Wednesday, November 3, 2010

Nothing fishy about a cure for Alzheimer's

So B vitamins don't prevent dementia, and now comes the news that omega-3 fatty acid doesn't either, according to a paper in the Journal of the American Medical Association
Docosahexaenoic acid (DHA) is an omega-3 fatty acid identified as a potential treatment for Alzheimer disease. Epidemiological studies have shown that omega-3 fatty acid consumption reduces Alzheimer disease risk and DHA modifies the expression of Alzheimer-like brain pathology in mouse models.
Several studies have found that consumption of fish, the primary dietary source of omega-3 fatty acids, is associated with a reduced risk of cognitive decline or dementia. Some studies have found that consumption of DHA, but not other omega-3 fatty acids, is associated with a reduced risk of Alzheimer disease. Studies of plasma fatty acids have confirmed the dietary studies, finding that plasma levels of omega-3 fatty acids, and especially DHA, are associated with a reduced risk of Alzheimer disease. The most abundant long-chain polyunsaturated fatty acid in the brain, DHA is enriched in synaptic fractions and is reduced in the brains of patients with Alzheimer disease The other major omega-3 fatty acid found in fish, eicosapentaenoic acid, is virtually absent from the brain.
These findings motivated researchers to conduct animal studies that used DHA, rather than mixed omega-3 fatty acids, for intervention studies aimed at reducing Alzheimer disease brain pathology in transgenic mouse models.
This was another randomized, double-blind, placebo-controlled trial of DHA supplementation in a group of people in the early stages of dementia.  They were included in the study only if they were medically stable, and didn't already consume significant quantities of DHA in their diet or as supplements.

Outcome measures were the rate of change in cognitive abilities as measured by standard tests, and scores on variables such as activities of daily living.  A subset of the sample underwent MRI to determine with the rate of brain atrophy had changed.  In addition, plasma fatty acids were measured before and after the study.  And they assessed the effect of DHA supplementation on progression of dementia in people with the APOE4 risk allele compared with those without.  The study lasted for 18 months.

Despite the fact that they enriched their sample for people with low baseline DHA levels, they found no evidence of a benefit from DHA supplementation either in slowed progression of dementia or of brain atrophy.  They did find some weak indication that carriers of the  APOE4 allele who received DHA rather than placebo had somewhat slower progression, but the analysis wasn't adjusted for multiple testing, which could erase the apparent effect -- "weaken the interpretation that this effect is clinically meaningful".

The authors say their results are strongly negative, but the possibility that starting supplementation long before the initial stages of dementia, when the architecture of the brain is starting to change, long before cognitive effects are noticed, could be preventive can't be ruled out.

So, like any complex trait, dementia is a heterogeneous collection of phenotypes with multiple causes. Tests of things like ability to carry out activities of daily life can't produce a detailed picture of what's gone wrong structurally in the brain -- nor are they meant to -- and so can't be a way to help sort people into more homogeneous groupings.  Indeed, a subset of the study group carries the Alzheimer's risk allele, APOE4 and these people may have responded differently to DHA supplementation (APOE4 is an allele that confers somewhat increased risk of dementia, but by no means guarantees it--but see NOTE below).  It's possible that there are other variables that could be used to create more homogeneous groups that might better respond to DHA -- or the B vitamins -- but what they are is not known.  So, a mixed grouping of phenotypes is one possible explanation for the negative results of this study, and heterogeneity is always a potential problem with complex traits.  But even so, it's very unlikely that a single dietary component is going to be either the cause or the cure for dementia, or it would have been found by now.  Science is very good at finding causes with large effect. 

But we conclude as we did when we wrote about Alzheimer's disease here: Whether we're wishing for something that's not possible in the face of causal complexity, or a stunning treatment will answer our wishes, nobody knows.  That's what keeps us tossing resources down the well.

NOTE:  We were just meeting yesterday with an expert genetic epidemiologist who works intensely on  Alzheimer's disease.  He told us that although many studies have implicated the APOE4 allele in Alzheimer's, it is still not clear that it is that gene rather than something else nearby on the same chromosome that is actually responsible--even though the E4 allele has been institutionalized as a major 'success' in disease mapping and chronic disease genetics.  So even this, largely because of its modest effects and the complexity of variation at the chromosomal level, is very difficult to nail down definitively.


James Goetz said...

I suppose a lesson in cause and effect follows: With no doubt, B12 deficiency greatly increases the chance of dementia and other mental illness, perhaps at any age. And there are endless anecdotes of apparent miraculous recovery from mental illness following B12 therapy. This could cause wishful thinking about B12 preventing dementia unrelated to B12 deficiency, but that's not how causation works.

James Goetz said...
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