by D. F. Swaab
FIGURE 29. A Gallyas silver stain of brain tissue (cortex) from an eighty-five-year-old, showing the two types of lesions associated with Alzheimer’s: the large, round, amyloid-containing plaques between the neurons and the black neurofibrillary tangles in the neurons. The bar is a size marker (100 micrometers). Courtesy of Unga Unmehopa.
FIGURE 30. In frontotemporal dementia, the front of the brain (shown at top center) shrinks dramatically, while the rest of the brain remains intact. Courtesy of the Netherlands Brain Bank.
A variant of Creutzfeldt-Jakob disease is mad cow disease, which originated when infected protein from the brains of cows ended up with other offal in hamburgers. Huntington’s disease is an inherited form of dementia. People in whose families it runs are familiar with the symptoms, having seen them in relatives: jerky movements and lack of coordination. When they start displaying those symptoms they know that they are on the road to developing dementia.
So there are many forms of dementia, but most result from Alzheimer’s. If you knew nothing about all these different types and diagnosed all patients with dementia as having Alzheimer’s, you would ultimately be proved right in most cases; microscope samples would reveal either Alzheimer’s or a mixture of vascular changes of which Alzheimer’s was a part.
What Causes Alzheimer’s?
Alzheimer’s can be seen as a premature, accelerated, and severe process of brain aging.
In recent decades, research into Alzheimer’s has devoted considerable attention to a couple of rare genetic forms of the disease. In Belgium, there are two families in which members develop Alzheimer’s at the age of thirty-five. Most die between the ages of forty and fifty. In families like these, mutations have been found in the genes for beta-amyloid precursor protein (βapp) and presenilin 1 and 2. However, we need to bear in mind that these mutations account for less than 1 percent of all Alzheimer’s patients. Age and a variant form of a gene called apolipoprotein E-ɛ4 (ApoE-ɛ4) are by far the main risk factors for the form of Alzheimer’s that occurs in 94 percent of Alzheimer’s patients over sixty-five. The ApoE-ɛ4 gene is thought to be responsible for around 17 percent of all cases of Alzheimer’s. But unlike the three above mutations, simply having that form of the gene doesn’t mean that you will definitely develop the disease, just that you’re more likely to do so. After learning how to identify the ApoE-ɛ4 gene, our students wanted to find out whether they had it. But we forbade them from testing themselves for the gene. Knowing that you have the ApoE-ɛ4 gene can lead only to worry. You may never develop Alzheimer’s—but you’ll be tormented by the knowledge that if you do get it, there’s no cure. Molecular genetic research of archived samples taken from the brain of the first person diagnosed with Alzheimer’s a hundred years ago, a fifty-one-year-old woman named Auguste D., revealed neither any of the known mutations nor ApoE-ɛ4. So this was a case of someone who developed Alzheimer’s at a very early age without having any of the genes that are mostly responsible for the condition.
Clearly, extremely complex interactions between genetic background and the environment play a role in determining whether someone will develop Alzheimer’s. But how do all those different factors lead to the same form of dementia? The most popular hypothesis is that risk factors result in a buildup of toxic amyloid beta peptides (β A4) in the form of plaques, which are thought to alter transport proteins and make them stick together (the tangles), disrupting cell function and causing the neuron to die. Like deadly relay runners, infected neurons then pass on toxins, spreading the disease through the brain in a six-stage pattern described by Braak and Braak. Indeed, Alzheimer’s does seem to follow a set neuroanatomical route, starting in the same brain structure (the entorhinal cortex, fig. 26), traveling on to the limbic system and finally to the cerebral cortex. Although there’s much to be said for this theory, known as the amyloid cascade hypothesis, in the case of the rare families that have βapp mutations, there are at least as many arguments against it in the case of the most common form of Alzheimer’s, which is non-inherited. So far, studies of transgenic mice haven’t shown that amyloid cascades are responsible for the creation of tangles in the sporadic type of Alzheimer’s. I lean toward the theory that Alzheimer’s is simply an accelerated form of brain aging. Every active neuron sustains damage, just as a car engine does, through wear and tear. Unlike car engines, neurons can repair themselves—but only to a certain extent. Tiny flaws remain and mount up over the years, causing the degeneration that is the aging process. In the case of individuals whose brains aren’t good at repairing themselves or who incur a lot of brain damage, like professional boxers (see chapter 12), this degeneration is more serious and occurs faster, resulting in plaques and tangles, which lead to the onset of Alzheimer’s. If this theory is correct, the only way of preventing Alzheimer’s would be to halt brain aging. And that’s bad news, because we’re a long way from being able to do that.
