Cognitive ability: use it or lose it?

A study just published in the Journal of Economic Perspectives tells us that if we want to retain our cognitive ability into old age we shouldn't retire.  The old 'use it or lose it' axiom.  But, as Gina Kolata points out in the NYT write up about the study, it could just be that people who are losing their cognitive skills retire earlier than those who aren't.  Does this study sort this out?

The authors analyzed the results of memory tests given to 22,000 Americans over age 50, administered by the National Institute on Aging every 2 years.  The test is a measure of how well people remember a list of 10 nouns immediately after hearing them, and then 5 or so minutes later, after having been asked other survey questions.  A perfect score would be 20.  Studies have been done in a number of countries in Europe and Asia, so that cross-cultural comparisons can be made.

As Kolata wrote,

People in the United States did best, with an average score of 11. Those in Denmark and England were close behind, with scores just above 10. In Italy, the average score was around 7, in France it was 8, and in Spain it was a little more than 6.

Examining the data from the various countries, Dr. Willis and his colleague Susann Rohwedder, associate director of the RAND Center for the Study of Aging in Santa Monica, Calif., noticed that there are large differences in the ages at which people retire.

In the United States, England and Denmark, where people retire later, 65 to 70 percent of men were still working when they were in their early 60s. In France and Italy, the figure is 10 to 20 percent, and in Spain it is 38 percent.

So, if it's true that retirement leads to cognitive decline, what is it about retirement that would do this?  It's hard to think of a single factor that all employment shares, other than a paycheck -- not everyone has a schedule, or punches a clock, or irons a shirt in the morning, or has to be at an office at 9, or socializes at the water cooler, or leaves their work behind when they go home at 5.  We can't even say that everyone must be competent at their job (see our post on the Ig Nobel prize winning paper about this very subject.)  And certainly not everyone is happy at work.  Similarly, not all retirements are equal.  So what's the common denominator?

The authors propose two possible answers.  One is the "unengaged lifestyle hypothesis", or mental retirement which accompanies actual retirement.  The other is that with the prospect of retirement, the soon-to-be-retiree slows down mentally in preparation, and stops "investing in human capital".  The "on the job" retirement effect.

Well, neither of these are very compelling explanations to us for a number of reasons including that a lot of people are busier in retirement than when they were employed, and we all know employed people who checked out long before they even gave retirement a thought.

Indeed, a number of further questions remain unanswered, in addition to Kolata's question of which came first, retirement or decline.  What would the slope of the line look like in 10 year olds cross culturally, for example?  Or  40 year olds?  That is, is the difference in ability (and, by the way, the top score, 11 words remembered correctly out of 20, doesn't strike us as all that good!) only apparent in older people?  Does the ability to remember 10 words actually indicate cognitive abilities such as reasoning or logic?

And, of course, there's the Bear Bryant phenomenon that we have to think about here at Penn State. Bear Bryant was the legendary coach of the University of Alabama football team.  At the tender age of 69, perhaps knowing that his best years were behind him, he decided to retire.  When a reporter asked him what he would do in retirement, he joked that in a week he'd be dead.  Four weeks later, he was!

Now this is relevant because our coach here at Penn State, the even more legendary Joe Paterno, is about to turn 84, with 2 years remaining on his contract.  That may be more games than his team will win the rest of the year, but the point here is that there have been quips that he doesn't want to end up like Bear Bryant.  So if he never retires.....he'll be immortal!

So the premonition spook could be a factor in peoples' retirement decisions, when, or perhaps if, they have a choice.

But before we decide to work til we drop, or work so we won't, we need to see the results of a more rigorous study.

It's stressful, worrying about dementia

Remember the big news just a few months ago about the declining incidence of dementia?  There was a story in the New York Times, and many other sites, about a couple of papers in The Lancet (papers here and here.)  We blogged about it at the time.  Gina Kolata in the NYT said this:

A new study has found that dementia rates among people 65 and older in England and Wales have plummeted by 25 percent over the past two decades, to 6.2 percent from 8.3 percent, a trend that researchers say is probably occurring across developed countries and that could have major social and economic implications for families and societies. 

Another recent study, conducted in Denmark, found that people in their 90s who were given a standard test of mental ability in 2010 scored substantially better than people who had reached their 90s a decade earlier. Nearly one-quarter of those assessed in 2010 scored at the highest level, a rate twice that of those tested in 1998. The percentage of subjects severely impaired fell to 17 percent from 22 percent.

Er, but now a study published in BMJ Open this week reports that the more stress women experience in middle age, the higher their risk of dementia as they get older.  This was a prospective study of 800 Swedish women born in 1914, 1918, 1922 and 1930, who underwent a psychiatric examination in 1968, and who were re-examined in 1974, 1980, 1992, 2000 and 2005. They were asked whether they had undergone any of 18 major stressors, including divorce, widowhood, work-related stress and illness of a relative.

Anonymous German picture puzzle, 19th C; source

In the 37 years of follow-up, 19.1% or 153 women developed dementia (425 of the subjects had died over the course of the study), and number of stressors was found to be associated with risk.  And, importantly, risk and number of psychosocial stressors was "independent of long-standing perceived distress." 

Our study shows that common psychosocial stressors may have severe and long-standing physiological and psychological consequences. However, more studies are needed to confirm these results and investigate whether more interventions such as stress management and behavioural therapy should be initiated in individuals who have experienced psychosocial stressors.

What's the mechanism?  The idea is that long-standing exposure to stress hormones may cause "dysregulation in neuroendocrine systems".   But the researchers don't find a one-to-one correlation between stress in midlife and dementia -- that is, not everyone who reported stress became demented and not everyone with dementia had reported major stresses.  The investigators suggest that that is because individuals respond differently to stress.

Well, that's a bit hand-wavy.  Of course, it's always difficult, or even impossible, to apply associations found at the population level to individuals.  Not everyone with high cholesterol levels has a heart attack, and not everyone with high stress will become demented, even if cholesterol and stress are real risk factors.  It means that there are other, unmeasured risk factors involved, that the effect of stress or cholesterol depends on or interacts with unknown variables. So, of course more research is needed (she said snidely).  Or... a different approach to understanding causation. 

But, let's go back to the Lancet papers of July, that reported that incidence of dementia is going down.  Yes, that's on a population level, and it's possible that everyone with dementia in these studies (samples in Denmark, England and Wales) experienced more stress in midlife than those without.   But, if stress is a strong risk factor for dementia, and we were to accept that rates of dementia are really going down, then this would mean that levels of stress in midlife are declining as well.  That is, by the measures in the BMJ Open study, less work-related stress, less divorce, less family illness and fewer parents dying.  Not likely.

Now, it's possible that the younger cohorts in the Swedish study will or did experience less dementia than those born earlier, as in the Danish and British studies, but that question wasn't asked of the data, and anyway the sample size is too small to show a reliable effect if it's stratified by birth cohort.  So, we don't know if incidence of dementia is falling in Sweden as it seems to be elsewhere.  But if it is, that means, to us at least, that something is overriding the effect of stress as a risk factor. 

