It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

  It is also why the notion of serotonin resistance is so appealing as a causal factor in mood disorders. Over hundreds of millions of years, regulatory systems evolved to ensure that highly reactive signaling mechanisms in the brain stay operational within safe bounds. They include ways to fine-tune the volume controls in the limbic system, but the extraordinary changes in human history have pushed these buffering mechanisms to the limit. The ancient limbic system that regulates mood now has to integrate high-level brain functions that have been around for just hundreds of thousands of years, not to mention cultural practices that have been around for just tens of thousands of days.

  As a result, we’re hypersensitive to new mutations that naturally appear in all those mood-related genes every generation. A person who happens to inherit several of these, no matter how rare they are, is at risk. It may take a few thousand generations to recalibrate. Or it may be that selection in modern humans is so weak that there never will be an opportunity to recalibrate and those little mutations will gradually accumulate in the gene pool. There’s a depressing note to end this chapter on: Maybe the ultimate fate of the human species is never-ending deterioration of our mental stability.

  7. The alzheimer’s generation

  slow walk to dementia Alzheimer’s disease (AD) is the gradual unraveling of memory in a virtual reversal of the lifetime assembly of the mind.

  alzheimer’s on the march By the age of 65, less than one percent have AD. By the age of 85, as many as half of us will have it. Without a cure, the Baby Boomer Generation may eventually go down in history as the Alzheimer’s Generation.

  tangles and plaques Tangles of Tao and plaques of Amyloid beta clog up the brain, but it is likely that these good proteins turn bad long before autopsy confirms their guilt.

  early onset FAD Familial AD is for those in their forties and is traced on the whole to just three genes, the building block and scissors that make Amyloid beta. If it is in the family, perhaps it is best to see a genetic counselor.

  late-onset LOAD The vast majority of AD is late onset, beyond retirement. There is one major risk factor, ApoE, but even that is far from diagnostic. The risk comes from our primate ancestors, and most people are actually protected by the modern allele.

  just growing old Extension of life span is one of the most remarkable of all human attributes, and the last two generations have seen the most dramatic gains in the history of life on Earth. No surprise then that we’re out of equilibrium, and that the most complex of our organs, the brain, often gives way first.

  Slow Walk to Dementia

  Surely the most aggravating sign of the teasing and fickle nature of our genes is their insistence on gradual decay. And there is no more certain sign of their power than the decline of Ronald Reagan. Within a decade of leaving the Oval Office of the White House, the man who helped bring the Soviet Union to its knees was himself reduced to a mental crawl by a handful of errant nucleotides sitting around in his genome.

  Many would say they saw the signs of Alzheimer’s disease well before he even left the Presidency. But who can say whether his inability to remember the press corps’ questions was an early sign of dementia, or the polished acting performance of a master politician? What we do know is that the course of the disease was little different from that which tens of millions of Americans now face. The gradual unraveling of the mind, the journey from maturity through despair to senility, unfolds as a mirror image of the 20-year journey from infancy through hope to adulthood.

  Nothing generalizes anxiety more than early signs of memory loss in middle age: misplacing the car keys on a regular basis, or forgetting the name of a casual co-worker at some embarrassing juncture. If someone in your family is known to have suffered from Alzheimer’s, perhaps only a great-uncle you never met, the natural presumption is that you are next in line, that the genes that somehow bypassed your parents have caught up with you and now sentence you to a decade of dementia—inevitably to the point where not only can you not recall a conversation from the day before, but you do not even recognize your own self.

  The fear is enhanced by the knowledge that close friends and family will bare the brunt of the burden. They will be the targets of your cantankerous acts of cruelty; they will take you to the bathroom and clean up the filth; they will daily live the hell that after a time becomes oblivious to you. They will be the ones who struggle after you are gone to displace the memories of your failing days with the positive images of the real person who accomplished so much, gave such love, and meant the world to so many.

  Then there is the financial worry. The majority of health care is spent on the last few years of life ordinarily, but with Alzheimer’s patients the costs are spread over a decade, many not covered by insurance. Nursing home care and medical expenses are estimated to start at $70,000 a year, considerably more than Social Security will cover, so they eat into savings meant to provide a long and happy retirement for your spouse, if not a nest egg for the kids. This equation doesn’t factor in the lost earnings of the daughter who gives up a couple of years and possibly a promising career to provide personal care.

  Adding further to the anguish is the inevitability of it all. Yes, eating more fish rich in omega-3 fatty acids helps ward off memory loss, ginkgo biloba seduces many into thinking it does, doing crossword and sudoku puzzles can’t hurt, and an active mental life is perhaps the best advice of all. A few years ago, Elan Pharmaceuticals grabbed headlines with a vaccine that showed enormous promise in halting the course of disease, until a fraction of patients came down with pathological inflammation of the brain. No one knows when a viable cure will emerge, so for now diagnosis of dementia is like a slow death sentence with little hope of reversal. May we each have the grace to deal with the progression with humor and understanding.

