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. 

Wicked smart apes

I tried to hate it. I really did.

But despite all the Hollywood violence; despite its (inadvertent but dangerous) glorification of the life of a pet chimp and of having one; despite the digital movements that weren’t always quite right… I still enjoyed Rise of the Planet of the Apes.

[If you’re worried about spoilers, (A) Don’t read the title of the movie, and (B) Don’t read any further until you’ve seen it. But to be honest, I'm not sure I reveal anything that wasn't already revealed in the trailers.]

I can't control how apologetic I feel for liking this flick so much. As a human I care deeply what other humans think of me and my movie tastes. And in a weird way I care what chimps, bonobos, gorillas and orangutans would think of me liking it. I guess I shouldn't apologize for being human and I can't easily stop being such a dork.

Perhaps it was the near-future sci-fi possibility of it. Perhaps it was all the sneaky little throwbacks to the original flick. Perhaps it was the attempt to tackle issues of personal bias, emotions, and capitalistic greed in the world of science. Perhaps it was the way James Franco wore that little white lab coat. Perhaps it was my adoration of apes overpowering the fact that these were mere digitized computer actor-humans. Perhaps it was the triumph of the apes! Perhaps it was impossible to go anywhere but up from my subterranean expectations. Perhaps I’m just a human and we humans love our big loud, manipulative blockbuster movies, especially ones that ask, “What does it mean to be human?”

The shows were all sold out on Sunday in West Warwick, so I’m betting most of my students will see this movie—if not this summer, then soon. And I’m sure to be fielding the questions they’re bound to have after watching it. You may have to field the same ones.

I may even use the movie as a teaching tool to help with topics like gene therapy, virus biology and therapeutic use, non-human disease models and test subjects, transgenic lab animals, and inheritance.

Although I’ve worked with custom-engineered virus vectors to modify and to shut down specified protein synthesis in epithelial cells, my experience stops there. And to help me try to make sense of this movie, I asked Ken and Anne to answer some questions that movie goers are bound to wonder.

Ken and Anne: Fire away.

Holly: In the movie Rise of the Planet of the Apes, a scientist invents a possible treatment for Alzheimer’s that regenerates neurons and they test it on chimpanzees in a fantastic lab (and the scientist also administers it to his father at home). The delivery system for the treatment is a virus vector injected into the bloodstream (for humans) or administered through a gas mask (for the lab chimps) that changes known genes associated with Alzheimer’s in humans (not chimps!). When a chimpanzee (who does not have Alzheimer's) is infected with the virus she becomes significantly more intelligent.

1. How does one test a cure for a human disease in non-affected non-humans?

Ken: We've not seen the movie but here are some guesses at your questions. In principle (far from practice at the moment), one could get such a vector into a person that could target the particular gene in cells, and replace it with a gene the vector carries. (If this were incorporated in the germ line of the mother or father, it would be passed on to their kids as part of their genome.) Testing simply would be taking a DNA sample (any cells--blood, cheek swab, etc) and looking for the sequence of the inserted gene. This is what is done to make transgenic mice (but the gene is inserted into an egg, not breathed in by an adult).

Anne: There are 2 things that normally would need to be tested in developing gene therapy; the system for delivering the genetic modification, and the efficacy of that modification. In principle they could/should be tested separately, so the delivery system would be tested on normal subjects before the efficacy of the cure is tested, so that, if it doesn't work, the researcher knows it's not because of the delivery system. Testing of many pharmaceutical products is done in similar stages -- first determine whether it's safe on normal people, then whether it actually cures. The first stage is often done on 'professional guinea pigs', people who make their living volunteering to test drug safety. But you're right, it's not the cure that's being tested on people without the disease, it's the efficacy or safety of the procedure.

2. The Alzheimer's (AD) cure not only heals neural degeneration (as evident in the human test case), but it improves cognition too and when both humans and normal chimps are infected their intelligence increases literally over night. Could that be possible? How?