Do we know more now than we did last year about predicting who'll get dementia in old age?  Another way to put this is: will we know more in 6 months than we do now?  And yet another way is: at what point should we start believing any of these stories?  More generally, is there a better way to understand causation?  At present, for whatever reason, we seem to be doing little more than groping for a black cat in the dark. 

Faith in science? Industrialized agriculture and antibiotic resistance

Someone asked me the other day on Twitter whether I thought that the words "science" and "belief" were compatible.  I said yes, though I know that a lot of scientists think (...believe...) that faith has nothing to do with science.  Science is facts, faith is religion, based on sacred texts and the like, which are basically hearsay without empirically acceptable evidence.  But, the history of science indicates that this distinction is far from being so simple -- there was a time when people believed that the moon was made of cheese, diseases were caused by bad air, Newton was right about physics, the continents didn't move.  And these beliefs were based on empirical evidence, observation -- dare I say 'facts'? -- not mere guesswork.

In that light, two recent pieces about the role of agriculture in the rise of antibiotic resistance are interesting.  The New York Times described a new study in the Journal of Occupational and Environmental Medicine ("Persistence of livestock-associated antibiotic-resistant Staphylococcus aureus among industrial hog operation workers in North Carolina over 14 days," Nadimpalli et al.)
that reports that workers at industrial hog farms can carry antibiotic-resistant bacteria, Staphylococcus aureus, in their nostrils for up to four days.

Twenty-two workers provided 327 samples. S. aureus carriage end points did not change with time away from work (mean 49 h; range greater than 0-96 h). Ten workers were persistent and six were intermittent carriers of livestock-associated S. aureus. Six workers were persistent and three intermittent carriers of livestock-associated multidrug-resistant S. aureus. One worker persistently carried livestock-associated methicillin-resistant S. aureus. Six workers were non-carriers of livestock-associated S. aureus. Eighty-two per cent of livestock-associated S. aureus demonstrated resistance to tetracycline. A majority of livestock-associated S. aureus isolates (n=169) were CC398 (68%) while 31% were CC9. No CC398 and one CC9 isolate was detected among scn-positive isolates.

As the NYT piece notes, eight-six percent of this sample of hog farm workers carried bacteria for at least 24 hours, compared with about one-third of the non-farm worker population.

This is a problem because the resistant variety of S. aureus, MRSA, has made its way into hospitals and is responsible for thousands of deaths.  Further, many people believe that industrial farming is the cause of much of the antibiotic resistance that is now becoming such a problem, because animals are fed antibiotics to speed their growth, and many of those antibiotics are used to treat human diseases.  Indeed, the majority of the antibiotics used in the industrialized world are given to animals.  When bacteria on the farm become resistant to antibiotics, as this study shows, they don't necessarily stay on the farm.  How they spread has been difficult to document, but might include consumption of contaminated meat, and Nadimpalli et al. report another pathway.

Hog farm; Wikipedia

Responding to the increase in antibiotic resistance that many believe industrial farming to be responsible for, the US Food and Drug Administration this year put a voluntary ban on the use of antibiotics for growth promotion. Critics saw this as a weak response to a very large problem, but pharmaceutical companies and some farmers say it will do what it is meant to do; reduce the use of antibiotics for non-medical purposes, and thus reduce the possible evolution of resistant bacteria that are harmful to humans. Of course one always has to ask the political question of who wields the power and influence over any sort of decision that may affect a particular industry.

But much of this is controversial. Is agricultural use of antibiotics in fact to blame for the problem, or is it overuse of antibiotics by the medical system?  Indeed, there's less of a problem in, say, Scandinavian countries where for decades physicians have prescribed antibiotics at a much lower rate than they have done in the US. Do resistant bacteria really spread in considerable numbers from farm to city?  This may be less controversial with the publication of the Nadimpalli et al. paper, but critics will say that the sample size was small and anyway, documenting a mechanism doesn't mean this is what has happened.

We all tend to pick and choose facts to support our convictions.  Indeed, if you look at how scientists, in any field, cling to their explanations, 'convictions' is perhaps a muted term for what is being clung to.  How we think about these questions may well reflect what we believe more generally about the food system, how or even whether animals should be farmed for meat, whether we patronize farmers'  markets rather than industrially produced food, and so forth rather than what we, or anyone, actually know about the causes of antibiotic resistance.  That is, our personal sociopolitical positions seem clearly be correlated with, if not strongly influencing, our scientific position.

Yesterday, an opinion piece by Iowa veterinarian and pig farmer Howard Hill appeared in our local paper, and in papers around the country.  Hill believes that farmers are being unfairly blamed for antibiotic resistance in humans.

...the claim that "70 to 80 percent of all antibiotics sold in the United States each year are used in livestock" is a straw man. More than a third of those drugs aren't used in human medicine, another third are not considered highly important to human medicine, and most of them aren't used for growth promotion. Critics also ignore the fact that there are a lot more cows, pigs and chickens than people. In 2011, for example, 30 million pounds of antibiotics were sold for use in more than 3 billion livestock and poultry, compared with 7 million pounds for 311 million people, meaning each person used nearly five times more antibiotics than were used in each food animal.

Is he making selective use of the data?  Yes, but isn't everyone who talks about this issue?  And does that make our assertions wrong?  Doesn't prior belief influence our understanding of what the data show?

While Rome burns
President Obama yesterday issued an executive order aimed at combating antibiotic resistance.  The order accepts that industrial agriculture may have a role in increasing resistance, but it adds little to the FDA order of several months ago:

The Food and Drug Administration (FDA) in HHS, in coordination with the Department of Agriculture (USDA), shall continue taking steps to eliminate the use of medically important classes of antibiotics for growth promotion purposes in food-producing animals.

Not many teeth here.  Years ago Europe took much the same approach, requiring that the use of antibiotics for growth promotion be reduced, but a lot of reclassification of antibiotic use for medical purposes followed, as many expected in the US following the FDA announcement last December, which we blogged about here,  and again with this Executive Order.

Again in Scandinavia, the use of antibiotics for growth promotion has been banned, beginning in Sweden in 1986, but farmers have not suffered.  According to a piece in the BCMJ in 2011:

In 1986, Sweden became the first country to regulate the withdrawal of antibiotics used in food animal production. By 2009, Swedish sales of antibiotics for use in agriculture were reduced from an average of 45 tons of active substance to 15 tons. Sweden was followed by Denmark, the United Kingdom, and the Netherlands. 

Danish swine and poultry production continued to flourish with gradual reductions of antibiotic use beginning in 1992 and continuing to 2008 (latest data). During this time, Danish farmers increased swine production by 47% while reducing antimicrobial use by 51%. As well, poultry production increased slightly while reducing antimicrobial use by 90%. Denmark remains one of the largest pork ex­porters in the world.

So, whether or not growth promoting antibiotic use in animals is a major cause of resistance is not really an issue, and we needn't even continue to have the discussion.  If there is any chance it is, why not ban it entirely?  Experience in Scandinavia suggests there won't be dire economic consequences -- unless you're a pharmaceutical company making antibiotics for animals.

Faith in science
We have often written here about the economic interests that drive the course of Big Science.  Can we have faith in science if there is considerable faith in science?  People are, after all, only human, and people of all faiths, including science, defend their faiths.  Further, it's often impossible to disentangle belief from vested interest.   If you've got a hammer, or a hammer to sell, everything looks like a nail.

