MY FATHER'S IN THE MODERATE STAGE'S OF ALZHEIMER'S. HE'S NOT AS
SHARP AS HE ONCE WAS, ESPECIALLY IN REGARD TO HIS SHORT-TERM MEMORY. HE
STILL HAS HIS FACULTIES, BUT THEIR NOT FUNCTIONING AS EFFICIENTLY OR AT
THE HIGH LEVEL THAT THEY ONCE DID. WHAT'S THE CAUSE OF THIS? THE
LIFESTYLE HE LED FROM ABOUT AGE 40 ON, WHICH INCLUDES THE
DIET HE ATE COUPLED WITH HIS GENETIC PREDISPOSITION FOR THE DISEASE.
(THESE YOUNG PEOPLE SEE OR SPEAK TO MY FATHER IN OLD AGE, BUT AREN'T
GETTING AN ACCURATE IDEA OF WHO HE ONCE WAS. IN SOME RESPECTS HE'S
REVERTED TO HIS NEIGHBORHOOD DAYS.)
http://www.scientificamerican.com/article/genetic-risk-for-alzheimers-ignored-for-decades/?WT.mc_id=SA_Facebook
From a genetic standpoint, Alzheimer's disease has two forms of origin - the late onset sporadic and the early onset familial. Most Alzheimer's patients fall into the late onset category, accounting for 95 percent of the cases. The remaining 5 percent belong to the early onset familial type. The early onset, familial type of Alzheimer's disease occurs when certain genetic mutations get passed on from one generation to another. If one of the parents suffers from the early onset, familial type, the chances are that 50 percent of the children will likewise bear the disease. One defective gene passed on is enough for the development of the disease in a person. This type of Alzheimer's has been reported among individuals thirty to forty years old, hence the term "early onset." The late onset, sporadic type is composed of multiple factors that result in the occurrence of the disease. It can still be brought about by genetics, lifestyle, and environmental factors. Reports state that having a parent or a sibling with Alzheimer's significantly increases the chances that a person will get the late onset type.
The apolipoprotein e4 gene (APOE-4) has been implicated extensively in Alzheimer's. The presence of this risk gene can signify a late onset, sporadic type of the disease. APOE-4 is one of the APOE genes responsible for the regulation of protein production and transportation of cholesterol and fats among the cells in the body. Having at least one copy of the gene will increase the risk of getting Alzheimer's. It has been found that 40 percent of patients suffering from late onset, sporadic Alzheimer's have at least one copy of the APOE-4 gene. Alzheimer's disease can still develop in those who lack the APOE-4 gene, and from the percentage above, it can be concluded that genetics do play a minor role in the development of Alzheimer's. The majority of patients with Alzheimer's disease have been found not to have genetic risk factors at all...
Understanding Alzheimer's: An Introduction For Patients And Caregivers. Ali, p. 24.
http://blog.23andme.com/health-traits/a-genetic-variant-protective-against-alzheimers/?utm_source=twitter&utm_medium=tweet&utm_campaign=blog
This chapter is about the genetic diagnosis of two of the commonest diseases that afflict people, one a swift and merciless killer, the other a slow and relentless thief of memory: coronary heart disease and Alzheimer's disease. I believe we are in danger of being too squeamish and too cautious in using knowledge about the genes that influence both diseases, and we therefore stand at risk of committing the moral error of denying people access to life-saving research.
There is a family of genes called the apolipoprotein genes, or AP genes. They come in four basic varieties, called A, B, C and - strangely - E, though there are various different versions of each on different chromosomes. The one that interests us most is APOE, which happens to lie here on chromosome 19. To understand APOE's job requires a digression into the habits of cholesterol and triglyceride fats. When you eat a plate of bacon and eggs, you absorb much fat and with it cholesterol, the fat-soluble molecule from which so many hormones are made (see the chapter on chromosome 10). The liver digests this stuff and feeds it into the bloodstream for delivery to other tissues. Being insoluble in water, both triglyceride fats and cholesterol have to be carried through the blood by proteins called lipoproteins. At the beginning of the journey, laden with both cholesterol and fats, the delivery truck is called VLDL, for very-lowdensity lipoprotein. As it drops off some of its triglycerides, it becomes low-density lipoprotein, or LDL ('bad cholesterol'). Finally, after delivering its cholesterol, it becomes high-density lipoprotein, HDL ('good cholesterol') and returns to the liver for a new consignment.
