900s, there is still no cure for it. Researchers, like those at the HudsonAlpha Institute for Biotechnology, work tirelessly to gain a better understanding of the cause and pathology of Alzheimer disease in hopes that they can design more effective methods for treating and preventing the disease. The Myers lab at HudsonAlpha focuses on three main areas of neurodegenerative disease research: discovery, functional genomics, and biomarkers.
HudsonAlpha, along with many collaborators, is sequencing and analyzing thousands of patient samples from within the state of Alabama and around the world to learn more about the genetic causes of neurodegenerative diseases like Alzheimer disease.
HudsonAlpha has identified several new gene candidates and risk variants in relevant genes involved in Alzheimer disease. By discovering new genes involved in the emergence and progression of the disease, researchers can develop new diagnostic and treatment tools.
What does this newly discovered gene involved in Alzheimer disease progression do, and how can we leverage it for treatment? These are the types of questions that researchers in the Myers lab are trying to answer. The lab studies gene regulation, or the way in which genes are turned on and off. By discovering the “on/off” switches of genes involved in Alzheimer disease progression, they hope to be able to develop new treatments that block or slow down the disease.
In addition to the switches themselves, there are also a group of proteins called transcription factors that can bind to the switches and turn them on and off. Developing drugs to stop the transcription factors’ ability to turn on genes that drive Alzheimer disease pathology could prevent the onset or slow the progression of the disease. For example, Nick Cochran, PhD, a senior scientist in the Myers lab, studies the transcriptional regulation of the gene that codes for tau. He recently received a Pathway to Independence (K99) training grant to continue his research and impact on the Alzheimer disease research field.
In addition to discovering more effective diagnostic and treatment strategies, early detection of the disease is also critical for improving treatment outcomes. Researchers in the Myers lab are working to develop a blood test for the early detection of Alzheimer disease.
By studying small pieces of DNA and RNA in blood plasma from patients with and without Alzheimer disease, the researchers hope to find a biomarker for the disease. The discovery of a biomarker would provide earlier detection of the disease, allowing physicians to begin treating patients early in disease progression.