THE ROLE OF PROTEINS IN ALZHEIMER’S DISEASE
What causes plaques and tangles to form? Scientists have learned that the amyloid-beta peptide is responsible for forming amyloid plaques. This peptide is part of a much larger protein called the amyloid precursor protein (APP), which is thought to be lodged in the cell membrane of dendrites, the short, branching extensions of neurons (fig. 5.7). Two separate enzymes cut through the precursor protein, each in a different place, releasing the amyloid-beta peptide (fig. 5.7). Once released from the cell membrane, the peptide floats in the space outside the neuron.
It turns out that the production and liberation of the amyloid-beta peptide are normal occurrences in everyone’s brain. In people with Alzheimer’s disease, however, production of the protein may be accelerated, or clearance of the protein from the area surrounding the cell may be slowed. Either action can result in abnormal accumulations of peptides. What’s more, these peptides are sticky. They adhere to one another and ultimately form the amyloid plaques characteristic of Alzheimer’s disease.
Figure 5.7. The amyloid precursor protein (APP), which is lodged in the cell membrane, contains the amyloid-beta (A-beta) peptide (top). Two enzymes make cuts through the amyloid precursor protein: the beta cut, followed by the gamma cut (middle). These cuts release the amyloid-beta peptide into the space outside the cell, where it may form amyloid plaques (bottom).
Another protein involved in Alzheimer’s disease is called tau, and it is located inside the neuron. To function, a protein must have a three-dimensional shape. It assumes this shape by means of folding, a process in which the amino acids that make up the protein twist themselves into a very specific conformation. Think of it as exquisitely complicated origami. When a molecular defect causes the tau protein to misfold, it forms toxic clumps (fig. 5.8) that create neurofibrillary tangles.
Figure 5.8. A molecular defect causes the tau protein to fold incorrectly. When this happens, the protein clumps inside the cell, forming neurofibrillary tangles.
The combination of these two types of aggregates—plaques outside the nerve cell and tangles within the nerve cell—causes the death of neurons and is responsible for the progression of Alzheimer’s disease.
GENETIC STUDIES OF ALZHEIMER’S DISEASE
While Alzheimer’s disease usually occurs in people in their seventies or eighties whose families have no history of the disease, a rare, early-onset form runs strongly in some families. John Hardy, now at University College London, had an unusual opportunity to study the genetic basis of Alzheimer’s when Carol Jennings got in touch with him.
In the early 1980s Carol’s father was diagnosed with Alzheimer’s disease at age fifty-eight. Shortly thereafter, a sister and a brother of his, both in their midfifties, developed the disease. It turns out that Carol’s great-grandfather had had the disease, as had her grandfather and a great-uncle. In the main branch of the family, five out of ten children had Alzheimer’s disease, all at the same time. The average age of onset was about fifty-five (the record for early onset in familial Alzheimer’s is the late twenties).
Hardy and his colleagues wanted to know what genes were inherited by all of the affected siblings in the Jennings family but not by any of the unaffected siblings. They found that the five affected siblings and an affected cousin shared an identical section of chromosome 21, the smallest chromosome in the human genome. But two of the unaffected siblings also had a little bit of that section of chromosome 21. This told Hardy that the gene responsible for Alzheimer’s was not in the bit of chromosome 21 shared with the unaffected siblings. He then looked carefully at the part of chromosome 21 that had been inherited only by the family members with Alzheimer’s, and there he found the defective gene that causes amyloid-beta peptides to clump.11
This was the first gene identified in Alzheimer’s disease, and it opened up the study of the disease. Pathologists had already seen that amyloid-beta peptides form plaques, but Hardy showed that in the Jennings family the disease starts with a mutation in the gene for the amyloid precursor protein that causes the peptides to clump.