Autism -- back to blaming the mother?

Two recent reports of the cause of autism reach different conclusions, though they are alike in that neither implicates genetics, at least not directly.  The first, published in the International Journal of Epidemiology ("Maternal lifestyle and environmental risk factors for autism spectrum disorders," Lyall et al.), reviews the evidence for environmental risk factors and finds that diet can influence risk, and that folic acid supplements taken around conception are associated with reduced risk.  Further,

Although many investigations have suggested no impact of maternal smoking and alcohol use on ASD [autism spectrum disorder], more rigorous exposure assessment is needed. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically.

Lyall et al. call for larger epidemiological studies of maternal exposure to vitamins, fats and other nutrients, as well as pesticides and endocrine-disrupting chemicals, even though environmental epidemiological studies of autism have been done for decades.

The second paper, in  Molecular Psychiatry ("Elevated fetal steroidogenic activity in autism," Baron-Cohen et al.), reports the results of looking at hormone levels in amniotic fluid samples collected at between 15 and 16 weeks gestation from a sample taken from a registry of nearly 20,000 male infants in Denmark, born between 1993 and 1999.  The final sample was fairly small, including 128 male infants with autism and 217 controls; the 24 females in the registry who were later diagnosed with autism were excluded from the study because they were atypical for a variety of reasons.  Prevalence of autism is generally higher in males.

We find that amniotic fluid steroid hormones are elevated in those who later received diagnoses on the autism spectrum. Rather than the abnormality being restricted to a specific steroid hormone, a latent steroidogenic factor is elevated, which includes all hormones in the Δ4 pathway, as well as cortisol.

The effect on the developing brain, Baron-Cohen et al. suggest, may be epigenetic.  That is, steroids modify DNA in ways that affect gene expression without changing coding sequence.

Steroids and their receptors act as epigenetic fetal programming influences on early brain development. Through their nuclear hormone receptors, steroids can alter gene expression via direct or indirect influence on multiple epigenetic processes such as histone acetylation, DNA methylation and have transcriptional and post-transcriptional effects on noncoding mRNAs such as microRNAs. Furthermore, during early sensitive periods of brain development, there are sex differences in DNA methylation, methyl-binding proteins, chromatin modifications and microRNA expression, and these effects are mediated in part by early steroid hormone effects.

What is the source of the excess steroid?  "The fetus, the mother, the placenta or other external factors" -- that is to say, it could be anything and this study couldn't answer that question.  Indeed, it is also impossible to know, if the excess hormone really is involved, whether it's the cause of the disorder or the result.  Perhaps maternal stress is the source, the authors suggest, and perhaps, the authors note, steroids such as testosterone and cortisol are also elevated in other disorders with a skewed sex ratio.  In any case, they write, "Each of these sources require further investigation to determine how such influences might affect fetal development in autism."

Cortisol molecule

A story on the BBC website about this work quotes an autism "expert" saying that this is "an important first step" on the path to discovering what causes autism.  First step!? This is a curious way to describe things, since probably billions of dollars have been spent in the last 30 or 40 years on efforts to identify the cause of this disorder, much of it on genetic studies, with no robust results.  Given this track record, what criteria should we use to decide whether this study is worth paying any attention to?

As with many complex diseases and disorders, many genes with small effect have been identified, but none of these explains the high rates of autism now reported around the world.  It is interesting to see these two reports of possible environmental risk factors after a sea of genetic studies, though.  Decades ago autism was believed to be the result of "refrigerator mothering," but then blame swung toward genes and away from environment, and now it seems autism is epigenetic. The gene switch never could have been exactly right given the dramatic, rapid increase in prevalence of autism, and other than because genes are techy and faddish, why would one ever expect genes to be a main cause in the first place, other than as a rationale to do genetics (which we knew how to do) and a paucity of other ideas?  Or, environmental causes being difficult to replicate and confirm.

But many epidemiological studies looking for environmental causes have been done.  A 2010 paper in Current Opinion in Pediatrics reports, with respect to environmental risk factors, e.g.:

...the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy – thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos. There is no credible evidence that vaccines cause autism.

Older mothers and fathers have been associated with autism, birth order, toxic chemicals, vaccines and thimerosol, and so forth, though none reliably so.  And of those factors that have been replicated, they can't explain all cases.

Autism is a difficult trait to study.  The trait itself is hard to define, varies enormously, there are no biomarkers with which to make a definitive diagnosis, diagnostic criteria have changed over the years, and so forth.  But many traits are similarly complex -- asthma, schizophrenia, heart disease, etc. -- and similarly resistant to current methods for determining cause.  So it seems fair to assert that many attempts to determine causes of complex traits are fad-following approaches to understanding complexity with reductionist science.

Latest Bulletin from the Desecration Newsroom!

Well, sports fans, the latest episode in our Science Won't be Slowed Department, or in this case, the Desecration Newsroom is that the famous astronomer Tycho Brahe (1546-1601) will be disinterred.  The reason is the urgent, pressing 'need' for us to know whether the poor guy died because his bladder exploded or whether it was mercury poisoning.  (Note the fake nose.  That's not a scratch on the etching, but a prosthesis because Brahe had his shortie amputated in a duel; hence the frown)

Whether or not next of kin  (or perhaps Inspector Lestrade) were consulted for permission to dig into this story, we can't say.  But this seems to be turning into a habit, because the Honorable Dr Brahe has been dug up before!  That also seems to have been on another slow news day way back in 1901  when a hot medical bulletin was needed to fill the pages (the investigators at the time, being interested in sustainability of this disinterment project, only took a mustache snippet).

Here a distinguished team of 'scientists' somehow have funds and permission to go digging (is this what skull-duggery refers to?) for something to justify their promotions or tenure, or to show how deeply insightful they are.

Whether finding (or not) whatever they are looking for will tell whether Tycho's untimely death was due to his dabbling in the metallics of alchemy, or was assassinated by the King of Denmark, or was murdered by his rival Johannes Kepler is not clear. Given what they can find in clothing or bones, there seems to be no bones about the inevitably murky results.  Even the authors agree:

Professor Jens Vellev, from Aarhus University, is leading the team of scientists and archaeologists which opened the tomb in Tyn Church on Monday.

He says he hopes to get better samples of hair and bones than were taken in 1901.

The use of the latest technology to test the samples may also help shed more light on the mystery of the astronomer's death, although Professor Vellev is not promising anything.

"Perhaps, we will be able to come close to an answer, but I don't think we will get a final answer to that question," he said.

We're certainly relieved that the latest technology will be used, as well as to see that the Sustainability spirit is being maintained (i.e., 'we won't find a final answer, so we can justify another grant to dig the poor star-gazer up again next time we need a publication'). Apparently, grave-digging is OK by the Catholic Church, which we guess can find a way to rationalize anything attention-getting (pass the plate!), since a special mass is being held in 'honor' of the event  (Man helping God to understand why Brahe passed to wherever he went.  If it turns out it was just a burst bladder after all, is that a ticket to heaven, since it rules out alchemy?).

