First, some possible bad news for Paleo/Primal diet fans. See, there's a prospective cohort study of people >65 out of New York City. 2148 elderly were followed for about 4 years, and every 1.5 years they were given neurological and neuropsychological tests. In addition, a food frequency questionnaire was done at the beginning of the study to look into dietary patterns (DP). I'll just copy and paste the results:
RESULTS: Two hundred fifty-three subjects developed [Alzheimer's Dementia] during a follow-up of 3.9 years. We identified a DP strongly associated with lower AD risk: compared with subjects in the lowest tertile of adherence to this pattern, the AD hazard ratio (95% confidence interval) for subjects in the highest DP tertile was 0.62 (0.43-0.89) after multivariable adjustment (P for trend = .01). This DP was characterized by higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter.
Oof! Say it ain't so! (One will note that the protective diet was similar to a Mediterranean style diet, but not a saturated fat and organ meat friendly evolutionary-based diet.)
In a previous post, I discussed how cohort studies link diets high in omega 3 fatty acids and a reduced risk of Alzheimer's. The same review article I relied on in that post looked at several studies that seemed to show an increased risk with the consumption of saturated fat. The ApoE proteins are apolipoproteins - they are the key to how lipoproteins carry fats around in the brain rather like apolipoproteins such as apoB on LDL help carry fats around in the blood. ApoE4 is famously linked with an increased risk of developing Alzheimer's dementia.
That's worth peering at more closely, I think. It's all fair and good when we can snigger at the USDA for sloppy science. But are the Alzheimer's researchers also hopelessly biased by the lipid hypothesis? Stephan and Peter have done it a million times - picked apart study after study showing that the saturated fat could be an innocent bystander to high sugar or low omega 3 consumption. Is the same true here?
One advantage of Alzheimer's is that it is big news, and big money has gone into it. That means there are a zillion studies, and a number of thoughtful review articles with details spelled out. I'm not the world's expert on fat metabolism by any means, so having some of it spelled out is useful. If I need answers, perhaps some of them can be found here, in "Dietary fats, cerebrovascular integrity, and Alzheimer's disease risk." Let's roll up our sleeves and dive in.
First, an interesting quote: "The mechanisms by which dietary fats such as SFA increase AD risk may seem less of a scientific priority to delineate compared to dietary compounds that confer protection. Yet in some chronic disorders this approach has proven pivotal to developing effective therapeutic strategies for prevention and treatment of disease. For example, elucidating the role of cholesterol in atherosclerosis and cardiovascular disease led to the evolution of relatively safe and effective cholesterol-lowering drugs." Looks like lipid hypothesis fans at work! But they talk in detail about the actual biochemistry, and the actual biochemistry is even interesting, so let's go further.
In some previous posts, we talked a bit about the pathophysiology of Alzheimer's dementia. First you get a long build up of amyloid plaque, then tau protein tangles, inflammation, and brain cell death. But it turns out, the blood vessels of dementia patients are none to happy either. Changes in the blood vessels, including smooth muscle cell and endothelial cell proliferation seem to precede the last stages of plaque build up. In addition, the blood brain barrier (BBB), which functions to protect our brain much as our gut is supposed to protect our body from outside insults, seems to be poorly functioning in patient's with Alzheimer's.
Then there are the animal models. Saturated fat and cholesterol-rich diets seem to make amyloidosis worse in amyloid-prone strains of mice. And there is something interesting about fat metabolism and amyloid - when we eat fat, it is disassembled and then reassembled and escorted by chylomicrons through the blood to the liver for further processing. Turns out that amyloid-beta loves to hang out with chylomicrons too, so the more chylomicrons we have, the more amyloid-beta in the blood. And here is something very, very interesting - compared to low-fat diet fed control rats, saturated fat increased the amount of amyloid beta in the blood, whereas fasting rats seemed to have no amyloid beta in the blood at all. Low-carb diet fans (including me!) like to compare low-carb dieting to fasting. But there is a difference between eating fat and fasting - the fat floating from the gut to the liver via the chylomicrons. Here is a theory that suggests that ingestion of saturated fat causes a "post-prandial-hyperamyloidemia." Couple this theory with the finding that folks with Alzheimer's and mild cognitive impairment have greater amyloid beta in blood plasma measurements that include chylomicrons, and a saturated fat eater might have cause to be worried. However, there isn't much good evidence that a significant amount the gut-derived amyloid beta gets from the blood through the BBB into the brain, even in studies of mice designed to measure this effect. The worst thing reasearchers found was that the blood vessels in the brain don't seem to do so well if there is a lot of amyloid beta hanging around. It seems to cause constriction of the blood vessels and rigidity, rather like accelerated aging.
Accelerated aging? Hmmm. I usually don't associated fat with accelerated aging processes - I usually associate that with hyperglycemia (high blood glucose). And here's something interesting - RAGE, the receptor for advanced glycosylation end-products (pro-oxidant nasties that are especially prevalent in diabetics), is one small way that amyloid beta can get from the blood into the brain.
So what is the real meat of the saturated fat causes Alzheimer's hypothesis? Well, the researchers blame lipotoxicity. Yes, that lipotoxicity. Damage that long-chain saturated fat (particularly palmitic acid) causes to endoplasmic reticulum and cells by triggering cell death (apoptosis). Polyunsaturated and monounsaturated fatty acids are supposed to be protective.
A whole host of organ damage is blamed on this phenomenon - "the process has also been implicated in endothelial dysfunction and atherosclerosis, heart failure, kidney failure, steatohepatitis [fatty liver] and liver failure, autoimmune inflammatory disorders, susceptibility to infections, cancer and ageing." The researchers say the brain is particularly vulnerable, as cortical astroglia metabolize a heck of a lot of fat.
Oh, and remember, this end-organ damage occurs in the context of "fat-induced insulin resistance."
Stepping back to the big picture, please remember that "fat-induced insulin resistance" is physiologic, not pathologic. It is one of the ways a body adapts to a low carb diet. Pathologic insulin resistance occurs in the context of metabolic syndrome and diabetes - conditions exacerbated by the consumption of high carbohydrate and inflammatory Western diets. If you don't have pathologic insulin resistance, can you have lipotoxicity? I seriously doubt it.
The paper continues past the lipotoxicity theory to a discussion of membranes and lipid rafts. They review studies of mice and rabbits fed a "a Western diet rich in saturated fats and cholesterol" versus a similar diet enriched with DHA (an omega 3 fatty acid derived from fish oil). They suggest that the DHA helps membrane fluidity, enabling better transport and degradation of amyloid beta, whereas the straight-up cholesterol and saturated fat rich rats had the extra gut-derived amyloid and a woeful lack of lipid rafts to help the excess amyloid be disposed of. Here we go again - known health effects from a deficiency of omega 3 is being blamed on the saturated fat part of the Western diet.
The next theory that saturated fat causes Alzheimer's in the paper relates membrane toxicity to oxidized lipids. This is something we can all agree on! Oxidized lipids and cholesterol are bad, and cause inflammation, even in the brain. Problem is, sources of dietary oxidized cholesterol include skim milk, especially powdered skim milk, and saturated fats are actually far more difficult to oxidize than polyunsaturated fats such as vegetable oils and omega 3s.
I'm a bit biased. But so far I'm not impressed. It seems easy to poke holes in all the saturated fat causes Alzheimer's theories. Frankly, the most damning evidence is that Manhattan dietary study, which does not constitute proof. But we'll see. In the next post (most likely), I'll take a closer look at ApoE4 and fat metabolism.