ALZHEIMER’S: THE STAGES OF DETERIORATION
Be nice to your kids, they’ll choose your nursing home.
Text on a mug my daughter gave me
A third of those who suffer from Alzheimer’s are unaware that they have the disease. (Lack of awareness of illness is a medical condition in its own right, known as anosognosia.) They deny that there’s anything wrong with them and have to be dragged to a doctor by their partner. Someone I knew had taken his wife, who was developing dementia, to a symposium of mine at which there was much discussion of Alzheimer’s. A concerned friend asked her, “Wasn’t that a bit confrontational for you?” to which she replied, “No, but it must have been for anyone with Alzheimer’s.” Others, though, realize early on that something is wrong. When Harold Wilson was reelected as British prime minister in 1974, he noticed that he was beginning to lose his power of perfect recall. In 1976, to universal surprise, he decided to resign. Two years later, he experienced the first symptoms of Alzheimer’s.
The onset of Alzheimer’s can be insidious and its progress extremely protracted. When Ronald Reagan became president of the United States in 1981 at the age of nearly seventy, he solemnly declared that he would resign if he got Alzheimer’s. Looking back, there are indications that he developed the disease in 1984. Analysis of his performance in debates shows that he was starting to misuse articles, prepositions, and pronouns. He also paused five times more frequently and spoke 9 percent more slowly than before. In 1992, the condition manifested itself more plainly, and in 1994, ten years after those first changes in his speech patterns, Reagan wrote to his fellow countrymen to announce that he was one of the million Americans with Alzheimer’s. He died a decade later, twenty years after the onset of the disease.
Alzheimer’s travels through our brains by a fixed route. When we look at a brain sample under a microscope, we can see the first telltale signs of the disease, the tangles in the cerebral cortex of the temporal lobe (the entorhinal cortex, fig. 26). The next sign is abnormalities in the hippocampus. These changes appear before any symptoms do; in fact, the person who gave us permission to use their brain as a “control” in our studies wasn’t aware that they were already ill. At present, the very first signs of the condition can’t be identified while the sufferer is alive. But once it has progressed, severely damaging the temporal cortex (fig. 1) and the hippocampus (fig. 26), the first memory problems appear. The sufferer is unable to remember recent events, yet can still recall minute details of events in the distant past, like a party at elementary school. When the disease attacks the remaining areas of the cerebral cortex, dementia ensues. The rear part of the brain, the visual cortex (fig. 22), is the last to be damaged. Some painters with Alzheimer’s can have full dementia and yet at the same time retain their creative and artistic powers. Artists have been able to make excellent portraits in this state while being incapable of determining their value or negotiating a price for them. Their visual cortex functions right up to the end.
In Alzheimer’s, not only do microscopic changes follow a set pattern, but functional losses do as well. We
lose abilities in almost exactly the reverse order in which we acquire them. Dr. Barry Reisberg of New York has identified seven stages of Alzheimer’s. In Stage 1 you still function normally. In Stage 2 you start to lose things and find it hard to carry out your job but can still maintain a semblance of normality. In Stage 3, your co-workers notice that you can no longer handle difficult situations at work. In Stage 4 you have trouble with complex tasks, like handling finances. You then start to need help choosing what to wear (5). After that you need help getting dressed (6a) and getting washed (6b), you can no longer go to the toilet unaided (6c), and you develop urinary incontinence (6d) and fecal incontinence (6e). By Stage 7a you can only speak about half a dozen intelligible words, after which you lose the power of speech entirely (7b). You can no longer walk (7c) or sit unaided (7d). You then lose the ability to smile (7e)—a skill that made everyone so happy when you were a baby—and the ability to hold your head up (7f). The patient ends up in bed, curled up in a fetal position (fig. 31); if you insert a finger in his mouth, he will show a sucking reflex, having at that point fully regressed to the condition of a newborn baby.
