It’s a thief. It steals. It steals the things which everyone holds dearest. It deprives us of what we believed we could never be deprived of. It’s a cruel and ruthless villain without remorse, as it takes the best and brightest among us and clouds them in confusion and contradiction, dimming or diminishing their light before the end of life. This villain is Alzheimer’s Disease and one of our dear friends has become its victim. She is an amazing woman who is being robbed of her identity, her memories, and her history.
That’s what caused me to read The End of Memory: A Natural History of Aging and Alzheimer’s, and what has caused me to decide to continue to seek more information. I want our friend Mary back. Not the shell that the disease has left behind, but all of her. Unfortunately, The End of Memory doesn’t answer all the questions but it does clear up some misconceptions about the disease.
Who is going to get Alzheimer’s disease? That’s a terrifying and confusing question. More women seem to have the disease; however, the disease gets progressively more common based on age, and women live longer than men. It’s estimated that it impacts 10% of people over sixty-five and nearly 50% of those over eighty-five. There are numerous other factors that impact whether you’ll get the disease. For instance, a mutation of “presenilin 1” seems to cause early onset Alzheimer’s disease.
In fact, James Watson, the co-discoverer of DNA, had several sections of genes where indicators were for Alzheimer’s, so that no one would know what his genetic risk factors were. The risk factors aren’t isolated to one gene or one chromosome. In fact, chromosome 21 – the one associated with Down’s Syndrome – controls the production of Amyloid Precursor Protein (APP), which as we’ll see plays a major role in Alzheimer’s. Presenilin 2 is another marker for early onset Alzheimer’s disease, but genetically speaking it’s far and away from Presenilin 1 – and chromosome 21.
The last and perhaps most interesting gene is apolipoprotein E or APOE. There are three variants of this gene. The variant APOE2 reduces the risk for Alzheimer’s substantially (but not dramatically) for the roughly 7% of people that have it.
While genetic markers can account for a non-trivial portion of Alzheimer’s cases, it falls way short of a majority vote into whether you’ll develop the disease or not. The way that you know if you have the disease – besides the obvious cognitive impairment – is the presence of plaques and tangles.
Plaques and Tangles
Alzheimer’s Disease is notable because, historically, it’s been diagnosed post-mortem. The victim’s brain was examined posthumously, and the presence of what are called plaques and tangles are supposed to indicate the presence of the disease, as it was with patient zero. However, there’s a problem. These plaques and tangles appear in people without any (even mild) cognitive impairment at the time of their death. Conversely, some patients experiencing dementia have no plaques and no tangles. So it seems that most of the disease’s long history has been focused on the artifacts of the disease, but not necessarily the cause.
Plaques in the Intercellular Space
The first of two diagnostic criteria is the presence of plaques which reside in intercellular space (that is, the space outside the neurons of the brain). Plaques are the clumps of discarded amyloid beta proteins. They come together because their shape makes them sticky. However, what is amyloid beta? Well, it’s a part of the amyloid protein that has a variety of uses in the neurons of the brain. In the brain it is rare in that a protein is created and then sliced up by special enzymes. Some of the frequently unused segments of the amyloid are called amyloid beta. The role of amyloid and the amyloid precursor protein aren’t well understood, but it’s clear that there are many functions.
Plaques have been the target of therapies to improve the results for patients with dementia – and presumably Alzheimer’s disease. Some therapies have demonstrated marked reduction in plaques with no change in the cognitive impairment of the patient. This is bad news for trying to point to the plaques as the cause of Alzheimer’s disease. That means that the cause is elsewhere, perhaps in the tangles.
Tangles: Twisted Girders of the Neuron
Neurons have really interesting shapes. They reach out and touch other neurons via axons. Something has to maintain that shape of the cell. That’s the job of tau. Tau is a protein that allows a neuron to form its shape – and therefore its connection with other neurons. Tau is a normally rigid protein that keeps its shape, thereby maintaining the shape of the neuron. However, tau can also be changed to allow neural plasticity. This plasticity can be accelerated through the introduction of phosphorylate. When in periods of higher learning, the tau experience high levels of phosphorylation, and can therefore change shape.
