Wednesday, February 5, 2014

DDT as a risk factor for Alzheimer's disease

A new report in JAMA Neurology, ("Elevated Serum Pesticide Levels and Risk for Alzheimer Disease", Richardson et al.) links late-onset Alzheimer's disease with exposure to DDT.  It's an odd-seeming but interesting possible correlation for many reasons, but first, is it anything more than a correlation?

DDT being sprayed on Long Island beaches in 1945; Source

The authors' assumption is that Alzheimer's is due to a combination of environmental, genetic and lifestyle factors, and a handful of epidemiological studies has shown a correlation with pesticide exposure.  The authors write that their own previous small study (N of 20) showed elevated levels of one of the components of DDT in Alzheimer's patients, dichlorodiphenyldichloroethylene or DDE.

The current study was designed to test the correlation and its interaction with the APOE ε4 allele, the strongest genetic risk factor for late-onset Alzheimer's disease yet identified.  Serum levels of DDE were measured in 86 cases and 79 controls.  The study reports that the pesticide was detected in 70% of controls and 80% of AD patients, and that circulating blood levels were four times higher in cases than controls.
Levels of DDE were divided into tertiles, with the nondetects designated at half the limit of detection, and the OR was estimated using generalized estimating equations and corrected for age, sex, race/ethnicity, and location. Compared with the first tertile, the OR for AD diagnosis in the third tertile of DDE level was significantly increased (OR, 4.18; 95% CI, 2.54-5.82; P < 0.0001). The presence of an APOE ε4 allele alone was associated with increased AD diagnosis (OR, 3.70; 95% CI, 2.97-4.60; P < 0.0001). However, adjustment for APOE genotype did not significantly alter the association between DDE levels and AD diagnosis. Furthermore, DDE levels did not differ based on APOE genotype (data not shown).
Scores on the memory test were somewhat lower in those in the highest DDE tertile for patients with the APOE risk allele than for those without.

So, on the face of it, it looks as though exposure to DDT may be a risk factor for Alzheimer's disease. DDT was in use in the US from the 1940's to 1972, when it was banned.  Thus, the cohort now at highest risk of Alzheimer's was certainly exposed to DDT in their youth.  And, DDT has a long half-life of 8-10 years.  But, according to Richardson et al., DDE was found in the serum of 75 - 80% of the samples randomly collected from a large study of the general population carried out by the Centers for Disease Control in the US.  Clearly, exposure is widespread, and we can carry the result around in our blood and other tissues, including brain, for decades.  In addition, while DDT is no longer in use in the US, there are countries in which it is still widely used, legally and illegally, and we import food from some of these places, meaning that we are still being exposed to the pesticide.

But, if DDT is a risk factor, it's probably not a strong one.  The figure below shows that many of the cases had the same low level of serum DDE as controls, and yet remained unaffected.  Not all exposed cases had the risk APOE ε4 allele, so the interaction of genetic and environmental risk doesn't explain disease.  In some ways no surprise, since APOE ε4 is only one risk factor and isn't involved in all Alzheimer's cases (56 of the 86 cases in this study, and 28 of the 79 controls), and has different statistical effects in some ethnic groups compared to others, and there may be a difference between persons with one, versus two copies of the risk variant.

Further, Alzheimer's disease was characterized and well-known as a disease of the elderly decades before DDT was used commercially on a widespread basis, so it certainly can't explain all cases.

Perhaps the study explains some of the rise in the second half of the 20th century, and the now suggested decline of Alzheimer's risk?  A recent Lancet paper reported that a cohort of people now in their 90's performed better on memory tests than a cohort ten years their senior had done at the same age.  The suggestion was that perhaps incidence of Alzheimer's is now declining.  Could this mean that those exposed to DDT are now dying out, and therefore that incidence of AD will decline?  Not likely.

In fact all of these people would have been exposed to DDT, so if it is a risk factor, that would mean that some age at exposure must be riskier than others.  It's hard to imagine what kind of study could tease this out.  Complicating that is the fact that people respond to stories about Alzheimer's and what one can do to reduce risk -- crossword puzzles, for example, and so on.  These interventions confound the kinds of statistical risk analysis that is typically done.

And, what does it mean that DDE is four times higher in people with AD than without?  The assumption is that it's causal, but instead perhaps it represents a recent exposure to DDT that had nothing to do with AD, but everything to do with, say, where the beef they had for dinner last week came from.  In fairness, Richardson et al. acknowledge that they don't have the whole story.  More research is needed.

But let's look at the bigger picture here.  If 70-80% of us are walking around with components of DDT in our blood, and something like 10% of people over age 80 have dementia, and of those, 20% weren't exposed to DDT if the results of this study are reliable, that means that most of us who've been exposed aren't going to get Alzheimer's disease.  Again, even if DDT is a risk factor, it's apparently not a very strong one.  Or, it's only strong when exposure is very high.  And perhaps at some critical age, though we have no idea what that is.

Like all the other common chronic diseases that will eventually affect most of us, causation is likely to be complex, multifactorial, difficult to tag on genetics, and difficult to pin down.  And, as with other complex diseases, predicting who is at risk remains elusive.


Manoj Samanta said...

There is a new trend of measuring the 'quality' of papers through their internet citations (tweets, facebook post, media reports). One problem of such measurement is that it amplifies the pre-existing mental biases. For example, if one scientist argued about sun going around earth and another about earth going around sun in 16th century, and their relative outputs were measured based on public approval, we had no freaking chance of getting Galileo vindicated.

Anne Buchanan said...

You've just described another inherent problem with peer-review.