We Are Our Brains (49 page)

I once gave a lecture at an Alzheimer's café—an informal gathering for Alzheimer's patients that has become popular in the Netherlands—and was approached during the break by a man of about forty-five who said that he was in the early stages of dementia. I responded that I could see no outward sign of it. He told me that he'd already had a few small cerebral hemorrhages that he knew would persist, ultimately resulting in dementia. I asked him if he had relatives in the little Dutch fishing village of Katwijk. “Yes,” he answered. “Your diagnosis is spot-on, Professor!” The reason I asked was that there's a family in that village with a rare mutation that causes amyloid buildup in the blood vessels, leading to cerebral hemorrhage and dementia. Its members know exactly what fate has in store for them, because they have seen so many relatives deteriorate in this way. Yet it's a very rare form of dementia, just like Creutzfeldt-Jakob disease, which is caused by infections in abnormal proteins. It can have a genetic cause but was previously also transmitted in brain operations, before surgeons knew that their instruments needed to be sterilized in a certain way. People have also been infected through corneal transplants and the pituitary extracts formerly given to children lacking growth hormones. These hormonal extracts, which probably come from Russia, are sometimes still found in gyms, where they are used by bodybuilders who want to increase muscle mass. It's a highly risky business: You need only one Creutzfeldt-Jakob carrier to make the entire batch deadly.

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?

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.

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.