Why People Become so Forgetful Once They Get Alzheimer's Disease?
Have you ever heard about a disease called Alzheimer's? I bet most of you probably have heard of it from somewhere, even though you might not know exactly what it is. For many people who are out of the science world, "Alzheimer's" means the same thing as "senile dementia", which is actually incorrect if you speak scientifically. More interestingly, "dementia" itself has two different meanings in the clinical realm and the lay public. "Demented" is generally used by the lay public synonymously with "mad" or "insane". In clinical term however, dementia refers to a specific and pronounced decline of cognitive function in humans - a decline in mentation. (In Latin, dementia means "apart from mind".) "Senile dementia", often shortened as simply "dementia", refers to the progressive cognitive decline found in elderly people beyond what might be expected from normal aging, which is usually due to damage or disease in the brain. In specific, dementia can arise from a number of causes such as stroke, vascular problems, some medical conditions, or the abuse of drugs or alcohol. But among them, a pathological condition called Alzheimer’s disease (AD) is the most common cause of senile dementia. Because of this, it becomes that the two terms, AD and dementia, are often used interchangeably in public content. However, please keep in mind that there are other causes that can lead to dementia besides AD.
In 1906, a German psychiatrist Alois Alzheimer first described the disease that eventually bears his name. He wrote of a 51-year-old woman named Mrs. Auguste D who had "a strange disease of the cerebral cortex" that manifested as progressive memory impairment and other behavioral and cognitive problems. After Mrs. Auguste D. died in 1906, Dr. Alzheimer carefully examined her brain anatomy and neuropathology. He presented Mrs. Auguste D's case to the German psychiatrist community and described the neurofibrillary tangles and amyloid plaques that were found in Mrs. Auguste D’s brain (Alzheimer, 1907). “Tangles” and “plaques” have then come to be considered as the two main pathological hallmarks of the disease.
Simply speaking, the plaques are admixtures of a bunch of junks that brain produces. They are found in the extracellular spaces, i.e. the outside of the brain cells. A typical senile plaque usually contains lots of aggregated proteins called amyloid beta (Ab). Scientists have no idea why our brain produces such protein since it appears to have no function roles. As this junk protein aggregating into a toxic dense core, the nearby dendrites and axons (the extensions of neurons) are affected and start dying. In contrast to extracellular plaques, the second pathological hallmark of AD is localized intracellulary, i.e. inside of the cells. Many people may have an impression that a cell is like a small squishy water balloon (at least I used to think so), which of course is not true. The cell actually has its own skeleton structure inside that supports its external shape. It is called microtubule cytoskeleton. In AD, these microtubules and mircofibrils become tangling up with each other for some reason. And eventually the tangles cause the collapse of the cytoskeleton, which leads to the cell death. Remember how your kitten can make a ball of wool into a fearful tangle? Same thing can happen in our brain, but we haven’t yet found that "naughty kitten" which causes the neurofibrillary tangles.
Please don't think tangles and plaques are unique in Alzheimer's. Your brain is also producing plaques as you reading this line. Tangles and plaques can be found in many normal non-demented elderly, but rather in a very reduced number and would not cause severe neuronal loss and dramatic cognitive problems. One major task for AD researchers is to find out why the plaque and tangle forming processes are much more accelerated and pronounced in AD.
Now you are probably wondering how these pathological alterations at the cell level can lead to the behavioral and cognitive changes in AD patients. Among the symptoms of dementia caused by AD are losses of learning and memory capacity, decline in reasoning ability, attention problems, language difficulties and problems with perception. Forgetfulness is the most typical presenting symptom showed by AD patients in the beginning stage. These patients can remember how to talk, and may remember events from many years ago, but they have trouble remembering what happened in the past hours. Episodic memory formation is lost as the patients typically lost the recollection of their ongoing experiences on a daily basis. Common examples of memory deficits in this stage are the repetition of questions or statements and the misplacement of items. The patients at this early stage of AD are unable to recall recent conversations or events, whereas the past life experience and knowledge learned years ago are still retrievable, clearly showing the impairment in new information acquisition but not in the retention of old memory.