Ken: It could (in principle) fix damaged neurons in the patient (this is at the moment largely fantasy but by now there may be some precedents--we're not up to date on what claims may be being made.) If the person's inherited genes that led to AD also led to poor cognition, and if changing the gene once their brain is developed could goose up the neurons' activities, then this, too, could occur in principle. Suppose for example that the problem were a neurotransmitter receptor that was somehow not very efficient, and this were replaced so that signals traveled between synapses more rapidly. Again this is all 'suppose' at present!

Anne: If intelligence is due to synapse speed, say, one could imagine that could be upgraded quickly. It's harder to imagine that the biochemistry underlying chimp intelligence is the same as that that causes dementia, and that therefore they'd have the same fix!

3. Also—and this is the real question I’m interested in discussing especially considering the recent Mendel-Wasn’t-Right theme here on the MT!—A female chimp who has been infected actually passes the positive genetic affects onto her offspring. They even remark how her son is intelligent because it's "in his genes." How could this be possible?

Ken & Anne: In the same way as related to #1 above, the offspring would inherit the faster-firing receptor gene and would be smarter.

All of this assumes that one gene change would work across genomic background variation, with no side effects, and all that. But the dream of real gene therapy has been to do what you're describing (again, we didn't see the movie). A good example would be replacing sickle cell hemoglobin (the beta globin gene) with a normal version, or replacing the mutant Tay Sachs or Cystic Fibrosis gene with normal sequences. But to be inherited it has to involve the germ line cells.

There are some known mechanisms that illustrate how such a dream scenario could be plausible. Cells have receptors that bring what binds to them into the cell (usually, this is for some normal cell response to the environment). A virus could be engineered to be taken into some specific cell, like a neuron, in this way. The virus could be designed so that genes it carries are made into RNA corresponding to the 'good' gene version, along with code for a protein like reverse transcriptase that turns RNA into DNA and inserts it into chromosomes could be used. The latter is how viruses currently incorporate into DNA and cause trouble; our genomes are littered with such inserted elements. The difference is that they insert only occasionally and even then into random places in the genome, or places of their choosing.

To get this into places of our choosing, we would have to engineer the system to recognize some sequence of the target gene area and insert the virus's passenger gene at that place, excising the current (bad) gene there.

In any cell in which this occurred, the transgene would have replaced the normal gene, and the job would be done for that cell. If in a sperm or egg precursor, then that would be transmitted to (half of) the person's offspring.

There are versions of each of these transgenic techniques already in practice, but in every case there are limits relative to the desired outcome, and they mainly work in mice that have already been prepared for the experiment by manipulating mouse egg cells. We use such transgenic mice in our own work here on craniofacially relevant genes.

There used to be a lot of hope for such gene therapy, but failures have led many if not most companies to give up the effort. Mostly what is still being tried (I think) is and has always been to administer something to a patient and change his or her genes, or insert a compensatory gene, in affected cells. Injections of such things into muscle to alleviate muscular dystrophy, or by inhaler to alleviate CF, or to fix immune system problems have been tried and probably some at least are still under test.

That still leaves movie goers wondering how someone, like Caesar-the-chimp’s mother in the movie, could contract a virus orally or through the bloodstream which somehow finds its way to the eggs or sperm and then inserts its DNA into those cells and modifies them. That’s the only way the modified DNA sequence could be inherited by future generations, like Caesar, but it's not outside the realm of plausibility. Just think of the evolutionary possibilities!

Articulate nuns, dementia and belief

Here's a brief follow-up on our post the other day about Alzheimer's disease. It's a story that's been dribbling out for the past few years about a study of nuns and dementia. The first results from this study suggested that nuns who wrote the most articulate application letters when they were 20 were the least likely to have dementia as they aged. So, the association of early language ability with risk of dementia reported in this story from the BBC is not new--whether or not it's 'real' or actually predictive, given that we can surely all think of very articulate people who went on to develop dementia (the story itself mentions the British novelist, Iris Murdoch, perhaps the most famous example).