The problem comes when tau become tangled because of too much flexibility. These tangles are like the twisted girders of buildings torn apart by a tornado or a bomb. The original structure is absent, and all that remains is a mess. In the pathology of Alzheimer’s disease tangles – the mess of tau – are the intracellular indicator of problems.
Interestingly, the rate of tangles nearly directly predicts the level of cognitive impairment for a patient. That is, by looking at the number of tangles, you can reasonably predict the cognitive impairment – except in some outlying cases.
Newness of Alzheimer’s Disease
While digging into the disease, the obvious question might be, when did it start to develop? The answer is a bit trickier to understand, because cognitive impairment was historically seen as a natural consequence of old age. It’s difficult to retrospectively look at the historical records and separate the normal from the abnormal.
The incidence of Alzheimer’s has increased p over the last century; but how much of that is improved understanding of the diagnostics of cognitive impairment, and how much is due to our longer lifespans? In the year 1800, Americans of European descent numbered about five million – fewer than the number of patients with Alzheimer’s disease today. By 1900, it’s estimated that 4% of the population was over sixty-five, and population had grown to seventy-six million.
The key challenge is that cognitive impairment was considered normal. It was what was expected when you became old. Instead of it being recognized as a condition afflicting people, it was the normal. So in trying to look at the records to see if 300,000 or more of people over sixty-five had dementia is like trying to find a polar bear in a snow storm.
Due to improvements in medicine and safety, our life expectancy is increasing by about one year for every four years of time. Notwithstanding some limits to this process, such as the Hayflick limit to the number of times that a cell can divide, it appears that we’re increasing the life expectancy dramatically, and as a result will have a greater number of people who can count themselves lucky to be “old.” While this creates a need for care facilities to care for our elderly, it also creates an interest in preventing the cognitive impairment that used to be “normal” for elderly. (See Being Mortal for more on the care of the elderly.)
Correlations and Questions
Through the study of Alzheimer’s, some very peculiar correlations have appeared. One of the most famous studies of Alzheimer’s was what’s called “The Nun Study.” In this study, many of the members of the Sisters of Notre Dame agreed to be monitored for the development of the disease. From a statistical point of view, this was great because so many of the variables of their lives were similar and therefore could be discounted as contributing factors. One of the predictive factors that emerged was a small bit of writing that the nuns did sixty years before the onset of the disease.
Nuns write a small essay about their desire to enter the sisterhood. The density of ideas in that essay – the natural writing with multiple pieces of information tightly encoded into the few words that they are given – is a significant predictor of whether they’ll get the disease or not. Nuns who wrote dense prose were less likely to get the disease than those whose essays were less tightly packed.
While the prevalence of tangles tightly tracks the progression of the disease, this is an early warning sign that spans decades. It’s been well-studied that Alzheimer’s occurs less frequently in patients that are well-educated.
Interestingly, it seems that it may be the case that education forestalls the progression of the symptoms of the disease. So it appears that education may create a sort of cognitive reserve that can hold back the disease for a while. It’s believed now that if patients with higher education live sufficiently long they’ll encounter the disease and the onset of symptoms will be more rapid for them. In my typical glass half-full mentality, I’ll take the reduction of symptoms and rapid onset as a win.
Unrelated to Alzheimer’s, but complicating the measurement of the progression of the disease, is something called “terminal drop.” This is a precipitous drop in cognitive capacity in the months leading up to death. So is a person suffering from symptoms of the disease, or are they approaching death?
Cynics seem to be more prone to the disease, while those who enjoy regular leisure activities – particularly those which cause a person to be mentally active – seem to build cognitive reserve that helps to protect someone from the symptoms of the disease.
Spread of the Disease
With advances in imaging techniques, we’re able to peer into the heads of patients and see in more detail how the disease is progressing than we’ve ever been able to before; and with this, we’ve discovered some odd “coincidences.”
One of the factors of cognitive processing speed is the myelin sheath. Myelin is a fatty sheath that surrounds neurons and makes them more effective at communication. Myelin is produced by the oligodendrocytes, which are found in highest concentrations in the entorhinal cortex. This is the area most impacted by Alzheimer’s and is the interface between the hippocampus and the neocortex. The entorhinal cortex is one of the last areas developed in the brain, and one of the last areas to receive myelin.