  Alzheimer’s on the March

  The generation affectionately known as the Baby Boomers may yet go down in history as Generation A, the top of the letter A standing for that great pyramid of aging boomers destined to suffer more from Alzheimer’s disease than any generation in history. The statistics are stark: more than 65,000 deaths a year, five million Americans with Alzheimer’s currently, that number set to nearly quadruple by midcentury and to be dwarfed by the worldwide burden in the year 2100.

  The probability of contracting Alzheimer’s doubles every three years after the age of 65. At retirement, only one percent of people are afflicted, but five percent have it in their early seventies, the fraction rises to one-quarter by the early eighties, and at least one half of all nonagenarians have AD. I have looked high and wide in an effort to ascertain whether this represents an epidemic independent of people just getting older, but there does not seem to be any clarity on the issue.

  You would think that since Dr. Alois Alzheimer described the first case only in 1901 there must have been a dramatic increase in incidence of this form of senile dementia in the past century. His patient, Auguste Deter, was a woman in her early fifties living in Frankfurt, Germany, who presented to a psychiatric clinic with symptoms of memory loss, delusions, and mindless episodic behavior. She died within five years, not just the first recorded case of Alzheimer’s disease, but also the first case of the early onset form. The good doctor was a colleague of Emil Kraepelin, the man widely regarded as the father of the view that psychological problems generally have an organic biological, rather than purely psychological, basis. Together they performed an astonishing series of histological examinations on Frau Deter’s brain after her death, describing the characteristic cellular anomalies that remain the only clear definition of the disease.

  This is part of the reason why it is so difficult to know whether AD is on the rise. Senile dementia has been widely recognized throughout recorded history, but until the last century was more likely seen as a normal phase of life than a disease that afflicts some people and not others. Only in the past decade or so has it been widely appreciated that around two-thirds of cases of acute dementia are actually this geneti
cally influenced disease. Without autopsy, there is no sure diagnosis, the major alternative explanation being vascular dementia: basically, the consequences of myriad small strokes that increase in frequency as a person ages, slowly degrading the brain tissue. To this day, I have no idea whether my own grandmother had AD. She certainly lost her memory, went through a cantankerous period, and had odd behavioral lapses in her nineties, but no diagnosis was ever made that we are aware of.

  It is well known that the average age of people has increased over the past century. In North America, Europe, and Australia, more people are in their late thirties than any other age group, and most of these can expect to live well into retirement. China is just a decade behind, South America two decades, and India will get there by the middle of the century. For this reason alone, the absolute number of Alzheimer’s patients is set to rise toward the billions worldwide as the century proceeds, as will the proportionate contribution to human morbidity.

  The key statistic, though, is whether the fraction of people in each old age group with Alzheimer’s is increasing. It probably is, suggesting that any genetic variants that predispose to Alzheimer’s are becoming more potent. Some would argue that really what is happening is that the proportion of older people who have chronic health problems is increasing, particularly those with diabetes or coronary heart disease. Companies that make daily pill boxes would seem to be just as good an investment as ones that make baby clothes. Since Alzheimer’s might well be correlated with these metabolic diseases, the at-risk population is growing as a proportion of the elderly, who used to be an unusually spritely bunch. Even so, we’re almost certainly once more seeing an effect of the modern environment interacting with the historical human genetic endowment to produce a common disease.

  Tangles and Plaques

  When I went to take my dogs for their walk this morning, Razzie’s leash had a knot in it. No big deal, it only took a minute to undo, though a minute is a long time for a puppy with a world outside to explore. The weird thing is that I have no idea how this happened, in the same way that it defies common sense for the garden hose to get itself all twisted precisely and only on those days when the far back corner of the lawn needs watering. It is clearly in the nature of things to get all tangled up.

  This is also why fishermen spend half their lives on dry land, repairing their nets. No matter what they trawl through, nets pick up all sorts of detritus and gunk that clogs things up, and attract ribbons of seaweed that weave their way around the strands. In time these begin to eat away at the net, leaving holes and leaky gaps, and left untended, before long the whole thing is useless.

  The brain too is a network, of axons and synapses, sadly vulnerable to decay as it trawls through oceans of thoughts. When Alois Alzheimer stained Auguste Deter’s brain, he found it to be gummed up with plaques and tangles, and this pathology turns out to be the hallmark of the dementia that takes his name. All that white and gray matter may seem random and disordered to the untrained eye, but it is actually highly organized, with layers of complexity seemingly added according to experience. As a child grows, the neurons tie together, searing memories into the very structure of the assembled synapses. As the plaques and tangles grow denser, they undo these memories and seed degeneration, and the patient’s thoughts regress in an orderly reversal of their maturation.

  The stages of undoing eerily mirror their creation. First the ability to perform professionally and complete complex tasks goes, followed by simpler daily chores such as cooking and organizing schedules and personal finances. Then the things we take for granted such as getting dressed and taking baths are no longer possible. Incontinence follows, along with the inability to speak and even express emotions with a smile, all because some people are prone to growing plaques and tangles as they pass retirement age.