We thought MT readers would want to know about this hot new bulletin from the Your Research Dollars at Honorable Work, that is, science doing its duty to the society that pays it.

Does salt really cause cancer?

A new report on cancer incidence and mortality in the UK, described on the Guardian website, suggests that 40% of cancers in women and 45% in men are preventable, due to lifestyle choices. This is great news for people pushing healthy diets and exercise (perhaps not such great news for those pushing genetic causation).

Dr Rachel Thompson, deputy head of science for the World Cancer Research Fund, said: "This adds to the now overwhelmingly strong evidence that our cancer risk is affected by our lifestyles.

"We hope this study helps to raise awareness of the fact that cancer is not simply a question of fate and that people can make changes today that can reduce their risk of developing cancer in the future. 

So, what is this overwhelmingly strong evidence? The authors chose 14 different risk factors, as listed in the table below (taken from the paper).

Table 1. Exposures considered, and theoretical optimum exposure level

            Exposure                             Optimum exposure

Tobacco smoke                                                 Nil

Alcohol consumption                                       Nil

Diet

1.      Deficit in intake of fruit and veg        ≥5 servings (400 g) per day

2.      Red and preserved meat                     Nil

3.      Deficit in intake of dietary fiber        ≥23 g per day

4.      Excess intake of salt                             ≤6 g per day

Overweight and obesity                                BMI ≤25 kb m^-2

Physical exercise                                            ≥30 min 5 times per week

Exogenous hormones                                    Nil

Infections                                                         Nil

Radiation – ionizing                                      Nil

Radiation – solar (UV)                                 As in 1903 birth cohort

Occupational exposures                               Nil

Reproduction: breast feeding                      Min of 6 months

The study calculated the "population attributable fraction" of each risk factor, that is, how much excess cancer was due to exposure to the risk factor. They compared cancer incidence in those exposed with incidence in those not exposed and assumed any excess (or, in theory, deficit) was due to the risk factor.

They chose risk factors based on the following criteria:
1. There was sufficient evidence on the presence and magnitude of likely causal associations with cancer risk from high-quality epidemiological studies.
2. Data on risk factor exposure were available from nationally representative surveys.
3. There were achievable alternative exposure levels that would modify the risk.

They calculated the relative risk per unit of exposure for cancers with probable or convincing causal associations with each risk factor, based on observational epidemiological studies. These would be the same studies you see reported in the news every day, telling you that you should or shouldn't eat butter, should or shouldn't go out into the sun, should or shouldn't eat sugar.

But there is something rotten in the state of Denmark, because despite billions of dollars, hundreds of thousands of study subjects, countless studies over decades of time by the most prominent (or, that is, highly placed) epidemiologists, the actual truth about the data is very different, surprising as that may seem. Indeed, as far as we know, the only truly convincing risk factors in this list are tobacco, papilloma virus and radiation, and even there it isn't really clear how much radiation exposure is too much (and many would say no exposure is the only completely safe exposure, though some exposures may detect treatable dangerous conditions and be good in the net).

The other behavioral risk factors have been shown in some studies to account for a small fraction of risk, though the results aren't always replicable. Indeed we can assert what we've just said because, by chance we just heard a talk by Gary Taubes, a science journalist for the New York Times and Science, among other outlets, who has systematically been debunking the idea that low fat diets have been shown definitively to prevent heart disease and cancer. He says the data just aren't there and never have been, but that it's been a belief so entrenched that it can't be denied because of all the vested interest that would challenge.

Hey, we like a good heretic as much as the next guy. And Taubes has written some of the best stuff out there on why observational epidemiology can't answer basic questions about cause and effect (here and here, for example). His work on dietary fat is very convincing, and his more general point that observational epidemiology can't be the basis for dietary recommendations is equally convincing. (So it's confusing that he's now a strong advocate for the idea that processed sugar is toxic, and responsible for the obesity and diabetes epidemics all over the globe -- conclusions largely based on the same kinds of observational studies he debunks when it comes to risk factors he doesn't like.)

But we digress. We are more than willing to accept that environmental risk factors can lead to disease. If not, only genetic variation would cause disease, and that clearly isn't so! We write about this all the time on MT. We just aren't nearly as ready to accept that we know definitively what those risk factors and their associated risks are. Nor that everyone is equally at risk from every factor.

Some of the optimal exposure levels in the list probably come under the category of 'wouldn't hurt', but public health measures are, by design, meant to be population-based, and the economic costs of encouraging lifestyle changes on a population level are not trivial. Nor is the cost of lost credibility when the risk factors turn out to be less important than we've been told after all.

Worse, risk is always and necessarily estimated retrospectively by relating outcomes quantitatively to exposure histories. But what we want to know is the future risk, and we know very well that we cannot predict the mix or amount of exposures to who-knows-what risk factors in the future. This is a deeply troubling problem, since major changes in risk for many or even most complex disease have occurred, often because of unclear behaviors or exposures, just in the past 50 years or so.

So, here's the safest conclusion to date -- do (most) everything in moderation, and don't worry about it. Something will get you in the end, so try to have the best time you can before that.

Skullduggery (part ii)

On Nov 18, BBC science journalist Quentin Cooper covered the story of the exhumation of Tycho Brahe on Material World on BBC Radio 4 (the photo to the left is by Jacob C Ravn, Aarhus University).  As you may remember, we covered the same story here last week, and were a little less than enthusiastic about the science.  We called it the latest from the Desecration Newsroom.

Tycho Brahe was a 16th century Danish astronomer -- indeed, Oxford Historian of Astronomy and Medical Historian Allan Chapman, commenting on this story on Material World, called him 'the greatest founder of modern astronomy', whose 'influence was simply incalulable.'  He showed the world 'how to do modern mathematical astronomy.'


Another great early astronomer, Johannes Kepler, worked with Brahe for the year before he died, and was at the banquet at which Brahe suffered from urinary suppression soon before his death -- or was murdered, depending on your point of view. Kepler's account of the event had it that Brahe had a full bladder at dinner, but was too polite to excuse himself to go to the loo, thus leading to the cascade of events that killed him.

Or not.  Hair samples analyzed in the 1990s showed evidence of mercury, which suggested to some that he'd been so murdered, as described here.  

A new theory by Danish scholars claims that Brahe was poisoned with mercury on the orders of Christian IV, the King of Denmark, because the astronomer had an affair with his mother. It is even suggested that Shakespeare used the alleged liaison as an inspiration for Hamlet.

Peter Andersen, a Danish scholar at the University of Strasbourg, told The Times that the astronomer was poisoned by his cousin Count Eric Brahe, a Swedish diplomat in the service of the Danish Crown.

Last year Professor Andersen found the diary of the alleged murderer, in which he records many meetings with Hans, the brother of Christian IV, on whose orders he is believed to have gone to Prague to murder his cousin. 

Nonsense, scoffed Professor Chapman. If you had urinary suppression in the 1500s, you'd have a catheter inserted into your urinal system, it would have been filthy and you'd have lapsed into fever a few days later due to a generalized infection that began in the urinary system, and you'd soon be dead.  Mercury was used as a standard part of 16th century pharmacy, so of course you'd have been treated with it, and of course it would be found in your body later.  Even much later.  Further, as Chapman said, mercury was very slow acting so if you wanted to kill someone, you'd have used fast-acting arsenic, not mercury.  