The Alzheimer's disease promoting APOE4 gene is a double-edged sword, detrimental to the old, benefitting the young, http://www.sciencedirect.com/science/article/pii/B9780128040423001032#s0065 …
What marks APOE out as special is that it is so 'polymorphic'. Instead of us all having one version of the gene, with rare exceptions, APOE is like eye colour: it comes in three common kinds, known as E2, E3 and E4. Because these three vary in their efficiency at removing triglycerides from the blood, they also vary in their susceptibility to heart disease. In Europe, E3 is both the 'best' and the commonest kind: more than eighty per cent of people have at least one copy of E3 and thirty-nine per cent have two copies. But the seven per cent of people who have two copies of E4 are at markedly high risk of early heart disease, and so, in a slightly different way, are the four per cent of people who have two copies of E2.
But that is a Europe-wide average. Like many such polymorphisms, this one shows geographical trends. The further north in Europe you go, the commoner E4 becomes, at the expense of E3 (E2 remains roughly constant). In Sweden and Finland the frequency of E4 is nearly three times as high as in Italy. So, approximately, is the frequency of coronary heart disease. Further afield, there are even greater variations. Roughly thirty per cent of Europeans have at least one copy of E4; Orientals have the lowest frequency at roughly fifteen per cent; American blacks, Africans and Polynesians, over forty per cent; and New Guineans, more than fifty per cent. This probably reflects in part the amount of fat and fatty meat in the diet during the last few millennia. It has been known for some while that New Guineans have little heart disease when they eat their traditional diet of sugar cane, taro and occasional meals of lean bush meat from possums and tree kangaroos. But as soon as they get jobs at strip mines and start eating western hamburgers and chips, their risk of early heart attacks shoots up - much more quickly than in most Europeans.
Heart disease is a preventable and treatable condition. Those with the E2 gene in particular are acutely sensitive to fatty and cholesterol-rich diets, or to put it another way, they are easily treated by being warned off such diets. This is extremely valuable genetic knowledge. How many lives could be saved, and early heart attacks averted, by simple genetic diagnosis to identify those at risk and target treatment at them?
Genetic screening does not automatically lead to such drastic solutions as abortion or gene therapy. Increasingly a bad genetic diagnosis can lead to less drastic remedies: to the margarine tub and the aerobics class. Instead of warning us all to steer clear of fatty foods, the medical profession must soon learn to seek out which of us could profit from such a warning and which of us can relax and hit the ice cream. This might go against the profession's puritanical instincts, but not against its Hippocratic oath.
However, I did not bring you to the APOE gene chiefly to write about heart disease, though I fear I am still breaking my rule by writing about another disease. The reason it is one of the most investigated genes of all is not because of its role in heart disease, but because of its preeminent role in a much more sinister and much less curable condition: Alzheimer's disease. The devastating loss of memory and of personality that accompanies old age in so many people — and that occurs in a few people when quite young - has been attributed to all sorts of factors, environmental, pathological and accidental. The diagnostic symptom of Alzheimer's is the appearance in brain cells of 'plaques' of insoluble protein whose growth damages the cell. A viral infection was once suspected to be the cause, as was a history of frequent blows to the head. The presence of aluminum in the plaques threw suspicion on aluminum cooking pots for a while. The conventional wisdom was that genetics had little or nothing to do with the disease. 'It is not inherited,' said one textbook firmly.
But as Paul Berg, co-inventor of genetic engineering, has said, 'all disease is genetic' even when it is also something else. Pedigrees in which Alzheimer's disease appeared with high frequency were eventually discovered among the American descendants of some Volga Germans and by the early 1990s at least three genes had been associated with early-onset Alzheimer's disease, one on chromosome 21 and two on chromosome 14. But a far more significant discovery in 1993 was that a gene on chromosome 19 seemed to be associated with the disease in old people and that Alzheimer's in the elderly might also have a partial genetic basis. Quite soon the culprit gene was discovered to be none other than APOE itself.
The association of a blood-lipid gene with a brain disease should not have come as such a surprise as it did. After all, it had been noticed for some time that Alzheimer's victims quite often had high cholesterol. None the less, the scale of the effect came as a shock. Once again, the 'bad' version of the gene is E4. In families that are especially prone to Alzheimer's disease, the chances of getting Alzheimer's are twenty per cent for those with no E4 gene and the mean age of onset is eighty-four. For those with one E4 gene, the probability rises to forty-seven per cent and the mean age of onset drops to seventy-five. For those with two E4 genes, the probability is ninety-one per cent and the mean age of onset sixty eight years. In other words, if you carry two E4 genes (and seven per cent of Europeans do), your chances of eventually getting Alzheimer's disease are much greater than those of the population a large. There will still be some who escape either fate - indeed, one study found an eighty-six-year-old E4/E4 man with all his wits. In many people who show no symptoms of memory loss, the classic plaques of Alzheimer's are none the less present, and they are usually worse in E4 carriers than E3. Those with at least one E2 version of the gene are even less likely to get Alzheimer's than those with E3 genes, though the difference is small. This is no accidental side effect or statistical coincidence: this looks like something central to the mechanism of the disease.