  We know what they are and where they come from—they are made from our own genes—but have little idea yet why the acute accumulation occurs. The plaques are made of a jumble of protein pieces called Amyloid beta, or Aβ, peptides. These are cleaved from a longer protein known appropriately enough as Amyloid Precursor Protein (APP) that is thought to be required for normal brain development. The Aβ pieces probably don’t do much harm just floating around neurons on their own, but they can change their conformation and start aggregating into fibrils. When these are deposited outside the neurons they assemble into the characteristic Alzheimer’s plaques.

  Meanwhile, another essential protein, Tao, also aggregates inside the neurons, forming the so-called neurofibrillary tangles. Tao’s normal function is to stabilize the framework of the neurons: All cells have a kind of dynamic scaffold that keeps getting turned over, and Tao has an important and active role in this. If it becomes overactive, it assembles into long strands instead, creating the visible tangles.

  Two questions arise immediately. First, what is the relationship between Aβ, Tao, and dementia; and second, why does it take six decades for them to become pathological? I hope by now that you are not expecting a straight answer.

  For one thing, it is not at all clear any more that the plaques and tangles aren’t themselves just symptoms of whatever is going wrong. Toxic waste dumps are bad enough, but are just as much a sign that something else is going on that needs attending to. A growing body of evidence suggests that it is not so much the large plaques of Aβ aggregation that crop up between the brain cells, as it is the couplets or small gangs of these little protein pieces that are doing their damage inside cells. In the case of Tao, surely the long tangles aren’t much good for a person either, but they twist together only when they have gone absent without leave from their normal jobs. It also seems that they have a knack for making a royal pain of themselves, by glomming on to all sorts of proteins inside cells, including Aβ.

  The second question is even trickier, and I’d be lying if I implied that anyone has a good explanation for why proteins that work fine for 60 years suddenly turn bad. No one really knows why some of our finest writers remain as sharp and insightful into their nineties as they were in their prime, while others—Iris Murdoch and Ralph Waldo Emerson among them—are destined to lose their minds as surely as anyone else with AD. Something is disrupting a lifelong equilibrium between active forms of these proteins and their partners, setting off a chain of events that cascades into disease. It may have something to do with the oxidation and structural damage that nags away at us throughout our earthly time. But even this begs the question: Why some individuals but not others?

  Early Onset FAD

  A century after the disease was first described, we now have a good sense of the genetic factors leading to the early onset form that runs strongly in families. Three genes have been implicated: the precursor of Aβ and a pair of scissors that release it. These are thankfully rare forms of AD, but there are now more than 300 families in which three generations of early onset Alzheimer’s sufferers have been found. Most of these cases are attributable to one of more than 150 different mutations in the three genes. Some cases also clearly run in families but cannot be ascribed to these genes. For the most part, though, if there is a cluster of relatives all of whom show signs of dementia in their mid- to late forties, geneticists are likely to be able to devise a test that will tell younger family members whether they are likely to suffer as well.

  The most common culprit is called PRESENILIN-1, or PSEN1. Responsible for more than half of all early onset familial Alzheimer’s disease (FAD), it works in conjunction with the second culprit, PSEN2, to cut Aβ out of the APP precursor protein. Together they are part of the gamma secretase complex, not to be confused with the alpha and beta secretases. All these protein scissors have natural roles in appropriately cutting up APP (and various other proteins that need not concern us here, but feel free to look up Notch on the Internet). Alpha cuts off a bigger piece of APP that includes the start of Aβ, but it competes with beta for APP’s affections. The combination of beta with gamma ultimately drives up the levels of Aβ inside and outside n
eurons.

  Then there are the APP mutations, at least 15 known so far. Most of these change the genetic code exactly at the part of the protein that gamma secretase cleaves. One allele found in Sweden increases the ratio of beta to alpha secretase activity, others just increase them all, and some may even have the opposite effect. Ultimately, they all increase the amount of Aβ, or more precisely of an ever-so-slightly longer form of the protein that is just a little bit more pathological. All this stands to reason and confirms the causal role of this protein in promoting Alzheimer’s disease.

  APP is also the reason why adults with Down syndrome invariably also suffer from early onset Alzheimer’s. The gene is on chromosome 21, which is present in three copies, instead of the usual two, in Down’s people. Presumably with an extra copy of the gene, more APP is produced by the neurons, and this upsets the regular balance that the secretases deal with, resulting in prematurely high levels of Aβ. Most of the other Down’s features are thought to similarly arise because of an imbalance in the number of copies of one or more of the several hundred genes on chromosome 21. All but one of our other chromosomes are considerably bigger, and if a fetus has three copies of one of them by accident, it is likely to result in spontaneous abortion before too much development proceeds.

  Late Onset LOAD

  Late onset Alzheimer’s disease (LOAD) is a completely different story. It is more like all the other complex diseases we’ve considered so far. Although 50 percent of people with an affected brother, sister, or parent can expect to get Alzheimer’s by the time they reach their eighties, this percentage is not that different from the general population. It is natural to worry about your own fate when caring for a loved one, but the fact is that genetic counselors can tell you little about whether you are going to have senile dementia. On the other hand, if both sides of your family are clear, it is a good bet that you will be okay; but then it is better to look at it as though you are lucky enough to have an unusually protective genetic constitution.