Well, will the exhumation resolve the question?  No, not even according to the people doing the exhuming.  But photos of the great event can be seen here.  

Said Svend Aage Morgensen, "The main reason for exhuming Tycho Brahe is not to find out cause of death, because we could never know for sure....but Tycho Brahe is one of the great Danes... and we are interested in knowing everything about these persons; how they are living and what they are thinking and so on."

But now we're really confused.  CT scanning him will tell us what he was thinking or how he was living?  We've just heard that it wasn't done to determine cause of death, as that can't be determined.  

Cooper asked Morgensen what it was like to open the casket.  He described a scene with 100 journalists and many tv cameras, and said it was 'like seeing a Hollywood star entering a movie theatre' -- right, a spectacle.  They found, as expected, two jars, one containing the remains of Brahe's skull and the other the remains of his brain.  They took hair from Brahe's beard, eyebrows and head and samples from his bones, and his remains were CT scanned at a hospital in Prague before he was reburied on November 18.

Cooper asked if Morgensen was at all disturbed by disturbing Brahe.  No, he said, "We are quite confident that TB as a great scientist would have agreed to let science exhume him."  

Really.  You'd hope that Brahe would have wanted science to have a real purpose for doing so, not just the prurient desire to create a spectacle. 

The deep epistemological problem in 'personalized genomic medicine' . . . that nobody wants to acknowledge

Two recent studies, both published in The Lancet, one from Denmark, and reported in this BBC story, and the other from England and reported by Gina Kolata in The New York Times, clearly illustrate one of the most important issues in personalized genomic medicine. The BBC writes, "People born in 1915 scored higher in cognitive tests in their 90s compared with those born a decade earlier, according to the study in The Lancet."  People now living into their 90s are experiencing a substantially higher quality of life than in the recent past, or that could have been predicted in any reliable way.  They are experiencing much less loss of mental function as well.  And the story in the NY Times says dementia rates are dropping as 'predicted'.  Senility, clearly, is not inherent in the human genome.

Also on the BBC site there's a story reporting that air pollution is harmful for people with at-risk hearts.  This is tragic for those people, and had been suspected but not specifically predicted.  The point is not just that we should pay heed to the quality of our air, but that we can't really predict where there will be more, or less air pollution, nor pollution by what mix of agents, and so on.   Yet, if there are genomic factors affecting heart vulnerability (regardless of whether there are other genomic factors related to how we respond to airborne pollution), we cannot reliably estimate the risk associated with those genomic factors.

These stories are interesting, given that we are being promised, with few and often rather hidden caveats, that if you just let investigators sequence your genome, they'll be able to predict your future disease risks (and companies and various advocates of genomics-everywhere, promise that other personal traits like academic ability, musical or athletic ability, or tendency to abuse drugs or commit violent crimes etc., will also be predictable from your DNA sequence).

The longevity study is great news for those of us in the dotage range!  But it has much deeper meaning when it comes to the promises being made by the genomics industry.  The aging experiences of two cohorts were very different, but surely their genotypes were not.  Thus, the genotypes of neither cohort, those born in 1905 or those born in 1915, could have been used to predict either healthy or less healthy aging.  That is, neither result was predictable from genes.  That the result was 'predicted' as described in the NY Times story doesn't mean that it was or could have been predicted in any precise way, for the reasons we discuss here, and of course this has nothing to do with specific genetically based predictions, nor can it, in any useful way.

This is what it means to point out that environment, whatever that includes, is not just a trivial variable to be regressed out in terms of genotype effects.  It also shows the hollowness of the rationale that epidemiologists often use to justify big genomics studies, that they just want to be able to regress out genotype effects so as to identify the more important environmental effects.  That assumes, inherently, that genotype-based risks are stable and well-estimated.

Clearly, and to an important extent, most predictions based on GWAS and other related omics approaches, cannot be taken seriously except for very clear-cut strong effects--most of which do not and did not require massive genome-wide studies to identify.

Since environments--physical and lifestyle, etc.--cannot be predicted, not even in principle, this is why we  repeatedly say that the promises used to justify much that is going on today in genomics and biomedical genetics is more to satisfy the investigators than to deliver the promised benefits.  The point that environmental effects are estimated retrospectively (based on today's GWAS subjects' past history), but personalized medicine is about prospective (future) risk, and that future risk cannot be predicted when environments are important.

Every week there are studies showing these points.  This is not mysterious, nor new, nor technically subtle.  But the problem is fundamental.  So is it being conveniently ignored by those who want to continue with current approaches?  Is it wrong to question their underlying motives?

Skin color and vitamin D -- a beautiful theory destroyed by inconvenient facts?

I love a well-done challenge to an iconic evolutionary tale.  Such tales are often easy to devise but hard to test, so I was intrigued to see that there was a new paper challenging what has come to be a well-accepted theory in Anthropology, the story of why skin color lightened as humans left Africa and migrated north.  The new theory is all over the web (here and here, e.g.).  And, there are certainly good reasons to challenge this iconic tale... but they aren't in this paper.

We make most of the vitamin D3 (VD3) circulating in our blood when we're exposed to sunlight.  The synthesize is a multi-step process, and we can store the VD3 we produce for months at a time.  Light skinned people tend to have higher levels of circulating vitamin D3 than dark skinned people, because the dark pigment, melanin, blocks UV, and thus, VD3 synthesis.  Severe vitamin D deficiency leads to rickets, with its deformities and accompanying weakness and so forth, and less severe but chronic low vitamin D3 levels in people with light skin are a risk factor for osteoporosis, bone fractures, and perhaps chronic diseases like type 2 diabetes, and so forth.  Paradoxically, while on average darker skinned women have lower VD3 levels, they are also at lower risk of osteoporosis and fractures than their lighter skinned counterparts.

The wintery Lapporten mountain pass in Lappland, Sweden; Wikipedia

The iconic story about skin color has been that when darkly pigmented humans left Africa 30,000 or so years ago. they were leaving regions in which dark skin was maintained by natural selection, presumably because it really does protect against sunburn and skin cancer.  The descendants who eventually settled in northern Eurasian climes were then in places where lighter skin was beneficial because sunlight was weaker  and the melanin in dark skin would have prevented the synthesis of enough vitamin D to maintain strong bones.  So, during the many generations that it took humans to make their way from Africa to northern Europe, their skin lightened due to natural selection for a beneficial trait.

This hypothesis has been challenged before, for numerous reasons -- notably in a paper by Ashley Robins in the American Journal of Physical Anthropology in 2009.  Among other problems with the hypothesis are that there was no evidence of excessive rickets in the late Pleistocene and early Holocene, when humans were expanding northward, that light and dark skin both can synthesize vitamin D when exposed to sufficient ultraviolet B (UVB) radiation and that early humans in northern Europe would have spent much of the summer and spring outside, partially covered with animal skin, able to manufacture enough VD3 to last through the winter when the rays of the sun were weak.