Recall that E4 is rare among Oriental people, commoner among whites, commoner still among Africans and commonest in New Guinean Melanesians. It should follow that Alzheimer's obeys the same gradient, but it is not quite so simple. The relative risk of getting Alzheimer's is much higher for white E4/E4S than for black or Hispanic E4/E4S - compared with the risk for E3/E3S. Presumably, susceptibility to Alzheimer's is affected by other genes, which vary between different races. Also, E4's effects seem to be more severe among women than men. Not only do more women than men get Alzheimer's, but females who are E4/E3 aRe just as AT RISK as those who are E4/E4. Among men, having one E3 gene reduces risk.
You may be wondering why E4 exists at all, let alone at such high frequencies. If it exacerbates both heart disease and Alzheimer's, it should surely have been driven extinct by the more benign E3 and E2 long ago. I'm tempted to answer the question by saying that high-fat diets were until recently so rare that the coronary side-effects were of little importance, while Alzheimer's disease is all but irrelevant to natural selection, since it not only happens to people who have long ago reared their own children to independence, but strikes at an age when most Stone-Age folk were long dead anyway. But I am not sure that is a good enough answer, because meaty and even cheesy diets have been around a long time in some parts of the world — long enough for natural selection to go to work. I suspect that E4 plays yet another role in the body, which we do not know about, and at which it is better than E3. Remember: GENES ARE NOT THERE TO CAUSE DISEASES.
The difference between E4 and the commoner E3 is that the 334th 'letter' in the gene is G instead of A. The difference between E3 and E2 is that the 472nd 'letter' is a G instead of an A. The effect is to give E2's protein two extra cysteines and E4's two extra arginines compared with each other, E3 being intermediate. These tiny changes in a gene that is 897 'letters' long are sufficient to alter the way APOE's protein does its job. Quite what that job is remains obscure, but one theory is that it is to stabilise another protein called tau, which is supposed in turn to keep in shape the tubular 'skeleton' of a neuron. Tau has an addiction to phosphate, which prevents it doing its job; APOE's job is to keep tau off the phosphate. Another theory is that APOE's job in the brain is not unlike its job in the blood. It carries cholesterol between and within brain cells so they can build and repair their fat-insulated cell membranes. A third and more direct theory is that, whatever APOE's job, the E4 version has a special affinity for something called amyloid beta peptide, which is the substance that builds up inside neurons of Alzheimer's sufferers. Somehow, it assists the growth of these destructive plaques.
The details will matter one day, but for now the important fact is that we are suddenly in possession of a means of making predictions. We can test the genes of individuals and make very good forecasts about whether they will get Alzheimer's disease. The geneticist Eric Lander recently raised an alarming possibility. We now know that Ronald Reagan has Alzheimer's, and it seems likely in retrospect that he had the early stages of the disease when he was in the White House. Suppose that some enterprising but biased journalist, anxious to find some way of discrediting Reagan as a presidential candidate in 1979, had snatched a napkin on which Reagan had wiped his mouth and tested the DNA on it (gloss over the fact that the test was not then invented). Suppose he had discovered that this second-oldest-ever presidential candidate was very likely to develop the disease in his term of office and had printed this finding in his newspaper.
The story illustrates the dangers for civil liberties that genetic testing brings with it. When asked if we should offer APOE tests to individuals curious to know if they will get Alzheimer's, most in the medical profession say no. After cogitating on the issue recently, the Nuffield Council on Bioethics, Britain's leading think-tank on such matters, reached the same conclusion. To test somebody for a disease that is incurable is dubious at best. It can buy reassurance for those who find themselves with no E4 gene, but at a terrible price: the almost-certain sentence to an incurable dementia for those with two E4 genes. If the diagnosis were absolutely certain, then (as Nancy Wexler argued in the case of Huntington's - see the chapter on chromosome 4), the test could be even more devastating. On the other hand, it would at least not be misleading. But in cases where there is less certainty, such as the APOE case, the test would be of still less value. You can still - if you are very lucky — have two E4 genes and live to an old age with no symptoms, just as you can still - if you are very unlucky - have no E4 genes and get Alzheimer's at sixty-five. Since a diagnosis of two E4 genes is neither sufficient nor necessary to predict Alzheimer's, and since there is no cure, you should not be offered the test unless you are already symptomatic.