FIGURE 31. In the final stage of Alzheimer’s, the patient lies curled up in bed in a fetal position. Courtesy of Professor E.J.A. Scherder of the Clinical Neuropsychology Department of VU University in Amsterdam.
Language and music are stored in a part of the memory that’s only affected at a late stage of Alzheimer’s. The ability to speak only disappears in Stage 7. Musical skills can be retained for a very long time. A professional pianist with Alzheimer’s could no longer comprehend anything that was said or written, including sheet music. Yet she could retain pieces of music that she heard for the first time and reproduce them with musical feeling. At a later stage she could still play the melodies with which she was familiar, a pastime that gave her great satisfaction. A case has also been described of a violinist with Alzheimer’s who retained his musical skills. The inverse of the brain’s retention of musical skills is true too; music is one of the earliest influences in an infant’s development. Indeed, the effects of music on brain function can be seen very early on. Premature babies in incubators become calmer, have better oxygen values, and are able to leave incubators earlier if music is played to them. Newborn babies are much more interested when a mother sings than when she speaks, and they already have a sense of rhythm. So, rather like businesses undergoing reorganization, Alzheimer’s functions along the lines of “last in, first out,” with the most senior members of staff being allowed to stay put. But of course the brain isn’t being reorganized in Alzheimer’s; it’s being demolished.
“USE IT OR LOSE IT”: REACTIVATING NEURONS IN ALZHEIMER’S DISEASE
As long as a brain with Alzheimer’s still has neurons—even if they are shrunken and no longer function—they can in principle be reactivated.
Despite the marked shrinkage of the cerebral cortex in Alzheimer’s (fig. 32), which can cause the brain in the skull to resemble a walnut in its shell, it retains all its neurons. In contrast to what’s generally thought, brain cells don’t die en masse as a result of Alzheimer’s. Cell death is limited to regions like the entorhinal cortex, part of the hippocampus, and the locus coeruleus and only occurs at an advanced stage of the disease. Conversely, reduced activity, leading to neuronal shrinkage (fig. 33), affects the entire brain from an early stage. This also explains why symptoms can fluctuate so strongly at the beginning of the disease. Someone can show marked signs of senility one moment but be able to carry on an intelligent conversation the next. If the memory disorders in the early stages of Alzheimer’s were indeed due to cell death, such fluctuations wouldn’t occur, as cell death isn’t reversible.
FIGURE 32. A characteristic symptom of Alzheimer’s is marked shrinkage (atrophy) of the entire cerebral cortex, which can cause the brain to look like a walnut (a normal brain is shown underneath). Courtesy of the Netherlands Brain Bank.
FIGURE 33. Microscope slides showing atrophied neurons in the nucleus basalis of Meynert. A is a control sample taken from a healthy patient, showing the large neurons extending their nerve fibers into the cerebral cortex, where they release the neurotransmitter acetylcholine (see also fig. 25). B shows how Alzheimer’s causes these cells to shrink (the arrow points to a group of three dramatically shrunken neurons). Courtesy of Dr. Ronald Verwer.
Activation Versus Alzheimer’s
While patients are of course indifferent to whether their dementia is due to loss of neurons or reduced neural activity, the difference is crucial for developing therapeutic strategies. If neurons are still there, albeit atrophied and nonfunctioning, it should, in principle, be possible to reactivate these cells, which is a focus of our research.