One might also note that the earliest depictions of human variation in art, not to mention evidence such as mummies, go pretty far back and show that Egyptians and others in their intensely sunny part of the world were not dark-skinned and they knew they were different from sub-Saharan Africans. So were they a back-flow from Europeans who had already become lighter? Or was lightening already a fact of human life before the expansion?  Why are some African indigenes light skinned though living in the open desert?  On the other hand, if sunlight exposure is not the reason that dark skin evolved, why are Americans darker in the tropics, especially those who live in jungle shade?

Now a paper in a recent issue of Evolutionary Biology ("Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production", Thyssen et al. -- paywall) challenges the accepted wisdom for another reason.  Thyssen et al. suggest that in northern latitudes, the skin wouldn't have been able to synthesize the required levels of vitamin D by loss of pigmentation alone, but a change in a protein that helps to maintain the skin as a barrier to outside elements could have facilitated increased VD3 synthesis.

We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence of FLG mutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differ- ences in circulating 25-OH-VD3 levels in these same populations.

That is, it was changes in the filaggrin protein that enabled people in northern climates to make enough vitamin D, rather than decreased melanin.  And, indeed, Thyssen et al. write, the difference in skin color from the tropics northward is not nearly as finely graded as filaggrin variants; this, they believe, is a convincing reason that the latter is more likely to explain why northern peoples produce enough VD3.

Vitamin D by frequency of FLG variation; source Thyssen et al.

The authors also write that because people with dark skin can produce vitamin D as efficiently as people with lighter skin, this would have meant no adaptive pressure on skin color as people moved northward.  While skin did lighten in the far north, it didn't lighten everywhere -- Inuit and northern Asians, for whom seafood, the best food source of vitamin D, has long been a large part of the diet, still have substantially pigmented skin.  Some Africans don't, though living in open, sun-blazed unforgiving desert.  And, even the lightest skinned inhabitants of the far north can't synthesize enough VD3 to maintain healthy bones, so something other than pigmentation must have changed.

And indeed the VD3 pathways did change, at least in some people; polymorphisms in genes involved in VD3 synthesis and transport have been identified in Europeans (Wang et al., 2010), and are associated with increased vitamin D3 levels.  Thyssen et al. also report European variants in the FLG gene, which is involved in skin architecture.  The variants seem to enhance UVB sensitivity, but they also seem to increase susceptibility to various conditions such as dry skin, ichthyosis vulgaris, and allergies.

This is sounding like a good story.

But...
There are problems.  The correlation between these variants and VD3 synthesis are, as Thyssen et al. themselves say, currently only correlations, not demonstrated causal relationships.  The authors suggest that looking for FLG variants in Inuit populations could make or break their hypothesis; if they had lower frequencies of these variants, it would be supportive because they have always eaten vitamin D-rich seafoods, and have darker skin than most peoples in the far north.  Nice idea.

Unfortunately for this whole hypothesis, however, the frequencies of the FLG variants that Thyssen et al. are reporting are, well, very low; 7.02% in Sweden, 7.86 in Denmark, 11.0 in Canada.  Yes, there is a gradient (0.91% in Tunisia), but these kinds of frequencies really can't explain why whole populations in northern latitudes don't have rickets. So at present these are strong claims and shouldn't be treated as if they show a major new theory, based on the rather thin evidence available to date.

It's often difficult to reconstruct evolutionary scenarios, which is why strongly held stories such as the vitamin D/skin color story should not be so strongly held.  While there are, we think, compelling reasons to question the conventional wisdom about vitamin D and skin color, this new report isn't yet a convincing replacement.

However, it does raise the question of whether there are other vitamin D synthesis or absorption pathways that aren't yet known, and that might explain, for example, why lower serum vitamin D levels aren't as deleterious in dark-skinned women as in light-skinned women.  Melanin is in some immune pathways, so there could be other correlates of 'climate' that don't involve vitamin D. Indeed, this story may not yet be completely told.

The anti-Lamarckian gut reaction: keep the bar high--but your minds open

Biologists tend to ridicule Jean-Baptiste Lamarck for his version of evolution, expressed in his 1809 Philosophie Zoologique.  Laughing at him is one of our favorite sports.  Of course most of those who do the laughing never bothered to do any actual reading of Lamarck's famous book, but who's gonna sweat the details?

So what was it that he said, and why was it so risible?

Larmarckian Inheritance

Jean Baptiste de Lamarck

About 50 years before Darwin's famous theory was published, Lamarck explained the diversity of complex organisms by what we term the inheritance of acquired characteristics.  In his theory, traits that were used by an organism were transmitted to its offspring, and traits that were not used were not transmitted.  Very gradually, organisms would develop, refine, and elaborate useful traits.  Lamarck may have been wrong but not entirely so, given the data and attitudes of the time, and he was seeking a material explanation for biological complexity and its origins.  Good overviews can be found in the prefatory material to the 1984 English translation of Philosophie Zoologique published by the University of Chicago, and by SJ Gould's 2002 The Structure of Evolutionary Theory.  Other authors seem typically more derogatory and pejorative and less clearly acknowledging what Lamarck actually said.

The point is not to defend Lamarck, but to see why his views evoke such gut negative reactions.  The modern purely materialist theory of evolution (largely of Anglo-American origin) stresses randomness of inherited change due to external forces of mutation, and the brutal screening by natural selection to favor those genotypes that confer advantageous traits on their bearers.  Self-satisfied in what really is somewhat our own arrogant dogma (see our series on the mythology of natural selection, which begins on Monday of next week), we brook not even the slightest breach in our own dogma.  Still, in the way he tried to explain things, Lamarck does seem to have been mistaken, and his ideas (which were in the air at the time) in a way set the table for a better kind of material explanation for evolution and the traits of organisms, due to Darwin, Wallace, and a few others who ventured correct partial statements of things.

Lamarck's idea was that what organisms do during their lives, in response to the challenges of their environment, is somehow materially transmitted to their offspring.  This is an inner rather than outer source for the variation: systematic habit-induced physical change rather than externally screened random variation.  It didn't help Lamarck that the Soviet era genetics tried to appropriate Lamarckian rather than Darwinian evolution for various ideological and sociopolitical reasons, nor that some of Lamarck's contemporary rivals denigrated him, nor that Darwin found basic holes in the idea (despite holding a very similar theory of inheritance). 

Our point here is that there are some very good reasons based on 19th and 20th century biology, to hold the view that Lamarck's mechanisms don't hold much water, and this is why when one argues for anything that might seem even the slightest bit Lamarckian, the ridicule begins and the burden of proof is raised to a much higher level than when biologists venture their routine Just-So stories about how the elephant got his baggy skin.

What we do know
One thing we know very well is that gene usage does involve experience-based feedback onto cells' genomes. Cells use a subset of their genomes, and which subset is dictated by their context--by aspects of the cell's local environment.  Indeed, cells are loaded with environment-sensor (like receptor molecules) that monitor the world outside the cell and adjust gene expression accordingly.  This is clear, experience-based modification of the genome.  Of course, the modification is epigenetic:  it is not a change of the code book (the DNA sequence) itself and that is the key.  It is a change in the DNA molecule that affects how it's used, but not the sequence-based code.  To oversimplify, it is the binding of a molecule to a specific sequence-based bit of DNA near a gene that affects whether that gene is used by the cell at that time. When circumstances change, the molecule may leave the DNA, changing whether the gene is used or not.  Because the molecule binds to specific DNA sequence, epigenetic change does involve DNA sequence, but doesn't change it.