Hardy and other scientists have since found many additional mutations. A group of scientists in Toronto found families with inherited Alzheimer’s who have mutations in the genes that code for a protein called presenilin.12 These mutations prevent presenilin from helping to digest amyloid-beta peptides floating in the space between neurons. This finding fits together beautifully with Hardy’s discovery. Both studies show that all of the families with early-onset Alzheimer’s have mutations that lead to amyloid-beta peptides forming deadly clumps in the brain. Put another way, all of the mutations seem to converge on a single pathway that leads to early-onset, familial Alzheimer’s (fig. 5.9).
Figure 5.9. Several different pathways that lead to early-onset Alzheimer’s disease converge to yield a common product: amyloid-beta aggregates. Clusterin is a type of protein that is produced in greater than usual amounts in people with Alzheimer’s disease. It interacts with amyloid-beta peptides to exacerbate the loss of tissue in the entorhinal cortex.
These genetic studies of families with inherited Alzheimer’s led scientists to wonder whether there might be mutations that reduce the number of amyloid-beta peptides. If such mutations exist, do they protect against Alzheimer’s disease?
Thorlakur Jonsson and his colleagues at deCODE Genetics, a biotechnology company in Iceland, have found just such a mutation.13 It causes one amino acid to be substituted for another in the amyloid precursor protein, and it results in fewer amyloid-beta peptides being generated. This mutation is particularly interesting because a different amino acid substitution at the same site on that precursor protein causes Alzheimer’s disease. Even more fascinating, people over age eighty who have the protective mutation display better cognitive functioning than people of the same age who lack the mutation.
RISK FACTORS FOR ALZHEIMER’S DISEASE
Several scientists have been trying to work out the risk factors for the more common late-onset Alzheimer’s. The most significant risk factor found to date is the apolipoprotein E (APOE) gene. This gene codes for a protein that combines with fats (lipids) to form a class of molecules called lipoproteins. Lipoproteins package cholesterol and other fats and carry them through the bloodstream. Normal amounts of cholesterol in the blood are essential for good health, but abnormal amounts can clog the arteries and give rise to strokes and heart attacks. One allele, or variation, of this gene is APOE4. The APOE4 allele is rare in the general population, but it puts people at risk of developing late-onset Alzheimer’s disease. In fact, about half of the people with late-onset Alzheimer’s have this allele.
Since we can’t change our genes, is there anything else we can do to lower the risk of developing Alzheimer’s? One possibility has emerged recently, and it has to do with the way our body handles glucose as we age.
Glucose is the body’s main source of energy, and it comes from the food we eat. The pancreas releases insulin, which essentially enables the muscles to absorb glucose. As we age, all of us become a bit insulin resistant, meaning that our muscles are less sensitive to the effects of insulin. As a result, the pancreas tries to crank out a little bit more insulin, and this makes glucose regulation less stable. If glucose regulation becomes too unstable, we develop type 2 diabetes.
A number of studies have shown that type 2 diabetes is a risk factor for Alzheimer’s disease. Furthermore, changes in glucose regulation that accompany type 2 diabetes seem to affect the areas of the hippocampus that are involved in age-related memory loss. The important thing is that we can actually modify these age-related changes through diet and physical exercise, which can increase our muscles’ sensitivity to insulin and thus aid in the absorption of glucose.
Environmental factors and comorbidities, or other diseases that people have, may also contribute to the susceptibility to Alzheimer’s disease, but all studies to date point to amyloid clumping as the fundamental cause of dementia. This is a very powerful hy
pothesis, and it has been extremely useful in guiding research. Recent studies have therefore focused on preventing clumping and clearing preexisting amyloid clumps by using antibodies that specifically recognize these clumps. As we have seen, disorders such as schizophrenia and depression seem to be caused not by a single gene but by hundreds of genes, so figuring out how those disorders come about is much more difficult. Even though it feels slow, our progress in understanding Alzheimer’s disease has been amazingly rapid.