Growing up bilingual, having a good education and a challenging job, and remaining active in old age reduce the likelihood of Alzheimer’s. This suggests that maximizing brain activity has a preventive effect. There are, moreover, areas of the brain in which neurons aren’t affected by the disease. We have found such areas to be extremely active, sometimes even becoming more active as aging progresses. In 1991, I paraphrased the hypothesis that activating neurons appeared to provide some protection against aging and Alzheimer’s as “Use it or lose it.”
Studies also show that activation can reduce Alzheimer’s pathology. Transgenic mice with considerable buildup in their brains of the toxic protein amyloid (a symptom of Alzheimer’s) were placed in an enriched environment—a large cage in which they could play with one another and in which they were regularly treated to new toys. When mice remained in this environment, their amyloid levels decreased (and went down even further if they also got more exercise than usual). Sadly, the research team headed by Erik Scherder at the VU University in Amsterdam couldn’t link extra physical exercise to improved function in Alzheimer’s patients. Yet he did find, in an earlier study, that general stimulation of the group’s brains (through transcutaneous electrical nerve stimulation) had a beneficial effect on cognition and mood. The team headed by Mark Tuszynski in San Diego is using gene therapy to stimulate the nucleus basalis of Meynert (fig. 25), a brain structure that’s important in memory, in Alzheimer’s patients with promising results (see chapter 11).
Stimulating the Biological Clock with Light
To test the effectiveness of activating neurons affected by Alzheimer’s, we opted to stimulate the circadian system. The study also had clinical importance, because nighttime restlessness is the main reason that people with dementia are institutionalized. It makes them putter around late at night, turning on the gas and doing other potentially dangerous things, or go out and wander the streets. Sooner or later their partner can no longer cope with the Herculean task of caring for them and keeping an eye on them day and night. The circadian system (from the Latin circa, meaning “around,” and diem, meaning “day”), which is responsible for all our day and night rhythms, is affected very early on in Alzheimer’s. Patients no longer get their nightly peak of melatonin, the sleep hormone secreted by the pineal gland. We established that these early changes are caused by the biological clock, the suprachiasmatic nucleus, a structure that can easily be stimulated by means of light therapy. As expected, light therapy improved circadian rhythms and reduced restlessness in Alzheimer’s patients. It didn’t work in patients with impaired vision—a nice control demonstrating the effectiveness of light. A three-and-a-half-year follow-up study by Eus van Someren and his team showed that more light doesn’t just stabilize rhythms but also improves mood and even slows the deterioration of memory. The combination of more light during the day and melatonin supplements before sleep proved even more effective in some respects.
FIGURE 34. Thin slices of tissue removed from the brain of a patient with Alzheimer’s within ten hours of death. At this stage, neurons can be cultured for many weeks. In this model, stem cells proved to secrete an unknown substance that improved the survival of the cultured neurons. After forty-eight days in normal culture conditions (A), only a few neurons
are still active and intact (indicated by arrows). These are outnumbered by neurons with leaky membranes (triangles), evident from their colored nuclei. Many nuclei of dead cells can also be seen (small dots, some of which are marked with an asterisk by way of example). B shows how, after a slice of this kind is cultured with stem cells, there are many more active, intact neurons (arrows) and fewer leaky (triangles) and dead (asterisks) cells. Courtesy of Dr. Ronald Verwer.
The results of this simple intervention are fully equal to those of current anti-Alzheimer’s drugs and do not have any of the side effects. Although stimulating the biological clock can improve the quality of life of Alzheimer’s patients and their carers, it isn’t, of course, a therapy for the disease itself. However, it does prove an important principle, namely that even if neurons are affected by Alzheimer’s, their function can be restored through stimulation.
Current Research
The Netherlands Institute for Neuroscience (NIN) is currently looking at substances that can activate neurons in other areas of the brain. Ronald Verwer has devised a procedure that enables neurons in thin sections of brain tissue obtained within ten hours of death to be cultured for several weeks. This allows us to test the effects of potentially activating substances without inconveniencing patients. In this model, stem cells proved to secrete a substance that promoted the survival of the cultured neurons (fig. 34). But as yet we have absolutely no idea what the nature of this compound is.