These early symptoms of AD remind the scientists of the cognitive changes manifested by another group of patients who lost their hippocampus. Hippocampus (meaning “seahorse” in Greek) is a structure located in the medial temporal lobe of our brain. It got its name from its curved shape in coronal sections of the brain, which much resembles a seahorse. Today, the hippocampus is generally believed to play a crucial role in the formation of new declarative memories about experienced events. A fancy scientific term of this process is called “memory consolidation”. In brief, the hippocampus serves as a short-term memory store that eventually uploads memory to the neocortex for longer-term storage. I know many people like to draw an analogy between human brain and computer (indeed, in Chinese language, the word “computer” literally means “electronic brain”). If you look the brain as a super powerful computer, the hippocampus will be its RAM (random access memory) which temporarily stores information and later uploads them to the hard disk, i.e. the neocortex, for permanent storage. What if the function of the hippocampus is disrupted? Let’s look at the famous case of a patient named H.M. H.M. is an unfortunate victim of neurosurgical experimentation who had his medial temporal lobes removed as a treatment for epilepsy, the removed parts including most of his hippocami on both sides of his brain. The lesion partially treated the epilepsy but essentially completely destroyed H.M.’s capacity of forming long-term memory. He became unable to form any new long-lasting declarative memories (anterograde amnesia) and has been living a minute-to-minute existence for the past five decades of years. However, his prior memories are mostly intact for his lifetime up to several years before the surgery and he is able to consistently recall them (Scoville & Milner, 2000).
Surprisingly, most AD patients in the initial stages have shown the same memory problems experienced by H.M. You then might be thinking, oh, maybe there’s something wrong with their hippocampus! And that’s exactly what the scientists have found out. Early in the course of AD, plaques and tangles are found particularly abundant in a brain region called “entorhinal cortex” which sits right next to the hippocampus. This region is like a gateway to the hippocampus, and all the information going into or going out from the hippocampus have to pass through it. Without the input from the entorhinal cortex, the hippocampus cannot function properly. Very soon, the hippocampus itself gets occupied by the plaques and tangles, thus loses its ability to establish or consolidate memory for ongoing events. As the disease progresses, the plaques and tangles also start to spread out to other brain structures, meanwhile the initially affected areas are worsening. In brief, the circuitry that is critical for normal declarative memory, i.e. the hippocampus and its adjacent region appear to be the first target affected by AD neuropathology such as plaques and tangles. That is why people start to become so forgetful once they get Alzheimer's disease.
The sadness is that the “forgetfulness” is only a start for AD patients. As the plaques and tangles start to spread out to other limbic regions and cerebral cortices, patients in the middle stage have even more profound anterograde memory loss and also start to show retrograde amnesia. That is, recalling remote memories of long past life experience and events becomes difficult now. Recognition of known individuals progressively declines and verbal communication becomes incoherent. In many cases, AD patients also display mood disorders such as severe depression, since these victims are aware that they are deteriorating mentally and are “losing” loved ones. Eventually in the final stages of AD, during when the whole neocortex as well as other brain structures are profoundly affected by tangles and plaques, the patients become unable to execute the most basic cognitive functions, thus are unable to take care of themselves. They are completely bedridden until death.
In these days, AD affects up to half million of people in Canada (Canadian Study of Health and Aging Working Group, 2000), 4 million in US, and 12 million worldwide over the age of 65. It is estimated that by the year 2025 the number will go up to 20 million worldwide given the fact that at present there is no effective treatment for this disease. These dry statistical numbers probably don’t mean much to you at first glance. Let's look at it in this way then. Right now, about one in ten people over the age of 65 in North America have AD. If you live to age 85, you have about a one in two chance of developing this tragically debilitating disease. To me these statistics are sobering, especially given that we don’t have any effective treatment for AD. Since last century, human longevity has been greatly increased worldwide due to our expanding knowledge in biology and great improvement of health care and public hygiene. In the 18th century, the average human lifespan was around 30 years. But in the year 2005, the average life expectancy in Canada was estimated to be 80.1 years. Some scientists predicted that the USA would have 5.3 million people aged over 100 in 2100. Yes, thanks to the great Science. Nowadays we human are able to treat lots of disease and actively change our living environment to accomplish our longevity dream. But, today’s scientific advances are only able to make our bodies live longer, not our brains. It appears that our brain has a shorter “lifespan” than our bodies. Our brain starts to gradually degenerate irreversibly as early as in our 20's. In addition to the “normal aging”, we are facing more aggressive neurodegenerative conditions such as Alzheimer's that we haven't yet found a weapon to fight against. Does it make sense to become a centenarian while losing the ability to recognize your loved ones and losing all the precious memory from your past life? I don't know yours but my answer is a big NO. We need a healthy and functioning brain to make our longevity meaningful. While scientists worldwide are working so hard to seek treatments for Alzheimer’s and other brain diseases, please remember that your brain, just like the rest of your body, need to be looked after. It is your own responsibility to take care of your own precious brain.
Reference: Alzheimer A. (1907) Uber eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin. 64:146-48.
Canadian Study of Health and Aging Working Group: Canadian Study of Health and Aging Working Group. (2000) The Incidence of Dementia in Canada. Neurology. 55: 66-73.
Scoville WB, Milner B. (2000) Loss of recent memory after bilateral hippocampal lesions. 1957. J. Neuropsyychiatry Clin. Neuroscie. 12:103-13.