FRONTOTEMPORAL DEMENTIA
Alzheimer’s disease is not the only common dementia. Another common form is frontotemporal dementia. Frontotemporal dementia was discovered a decade before Alzheimer’s disease by Arnold Pick, a professor of psychiatry at the University of Prague. The disorder used to be considered rare, but we now know that it and Alzheimer’s disease account for most cases of dementia in people over the age of sixty-four. Moreover, frontotemporal dementia is the most frequent cause of dementia in people under age sixty-five, affecting an estimated forty-five thousand to sixty-five thousand people in the United States. It generally begins at a younger age and progresses more rapidly than Alzheimer’s disease.
Frontotemporal dementia begins in very small areas of the frontal lobe of the brain that are involved with social intelligence, particularly our ability to inhibit impulses (fig. 5.10). The disorder was once considered impossible to distinguish from Alzheimer’s disease in a living person, but today that is no longer true. Frontotemporal dementia commonly results in profoundly disordered social behavior and moral reasoning. People may commit uncharacteristic antisocial acts, such as shoplifting. One study found that early in the illness, about half of all patients either were arrested or could have been arrested for something they had done. Such behavior is not characteristic of people with Alzheimer’s disease.
Frontotemporal dementia also affects the parts of the brain that allow us to relate to others. People with this disorder who were once loving and kind may become indifferent to those around them. They also become vulnerable to addiction, engaging in regular overeating and taking up unhealthful habits, such as smoking. Sometimes they cannot control their spending and go bankrupt. This dementia has a huge impact on families because it affects people in midlife, many of whom have children.
Figure 5.10. Frontotemporal dementia affects the frontal and temporal cortices of the brain.
THE GENETICS OF FRONTOTEMPORAL DEMENTIA
The biological mechanism of frontotemporal dementia—a disorder that results from damage to the frontal and temporal lobes—is the same as that of Alzheimer’s disease: genetic mutations result in misfolded proteins that form clumps in the brain. That is why people with these two disorders have common symptoms. But some of the genes responsible for the protein misfolding are different in each disorder. The three mutated genes responsible for frontotemporal dementia are the gene that codes for the tau protein, the C90RF72 gene, and the gene that codes for progranulin, a protein with several roles in the brain. Each mutated gene damages the same region of the brain, and each does it by means of abnormal protein folding (fig. 5.11).
Figure 5.11. Mutations in three genes lead to frontotemporal dementia.
The mutated progranulin gene produces the normal progranulin protein, it just doesn’t produce enough of it. (The normal progranulin protein is thought to keep another protein, TDP-43, from misfolding.) The simplicity of this mechanism is encouraging. It suggests that a plausible way to treat frontotemporal dementia is either to find a drug that will increase the amount of progranulin in the blood and brain or to figure out a way of delivering progranulin to the brain. In fact, Bruce Miller, of the University of California, San Francisco, who has studied frontotemporal dementia extensively, thinks it may be one of the simplest neurodegenerative diseases to treat. He is now testing drugs that are designed to elevate progranulin concentrations in the blood and brain.14
Miller has made an additional discovery, one that supports the findings of John Hughlings Jackson, a great nineteenth-century neurologist. Jackson was the first person to realize that the two hemispheres of the brain deal with different mental functions: the left hemisphere deals with logical functions such as language and numbers, and the right hemisphere deals with more-creative functions such as music and art. Moreover, Jackson suggested that the two hemispheres inhibit each other. Thus, damage to the left side of the brain would make it incapable of inhibiting the right side, thus freeing up the right side’s creativity. Miller has described a series of patients whose frontotemporal dementia is restricted to the left hemisphere. A number of these people show outbursts of creativity, particularly people who were creatively inclined before the disease damaged their left hemisphere. The damage to the left hemisphere appears to have freed up the creative and musical right hemisphere.
These findings illustrate a remarkable principle of general brain function: when one neural circuit is turned off, another circuit may turn on. Why? Because the inactivated circuit normally inhibits the other circuit.