It’s the entorhinal cortex that seems to be ground zero for Alzheimer’s disease. It’s where the disease seems to cause the most damage.
Glucose (Sugar) in the Brain
There are some researchers that are calling for Alzheimer’s disease to be called Diabetes Type III. Diabetes mellitus exists in two forms, both of which impact glucose levels in the blood. Diabetes Type I is associated with the destruction of the insulin-producing cells of the pancreas, such that the body no longer produces insulin. Type II diabetes is associated with increased resistance to the insulin being produced. Insulin is important to the regulation of blood glucose levels, because it allows for the absorption of the glucose in the blood.
Glucose is the necessary energy component for us to function, but elevated levels of unabsorbed glucose in our blood is associated with a large number of comorbidities. In essence, our bodies function with a ratio of glucose in the blood that falls in a relatively narrow range. Glucose levels in the blood are constantly changing, but an adult should on average have a blood glucose of approximately 100mg per deciliter. This is measured through a test called Hemoglobin A1c or HbA1c. This measures the average glucose over a three-month period. The HbA1c lab values are typically converted back into an average blood sugar using a standard formula.
Diabetes has long been known as a factor in the development of dementia; however, what has been less clear is whether that was the result of the comorbidities related to diabetes, or whether it’s related to the diabetes itself. Because Alzheimer’s is sensitive to vascular issues, and diabetes has an impact on vascular malleability as well as a tendency to increase cholesterol, the relationship seemed reasonable and no specific cause was identified. However, research is beginning to indicate that the brain’s processing of glucose is impaired with Alzheimer’s.
The brain is a power-hungry organ. Taking up two percent of our body mass, it consumes roughly 20% of our glucose. As we learned in The Rise of Superman, it has a maximum sustainable energy use, and because of that, various areas of the brain may be switched off to accommodate the power needs of other parts of the brain. It’s not hard to believe that even minute changes in the management of glucose in an electro-chemical system could have dire consequences.
Unfortunately, this is where the trail ends at the moment. There is a belief that the disease may be triggered by changes in insulin resistance. There’s a higher rate of dementia in patients with elevated glucose levels (but not yet meeting the threshold for diabetes), but we don’t understand yet how changes in blood sugar impact the processing of glucose in the brain.
A few years ago my wife and I were showering together when she fainted. It was a terrifying experience for me. I’d never seen someone faint so closely. (It’s a small shower.) More than that, I saw the biological equivalent of what I see in my technology work. When a computer reboots, it goes momentarily silent as all power is lost and the fans stop. After that, the fans are on at 100% for a few seconds, and then things resume their normal median fan speeds. My wife’s breathing eerily took on the same pattern. She stopped breathing for a moment, breathed at a high rate of speed for a few more moments, and then settled into a normal breathing pattern. It was my first experience that technology sometimes follows biology.
When meeting with Mary, I was struck by a similar correlation. When a computer has a power supply problem – when the power supply isn’t able to produce all the power the computer needs – the computer is running along fine until you do something taxing to it. Once you ask it to do something which requires just a bit more power, it will reboot. It momentarily goes blank and starts the process of booting up again. Mary’s responses to me looked like this pattern. She’d get triggered into recalling a memory or making sense of the input she was receiving, and would fall out of that train of thought. Moments later when rediscovering the same novel stimulus, she would return to the train of thought and fall out of it at nearly the same place. Even in technology, there are a lot of variables that change the exact place where things fail, though the failure seems to happen at nearly the same time every time it cycles.
While this is a single observation by a non-clinical observer making a relationship to something man-made that has very little to do with the functioning of the human brain, it’s led me to wonder: what if what we experience as dementia is really just the inability of the brain to make the connections it once used to because of insufficient energy?
I don’t believe we’ll know whether the glucose hypothesis is right in time to help Mary. However, it’s something that I’ll continue to be interested in. I don’t want to accept The End of Memory. I’ll keep Mary’s memories and her memory alive in me as long as I’m able.