Alzheimer's and Omega 3s

Let's continue on our journey deconstructing and reverse engineering psychiatry from an evolutionary medicine perspective. That is, I assume the correct answer and see how the many pieces fit. There is a danger from this approach - if the main hypothesis is incorrect, I might be wasting a lot of time. But I'm having a bit of fun in the process, and it's quite remarkable just how many connections can be made using the intuitive evolutionary framework to lay out the data.

To date there are a large number of studies covering the topic of dementia and omega 3 fatty acids (1)(2). There are a couple of reasons omega 3s have been so thoroughly studied, and if you have the stamina, I'll take you through a bit of molecular biology.

First off, inflammation and Alzheimer's are linked, and omega 3s are basically anti-inflammatory. DHA is modified by phospholipases to become neuroprotectin 1 (your neurons' superhero - neuroprotectin!) Alzheimer's patients have lower phospholipase activity in brain tissue, CSF, and in platelets. All sorts of inflammatory stressors (lack of oxygen, exposure to amyloid, and IL-1b) cause the up regulation of phospholipase, leading to the formation of neuroprotectin from DHA, which then reverses the inflammatory cascade. Perfect negative feedback inhibition - which works best no doubt if the omega 3s and 6s are balanced in a more evolutionary style diet.

Secondly, an imbalance of AA (derived from omega 6) vs DHA (omega 3) may be critical to the formation of amyloid plaques in the first place. Amyloid precursor protein has to be cut in particular ways to make the toxic fragments that eventually aggregate into amyloid plaques. It seems that if brain cell membranes are rich in DHA, the squiggles and wiggles of DHA hide and protect the bad cleavage sites on amyloid precursor protein. AA squiggles and wiggles seem to expose the bad cleavage sites, making it easier to make plaque from amyloid precursor protein. DHA also seems not only to make it physically harder to cut amyloid precursor protein in the bad way, but DHA also chemically cripples the action of the amyloid-creating enzyme, gamma secretase. All this in addition to reducing the inflammatory action of plaque once DHA is formed into neuroprotectin!

So what about those studies of omega 3 and dementia? 17 reasonably good cross-sectional, epidemiological, and prospective cohort studies have been done over the years. Some of better quality than others, of course. 2/3 used food frequency questionnaires, the other 1/3 lab measurements of fatty acid ratios (from serum or plasma). Overall, the studies followed some 24,000 or so people in Japan, the US, Canada, and Europe, both those with dementia and regular population cohorts.

Results time! Some studies found no correlations, but for the most part, diets high in fish were associated with less dementia. Diets high in omega 6, saturated fat, total fat, and cholesterol were associated with more dementia. The association was especially strong for those people without the genetic predisposition for Alzheimer's - people without the ApoE4 allele. (ApoE is short for apolipoprotein E, by the way - yes, just like high density lipoprotein (HDL) and low density lipoprotein (LDL), apolipoproteins carry around fat and cholesterol, but in the brains. More about this in a later post).

The overall trend was enough to cause researchers to try prospective controlled trials with omega 3 supplementation in dementia. 6 have been done to date. The first one, in 2004, was badly designed at the beginning. 20 Alzheimer's patients were treated with 500 mg of the omega 3 EPA. Since EPA is not an important fatty acid in the brain as far as we know, there was no effect in cognitive decline between the supplement arm and the placebo arm of the studies. In Japan in 2006, 240mg of AA+DHA was compared to 240mg of olive oil daily for 90 days. The mild cognitive impairment group with the PUFAs showed some improvement, whereas the olive oil group had no improvement.

Also in 2006, a large (204 subjects) double blind randomized controlled trial was done with 1.7 grams DHA and 0.6 grams EPA or placebo for 6 months, followed by an additional 6 months of "open label" where everyone got the omega 3 treatment. Overall, there was no difference between the two groups, except one subgroup of mild cognitive impairment did better on the omega3s. Another small study in 2008 had similar results.

In 2009, 485 cognitively normal elderly folks were randomized to 900 mg DHA a day or placebo for 6 months. The treatment arm doubled their plasma DHA levels and showed improvement in some of the learning and memory tests (but not in the main study objective, the "global battery score") while the controls didn't improve. A second trial of 402 subjects with mild to moderate Alzheimer's dementia and 2 grams of DHA vs placebo did not meet the primary objective despite healthy increases in serum and CSF levels of DHA in the treatment arm.

Whew. So here we have science. Plausible molecular mechanism, followed by epidemiological studies, followed by randomized controlled trials. Overall, the science tells us that omega 3 is probably protective against amyloid and helpful in memory. Why? Because non-demented and mildly demented individuals benefited, while the more severe cases did not. In my last Alzheimer's post, I discussed how amyloid builds up over decades, and amyloid-zapping interventions in the end stage is like dousing a fire just after the house is burned down. Theoretically, omega 3s should have some benefit at the inflammatory stage too - I wonder what the outcome in more severe cases would be if the omega 6s and 3s where held to an evolutionary ratio of 2:1 or 1:2 or 1:1?

In general we are not talking about mega doses here. In the epidemiological studies, DHA intakes of 180mg a day correlated with a 40% reduction in dementia. Average Western diet intake is 80mg a day. Fatty fish three times a week or so would do the trick.

There are two schools of thought about getting the 3/6 ratios correct in the paleosphere. One way is to let time be on your side, avoid excess omega 6, and supplement prudently with Omega 3. DHA is easily oxidized, so you would want to supplement with oil you can taste - in fish, for example, or teaspoons. Another way is to take in high amounts of omega 3 to more or less wash out the omega 6. This method might make more sense if you are in a more desperate situation - mild cognitive impairment already, active heart disease, bad autoimmune stuff going on. The risk is that high amounts of PUFAs are tough on the liver and are bad to combine with sugar and alcohol, and likely cancer promoting. My perspective - if you can get away with it, take it slow. But compared to a number of other medical treatments for our various diseases of civilization, even higher doses of PUFAs for a short term is likely safer and possibly more beneficial.

(did this post on the iPad so I'm adding references later, when I get a moment at the bigger computer! - Done!)