Second, in many if not most multicellular organisms the experiences of life affect its body tissues.  If a vertebrate does hard work, its muscles and joints may gain improved strength--something all of us know very well.    But if cell structures are produced by genetically coded molecules, the code itself isn't changed by the experience.  More importantly, an entirely separate line of cells, the germ line (sperm, eggs, pollen, etc.) is separated from the rest of the body's cells early in development.  Pumping iron may pump up your pecs, but it doesn't alter the relevant genes in your germ cells.  Even if it would be a good thing, the basic idea for over a century, supported by lots of evidence, has been that there is no way for a (say) muscle-specific genetic change to be built into the genome of a muscle cell, much less into a germ cell.

Instead, if pumping iron is good for your reproductive success, then those who by good mutational luck carry muscle-related genetic variants will reproduce better, passing the screen of natural selection and proliferating their good genes into the future.

Arnold Schwarzenegger in Pumping Iron; Wikimedia

The problem with a Lamarckian genetic alternative would be that pumping iron selectively mutates the muscle-related gene and when it turns out to be useful then engineers that same mutation in his germ cells. There is no known mechanism by which a specific mutation in a specific useful gene can be engineered into a germ cell, just because it happened to be useful in a muscle cell.  If it exists it will have transformative effect on biology, and that is why the standard of proof is so high, and skepticism so great against anything that seems like such a claim.

In fact, there are many examples in the literature of trans-generational transmission of epigenetic states. Each has been blasted and for essentially this reason:  biologists are generally not willing to open a breach in their Darwinian selectionist firewall.  Since anything truly Lamarckian could threaten the most solid bits of biological-evolutionary theory, it is entirely appropriate that a high bar and burden of proof be maintained.  But if it's true, it really is no threat to the state of the world; it's just knowledge of a new mechanism for at least short-term adaptability of complex species. In fact, it was anticipated way back into the late 19th century.

Current contentious examples

We write this because a report has just appeared in Science that claims something that seems like Lamarckian inheritance.  In this example, a starvation induced in laboratory mice when they were pregnant led to an epigenetic change in various genes that, the authors say, led to risk of diabetes, and that risk also was characteristic of the next generation, the grandchildren, even though their mothers were not subject to starvation. As described in a commentary in 10 July Nature, the experiment is in effect a test of the aftermath of a winter of starvation in Denmark in 1944-45.  Children conceived during this time were born underweight, and experienced health problems which their children, too, seemed to go on to experience.  

This report was just the most recent of several related to claimed epigenetic transmission of chronic disease-related traits that have appeared.  An even eerier recent report claimed that male mice exposed to fear-stimulus in the presence of a specific odor, were conditioned to hyper-express an odor-receptor gene that detected that order, but then this same gene was marked for over-expression in their offspring, and their grand-offspring, even though there was no further fear-conditioning.  (We blogged about this here.)  Gene expression induced by experience in the nose and then the same gene primed in sperm cells to be expressed in the males' offspring--and maintained in the sperm-line for a third, grandchild, generations?  Are you kidding?  

And there are other reports of similar multigenerational epigenetic transmission, some of them in controlled experimental settings like these examples.

The key reason for the strong skepticism at reports like these is that a specific gene in a germ cell line, a cell not directly affected by the environmental factor, is modified by that experience and the modification is then transmitted.  This might not seem like a problem, except that, genome-wide, the epigenetic state is generally highly programed for embryonic development, with sperm and egg genomes are subjected to heavy genome-wide epigenetic reprogramming before conception.

The idea that an experience-based epigenetic responsive state can get into the germ line and be transmitted for several generations is a threat to a Darwinian dogmatist--emotionally, it's like trying to get a biblical literalist to accept that Genesis might be at least a bit metaphoric.

Science is about learning new things
But we shouldn’t just defend dogma by being dogmatic!  There really shouldn't be any problem at all with this kind of multi-generational transmission--if it's true.  If it is, then we just have learned of a new mechanism of adaptability by organisms by which they change their biological state to reflect their circumstances (like shivering when it's cold, or an adrenalin rush when frightened).  Somehow, the body would know which gene was modified epigenetically by experience, and finds that same spot in the genome of a sperm or egg cell and makes the same modification.  That this could be transmitted to future generations could be a fine adaptive mechanism because circumstances might not change, and organisms would be epigenetically prepared from birth to meet them.  If true or shown somehow to be general, we'll all say that this is a marvelous aspect of evolutionary adaptation, and how could we have missed it!  

One can conjure up various ways this might happen….except for the minor detail that we don’t actually know of any such mechanism!  That doesn’t mean it can’t exist but it’s proper that one must find it before the results will be accepted.  Still, the more results of this sort that are reported, the harder should be the search for something that a century of work suggested didn’t exist.  Can all these reports be wrong?  If not…..what can make them true?  If so, are they wrong for some murky methodological artifact?  At some point, sneering should stop and hard work to find the mechanism should start.

We've tried to outline what the controversy is and why it is reasonable to be very skeptical of these reports, that seem so 'Lamarckian' even if we take into account that he was writing, or guessing, based on the state of knowledge 200 years ago.  If indefinite proliferation of an epigenetic change is ever proven, then it will show that this sort of inheritance, even if not affecting DNA sequence directly, is a part of evolution. It won't be exactly Lamarckian, but it won't be exactly Darwinian either.  It will be a remarkable revelation whose discovery we'll celebrate.

But if it's warranted that we give these reports a very hard look, that should not require that we cling to a cartoonesque oversimplification of the current dogma, that everything about everything is the result of Darwinian style competitive natural selection.  And with this comment, we'll return to writing our series about selection and the origin and genetic basis of complex traits.

My grandmother's dementia and me

My father's mother had Alzheimer's disease, or dementia of some sort, as did her sister.  Both lived with us at different times when I was a child, my great-aunt until she died in the bedroom upstairs, and my grandmother until she was impossible for my parents to care for, at which time they found a very kind, very patient woman with a big house in the country, and she went to live there.

These two sisters, the only children in their family, were always close.  They both worked all their lives, and were extremely competent and very kind.  My great-aunt never married; her fiancé had gone off to fight in the Spanish-American war, but died during an outbreak of yellow fever in Florida before he ever got to Cuba.  But, she lived with a cousin for many years.  When my parents finally cleaned out the apartment after my great aunt died, one of the things they found in the attic was a skull that must have once been used for teaching anatomy.  No one had any clue how it ended up in that attic.  My parents have displayed in their living room for most of my life.  My mother's theory, after years of living with it, is that this is the skull of a poor man who was suffering from an abscessed tooth, and he shot himself in the head because he couldn't stand the pain.  Here's a sketch.