At first I found all these arguments convincing, but now I am not so sure. After all, it has been considered ethical to offer people the test for the HIV virus if they want it, even though AIDS was (until recently) incurable. AIDS is not an inevitable outcome of HIV infection: some people survive indefinitely with HIV infection. True, there is in the case of AIDS the additional interest of society in preventing the spread of the infection, which does not apply to Alzheimer's disease, but it is the individual at risk we are considering here, not society at large. The Nuffield Council addresses this argument by implicitly making a distinction between genetic and other tests. To attribute a person's susceptibility to an illness to their genetic make-up distorts attitudes, argued the report's author, Dame Fiona Caldicott. It makes people believe wrongly that genetic influences are paramount and causes them to neglect social and other causes; that, in turn, increases the stigma attached to mental illness.
This is a fair argument unfairly applied. The Nuffield Council is operating a double standard. 'Social' explanations of mental problems offered by psychoanalysts and psychiatrists are licensed to practise on the flimsiest of evidence, yet they are just as likely to stigmatise people as genetic ones. They continue to flourish while the great and the good of bioethics outlaw diagnoses that are supported by evidence merely because they are genetic explanations. In striving to find reasons to outlaw genetic explanations while allowing social ones to flourish, the Nuffield Council even resorted to calling the predictive power of the APOE4 test Very low' - bizarre wording for an eleven-fold difference in risk between the E4/E4S and the E3/E3s. As John Maddox has commented, citing APOE as a case in point, 'There are grounds for suspecting that physicians are not pursuing valuable opportunities out of diffidence at revealing unwelcome genetic information to their patients . . . but diffidence can be taken too far.'
Besides, although Alzheimer's disease is incurable, there are already drugs that alleviate some of the symptoms and there may be precautions of uncertain value that people can take to head it off. Is it not better to know if one should take every precaution? If I had two E4 genes, I might well want to know so that I could volunteer for trials of experimental drugs. For those who indulge in activities that raise their risk of Alzheimer's disease, the test certainly makes sense. It is, for example, now apparent that professional boxers who have two E4 genes are at such risk of developing early Alzheimer's that boxers are indeed best advised to take a test and not box if they find themselves with two E4S. One in six boxers get Parkinson's disease or Alzheimer's — the microscopic symptoms are similar, though the genes involved are not - by the age of fifty, and many, including Mohammed Ali, suffer even younger. Among those boxers who do get Alzheimer's, the E4 gene is unusually common, as it is among people who suffer head injury and later turn out to have plaques in their neurons.
What is true for boxers may be true for other sports in which the head is struck. Alerted by anecdotal evidence that many great footballers sink into premature senility in old age — Danny Blanchflower, Joe Mercer and Bill Paisley being sad, recent examples from British clubs — neurologists have begun to study the prevalence of Alzheimer's disease in such sportsmen. Somebody has calculated that a soccer player on average heads the ball 800 times in a season; the wear and tear could be considerable. A Dutch study did indeed find worse memory loss in footballers than in other sportsmen and a Norwegian one found evidence of brain damage in soccer players. Once more it is plausible that the E4/E4 homozygotes might benefit from at least knowing at the outset of their careers that they were specially at risk. As somebody who frequently hits his head on door frames because architects have not made them big enough for tall people to walk through, I wonder myself what my APOE genes looks like. Maybe I should have them tested.
Testing could be valuable in other ways. At least three new Alzheimer's drugs are in development and testing. One that is already here, tacrine, is now known to work better in those with E3 and E2 genes than in E4 carriers. Again and again the genome drives home the lesson of our individuality. The diversity of humanity is its greatest message. Yet there is still a marked reluctance in the medical profession to treat the individual rather than the population. A treatment that is suitable for one person may not suit another. Dietary advice that could save one person's life might do no good at all to another. The day will come when a doctor will not prescribe you many kinds of medicine until he has checked which version of a gene or genes you have. The technology is already being developed, by a small Californian company called Affymetrix among others, to put a whole genome-full of genetic sequences on a single silicon chip. One day we might each carry with us exactly such a chip from which the doctor's computer can read any gene the better to tailor his prescription to us.