So, although this possible association raises many questions (is senile dementia the quantitative end-point a life-long trait that begins at birth? Can articulateness be learned, or is inarticulateness a characteristic of a person that is also a predetermined product of a doomed brain? is this association meaningful?), that's not what caught our attention about this story.

What interests us is the assumed association of plaques with dementia. As the story says,

Dementia is linked to the formation of protein plaques and nerve cell tangles in the brain.

But scientists remain puzzled about why these signs of damage produce dementia symptoms in some people, but not others.

Why are scientists convinced that these signs of damage are what is producing dementia? This assumption is being questioned by some (e.g., The Myth of Alzheimer's: What You Aren't Being Told About Today's Most Dreaded Disease, by Peter J Whitehouse and Daniel George), but not by many. Indeed, a quick search of the literature suggests that this 'puzzling' finding is frequently reported, but it is assumed to represent 'pre-dementia' in those with plaques but without confusion. And, it's impossible to refute, as it can always be said about a clear-thinking person with plaques that they died before the disease became manifest. A few early observations led to an equation in peoples' minds of plaque and disease, and became entrenched.

But it's an assumption, a belief. It may fall out of favor, but that will take time as beliefs can fall hard. In fact, one prominent Alzheimer's researcher we've spoken with, a non-believer in plaques as causal, or even in the idea that a single disease called Alzheimer's exists, says that she thinks the field of dementia research is due for a real shaking up. It's time for a new model of dementia, and it will have to allow for complexity.

Although we all like to think that science is based squarely on fact, not belief, this is another example of how that's not as completely so as we'd like to think.

Health story of the day -- Java jolt cures Alzheimer's!

Here's a particularly cruel health result of the day, it seems to us. The BBC reports that coffee may reverse the symptoms of Alzheimer's, at least in mice force-fed the equivalent of 5 cups a day (or 2 lattes, 14 cups of tea, or 20 soft drinks -- wait, didn't we recently learn from the BBC that people who drink that much cola are susceptible to hypokalemic periodic paralysis?).

The new story says that caffeine seems to prevent plaques from forming in the brain, the 'hallmark' of the disease, or reduce those already there. Oddly, other researchers have found that these plaques are neither always found in people who had been given a diagnosis of Alzheimer's, nor are they always associated with dementia when they are found. So reporters aren't doing their job and/or researchers enjoying the limelight aren't coming clean (assuming they at least know their job).

This is a perfect example of a story prematurely reported about a scary disease, and thus that will sell. Because it will sell. Everyone fears losing their memory as they age, and quick and easy cures are surely eagerly sought by caretakers and the affected alike. Many have seen the awfulness of close and loved relatives with this disorder.

But mice are not people, and the dementia bred into an inbred strain of mice cannot be assumed to be the dementia any of our grandparents suffer or suffered from. As with all 'simple' diseases, the more researchers learn about dementias in people, the more questions they have--indeed, 'Alzheimer's' has always been a diagnosis of exclusion (that is, impossible to confirm until after death), and the signature amyloid plaques in the brain that were assumed to confirm the diagnosis on autopsy have been shown to be non-confirmatory after all. The idea of Alzheimer's itself as a single definable disease is fading within the research community as more is learned about dementias (unless perhaps your lab is committed to the line of inbred Alzheimeric mice it took you years to breed).

So, once again, scientists prematurely rush to the press with a story that may well cause caretakers to force-feed elderly patients with caffeine at best, and at worse cruelly encourage hope of a cure where in fact there is none. We write often about oversimplifying genetic determinism, but this is a case about oversimplifying environmental determinism--a problem that actually predated genetic determinism in the history of 20th century epidemiology. Surely by now both researcher and media should know better than to hype such claims.

There are many ways to get dementia. There are also many ways to get your morning energy boost even if tea, say, won't help your state of mind without drowining you or making you park all day in the bathroom. And there are many ways to spin a story to the news media.

But don't forget to have your coffee....or you'll forget to have your coffee!

Right.