Sketch by A Buchanan

My grandmother married and had one child, my father.  My grandparents, my great-aunt and her cousin all lived perhaps half an hour from us, in the town where my father had grown up, and my grandfather drove them all to visit us on Sunday afternoons.  He loved driving -- he enjoyed taking my sisters and me for drives in the country. What I remember most about these drives was the overwhelming odor of his strong cigars.  (He used to enjoy shooting woodchucks, too, happy to be doing farmers such a favor.  I remember going with him and my grandmother once on such an outing, but I refused to take a shot, which disappointed him.  He would steady his gun on the roof of the car, aim and shoot.  He draped the one woodchuck he killed the day I was with him over the gate into the field he'd shot it in, so that the farmer would take note.  One Sunday when they came to visit, there was a bullet hole in the roof of the car, over the passenger side -- I don't remember that that was ever explained.)

Dementia does unpredictable things to people.  My great-aunt -- Aunt, we called her, as my father had -- was always cheerful and sweet, if a bit confused.  Every morning she would ask where she was, but she was still able to play cribbage with us, she loved having us comb her long thin hair, past grey, now yellowed, and pin it into a bun.  I don't remember that she ever fussed about anything.

My grandmother, on the other hand, was distraught with worry from the moment she woke, to the moment she went to bed, and probably long after that.  She would sit at the kitchen table all day every day, every few minutes asking the same worried questions in the same frantic way.  She was miserable.  Occasionally she was able to access a part of her brain that reminded her that she was confused, and that made things even worse.

Apart from being two different versions of the same heart wrenching story that could be told by so many people, this raises several questions.  Was this two sisters with very different forms of the same disease?  Or, did they have two different diseases?

And, did the fact that both his mother and his aunt had dementia mean that my father was at higher risk of dementia himself?  Apparently not, as he is now in his late 80's, still very active, very engaged, mentally and even physically.  In turn, does this mean that my sisters and I don't have to worry about dementia ourselves?

Or is it secular trends in Alzheimer's disease that we should pay attention to?
One measure of a condition's impact is its prevalence.  That is the fraction of the population at a given point in time that is affected.  A recent BBC Radio 4 program, More or Less, discussed changes in Alzheimer's prevalence over time, after a paper reporting (among many other things) decreased prevalence of dementia in the UK was published in The Lancet ("Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: quantifying the epidemiological transition," Murray et al.). According to the study, prevalence of dementia in British people over age 65 has declined by more than 20% in the last 20 years; it's currently about 7 percent of that segment of the population.

This is in striking contrast to a recent report in the UK that estimates that 1/3 -- 33%!-- of the British children born in 2015 will have dementia in later life.  Tim Harford, presenter of More or Less, pointed out, though, that it's odd that this number was taken seriously by anyone, given that it is equivalent to thinking that predictions made 100 years ago, when AIDS wasn't known, antibiotics not yet discovered, and so on, would have any credibility. And, the 1/3 estimate was based on 20 year old data.  (A quick check of prevalence of dementia in the UK is a bit confusing -- many sites caution that the number of people with Alzheimer's disease is rising rapidly.  It's an Alzheimer's time bomb, they warn.  But, given that the population is both aging and increasing, this isn't, in itself, a surprise, or very meaningful in relation to individual biological risk because, again, it's the fraction of the population that is affected that is the significant statistic.  To be clearer, if more people live longer, even the same age-specific risk of getting a disease will lead to more people with the disease, that is, higher prevalence in the population.  Of course, the number of affected individuals is relevant to the health care burden.)

How predictable is dementia?
Carol Brayne, one of hundreds of authors on the Lancet report and interviewed for More or Less, speculates that the reported fall in prevalence has to do with changes in 'vascular health', as incidence of heart attacks and stroke have fallen as well.  She suggests that it seems as though the things we have been doing in western countries to prevent cardiovascular disease have been working.

But of course this assumes we know the cause of dementia, and that it's in some sense a cardiovascular disease.  But, we don't understand the cause nearly well enough to say this, and in fact, like most chronic diseases, dementia is many different conditions, with many different causes.

The genetic causal factors related to Alzheimer's disease include mutations in a few genes, but these account for only a fraction of cases.  Mutations in the two presenillin genes can lead to early onset Alzheimer's. The most commonly discussed genetic risk factor has to do with the E4 allele in the ApoE gene, whose physiology is related to fat transport in the blood.  It seems to be associated with the development of plaque in brains of people with late onset (60s and over) Alzheimer's, but the association is complex, people without the E4 allele also develop plaque, and people with plaque may not have dementia, and the causal mechanisms are unclear.  Risk seems to depend on whether one carries one or two copies of the E4 allele, and seems to be higher for women than for men, and is apparently affected by environmental factors, but it does seem to raise risk from something like 10-15% in people over 80 to 30-50%.

What this means, even if the statistics were reliable, the risk estimates stable, and environmental contributions minimal, is that it is obvious that even having two copies of the risk allele is not a guarantee of Alzheimer's disease. And, in some populations having two copies isn't associated with Alzheimer's at all (Nigeria, e.g.).  In addition, while the association with increased risk has long been described, the physiology is still not understood. GWAS have reported other genetic risk factors, but not nearly as consistently as ApoE4, nor as strong.

The reported decline in dementia prevalence is not new; we blogged in 2013 about dramatically decreasing rates in the UK, as well as in Denmark, as reported by Gina Kolata then.  So, how can it be declining rapidly, but the strongest risk factor we know of is genetic -- and the frequency of this variant is not changing enough to even begin to account for the data?  Or, is Carol Brayne right that dementia is a vascular disease, and vascular diseases are on the decline, so Alzheimer's is, too?

Indeed, even the definition of whether you 'have' Alzheimer's or not is changeable and not precise, and researchers don't even agree on what an Alzheimer's brain looks like.  A good discussion of these various factors, including social and economic aspects and the history of studies of Alzheimer's, is a book The Alzheimer Conundrum, by Margaret Lock, a fine medical anthropologist at McGill in Canada (and friend of ours).  

Can Alzheimer's be prevented?
The causes of Alzheimer's disease are so poorly understood that it's said that the best prevention is to exercise, quit smoking and maintain a social life.  Very generic advice that could apply to a lot of things!  If we don't know what causes it, and there are probably environmental risk factors, which we don't really understand, relevant past environmental agents are unknown, future environments impossible to predict, and genetic risk factors not good predictors, then we certainly don't know how to predict population prevalence rates, not to mention who is most likely to develop the disease.  (NB: this is pertinent to late-onset dementia; early-onset is more likely to have a genetic cause, and is thus more likely to be predictable.)

Given the experience of two generations in my family, should I or shouldn't I worry about developing dementia?  If my grandmother and great-aunt had the ApoE4 risk allele, my father may or may not, and my sisters and I may or may not.  If they did and my father does, it's a good example of an allele with "incomplete penetrance," for which either genetic background or environmental risk factors or both are also necessary.  Which makes predicting dementia difficult, whether or not we were to have the risk allele. If they didn't have it, something else caused their dementia, and we have no idea what that was.  Indeed, they were both social, never smoked, and walked to work for decades.

To me, as to most people, dementia is frightening.  But, obviously, my family history is useless in terms of determining my risk -- my grandmother had it, my father doesn't.

Still, every time I forget someone's name, I think of my grandmother.