LOOKING AHEAD
The first scientist to describe a protein-folding disorder was Stanley Prusiner, who observed misfolding in the 1980s in Creutzfeldt-Jakob disease, a rare disorder. Other scientists, as we have seen, went on to show that protein misfolding contributes to Alzheimer’s disease and frontotemporal dementia. At first glance, these dementias might seem to have little, if anything, in common with movement disorders. But a closer look reveals that Parkinson’s disease and Huntington’s disease also result from protein misfolding. We will turn to those brain disorders in chapter 7.
First, however, let us explore what brain disorders can tell us about another aspect of human nature: creativity. Just as our feelings, thoughts, behavior, social interactions, and memory have a biological basis, so, too, does our innate creativity. Earlier chapters touched on various expressions of creativity in people with autism, depression, bipolar disorder, and schizophrenia. Some people with Alzheimer’s and frontotemporal dementia also express themselves creatively, most often in visual art. In chapter 6 we will explore what we have learned about creativity from artists with these brain disorders.
6
OUR INNATE CREATIVITY: BRAIN DISORDERS AND ART
Artists—painters, writers, sculptors, composers—seem different from other people, blessed with special gifts that the rest of us lack. The ancient Greeks believed that creative people were inspired by the muses, the goddesses of knowledge and the arts. The Romantic poets of the nineteenth century had a different view of creativity. They argued that creativity arises from mental illness, which diminishes the constraints posed by habit, convention, and rational thought and enables the artist to tap into unconscious creative powers.
Today, we know that creativity originates in the brain. It has a biological basis. We also know that while certain forms of creativity arise in association with mental disorders, our creative capability is not dependent upon mental disorder. Moreover, the capability for creativity is universal. Each of us, in various ways and with varying degrees of skill, expresses it.
Yet the Romantics weren’t entirely wrong. For most people, our innate creative capability is not easily summoned. Scientists have yet to uncover the biological mechanisms of creativity, but they have discovered some of its precursors, one of which seems to be divesting ourselves of inhibitions, allowing our minds to wander more freely and to seek new connections between ideas. Such communion with the unconscious is shared by all creative people, but it is sometimes particularly striking in creative people with mental disorders.
This chapter explores what brain disorders, both psychiatric and neurological, can tell us about our creative capability. We begin by examining creativity from several perspectives. First, we focus on the work of an extraordinarily gifted contemporary artist. Next, we approach creativity from the perspective of the viewer. Finally, we explore what we have learned about the nature of the creative process and the biology of creativity.
In earlier chapters we saw peop
le with schizophrenia, depression, and bipolar disorder who express their creative gifts in art, literature, and science. This chapter focuses primarily on the visual art of patients with schizophrenia—so-called psychotic art—not only because it is beautiful and moving but because it has been collected and studied extensively. We go on to explore the influence of this art on modern art, notably on Dada and Surrealism. We then touch on the creativity of people with other brain disorders: bipolar disorder, autism, Alzheimer’s disease, and frontotemporal dementia. We conclude with some initial insights into what modern brain studies have shown about our innate creative capability.
PERSPECTIVES ON CREATIVITY
THE ARTIST
Chuck Close is dyslexic, and as a child there were many things he felt he couldn’t do. One thing he could do, however—and do well—was draw. He became particularly interested in drawing faces, which is intriguing because Close is also face-blind—that is, he can recognize a face as a face, but he cannot associate that face with a particular person.
Our ability to recognize faces resides in the right fusiform gyrus of the inferior medial temporal lobe of the brain. People with damage to the front of that region are face-blind, like Close. People with damage to the back of that region cannot see a face at all. Close is probably the only person in the history of Western art to paint portraits without being able to recognize individual people. Why, then, did he focus on being a portrait artist? Close says his art was an attempt to make sense of a world he didn’t understand. For him, it’s not so strange that he makes portraits. He was driven to make portraits because he was trying to understand the faces of people he knows and loves and commit them to memory. For him a face has to be flattened out. Once he flattens it, he can commit it to memory in a way that he cannot if he’s looking at it head-on. If he looks at you and you move your head half an inch, it’s a new head for him that he has never seen before. But if he takes a photograph of the face and flattens it out, he now can effect the translation from one flat medium to another.
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