Perhaps you have already sensed what the problem with this would be - and what is the real reason behind the experts' squeamishness about APOE tests. Suppose I do have E4/E4 and I am a professional boxer. I therefore stand a much higher than average chance of contracting angina and premature Alzheimer's disease. Suppose that today, instead of going to see my doctor, I am going to see an insurance broker to arrange a new life-insurance policy to go with my mortgage, or to get health insurance to cover future illness. I am handed a form and asked to fill in questions about whether I smoke, how much I drink, whether I have AIDS and what I weigh. Do I have a family history of heart disease? - a genetic question. Each question is designed to narrow me down into a particular category of risk so that I can be quoted an appropriately profitable, but still competitive premium. It is only logical that the insurance company will soon ask to see my genes as well, to ask if I am E4/E4, or if I have a pair of E3s instead. Not only does it fear that I might be loading up on life insurance precisely because I know from a recent genetic test that I am doomed, thus ripping it off as surely as a man who insures a building he plans to burn down. It also sees that it can attract profitable business by offering discounts to people whose tests prove reassuring. This is known as cherry picking, and it is exactly why a young, slim, heterosexual non-smoker already finds he can get life insurance cheaper than an old, plump, homosexual smoker. Having two E4 genes is not so very different.
Little wonder that in America health-insurance companies are already showing interest in genetic tests for Alzheimer's, a disease that can be very costly for them (in Britain, where health cover is basically free, the main concern is life insurance). But mindful of the fury the industry unleashed when it began charging homosexual men higher premiums than heterosexuals to reflect the risk of AIDS, the industry is treading warily. If genetic testing were to become routine for lots of genes, the entire concept of pooled risk, on which insurance is based, would be undermined. Once my exact fate is known, I would be quoted a premium that covered the exact cost of my life. For the genetically unfortunate, it might prove unaffordable: they would become an insurance underclass. Sensitive to these issues, in 1997 the insurance industry association in Britain agreed that for two years it would not demand genetic tests as a condition of insurance and would not (for mortgages smaller than £100,000) demand to know the results of genetic tests you may already have taken. Some companies went even further, saying that genetic tests were not part of their plans. But this shyness may not last.
Why do people feel so strongly about this issue, when it would in practice mean cheaper premiums for many? Indeed, unlike so many things in life, genetic good fortune is equitably distributed among the privileged as well as the less privileged - the rich cannot buy good genes and the rich spend more on insurance anyway. The answer, I think, goes to the heart of determinism. A person's decision to smoke and drink, even the decision that led to his catching AIDS, was in some sense a voluntary one. His decision to have two E4 genes at the APOE gene was not a decision at all; it was determined for him by nature. Discriminating on the basis of APOE genes is like discriminating on the basis of skin colour or gender. A nonsmoker might justifiably object to subsidising the premium of a smoker by being lumped with him in the same risk category, but if an E3/E3 objected to subsidising the premium of an E4/E4, he would be expressing bigotry and prejudice against somebody who was guilty of nothing but bad luck.
The spectre of employers using genetic tests to screen potential staff is less fraught. Even when more tests are available, there will be few temptations for employers to use them. Indeed, once we get more used to the idea that genes lie behind susceptibilities to environmental risks, some tests might become good practice for employer and employee alike. In a job where there is some exposure to known carcinogens (such as bright sunlight - the job of lifeguard, say), the employer may in future be neglecting his duty of care to his workers if he employs people with faulty p53 genes. He might, on the other hand, be asking applicants to take a genetic test for more selfish motives: to select people with healthier dispositions or more outgoing personalities (exactly what job interviews are designed to do), but there are already laws against discrimination.
Meanwhile, there is a danger that the hobgoblin of genetic insurance tests and genetic employment tests will scare us away from using genetic tests in the interests of good medicine. There is, however, another hobgoblin that scares me more: the spectre of government telling me what I may do with my genes. I am keen not to share my genetic code with my insurer, I am keen that my doctor should know it and use it, but I am adamant to the point of fanaticism that it is my decision. My genome is my property and not the state's. It is not for the government to decide with whom I may share the contents of my genes. It is not for the government to decide whether I may have the test done. It is for me. There is a terrible, paternalist tendency to think that 'we' must have one policy on this matter, and that government must lay down rules about how much of your own genetic code you may see and whom you may show it to. It is yours, not the government's, and you should always remember that.
Genome: Autobiography of a Species in 23 Chapters. Ridley, p. 259-270.
http://gamechangers.ru/sites/default/files/genome_the_autobiography_of_a_species_in_23_chapters_-_matt_ridley_0.pdf
