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A New Way Inflammation Causes Alzheimer’s Disease in ApoE4
Breaking News (April 2020)

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Quick Summary tl;dr

Inflammation leads to blood-brain barrier damage and Alzheimer’s disease.

This mechanism appears to be independent of the stereotypical hallmarks of Alzheimer’s, amyloid plaques and tau tangles.

This mechanism involves the CypA-MMP9 pathway, which you can help block with a Mediterranean-ketogenic diet.

This stunning paper, published April 29th 2020 in the prestigious journal Nature ( 1), provides new insight into how the  ApoE4 allele may contribute to Alzheimer’s disease (AD).

 This study found that ApoE4 causes a breakdown of the protective blood-brain barrier near the regions of the brain impacted by Alzheimer’s disease. They found that markers of this breakdown predict cognitive decline independent of the stereotyped hallmarks of AD (amyloid plaques and tau tangles) and specifically in ApoE4 carriers, and not in ApoE3 individuals.

The study provides strong evidence that the relationship between ApoE4 and blood-brain barrier breakdown appears to be mediated by the CypA-MMP9 inflammatory pathway. In a way, this is encouraging for ApoE4 carriers because it suggests that the 3-15-fold increase in Alzheimer’s disease risk associated with ApoE4/ApoE3 and ApoE4/ApoE4 genotypes may be largely due to inflammation — a modifiable risk factor!

(A notable, but nerdy, aside is that ApoE3 genetically downregulates the CypA-MMP9 pathway through the LRP1 receptor. But ApoE4 can’t downregulate CypA-MMP9 in the same way!)

While this exquisite basic science paper does not offer medical or nutritional advice, other research suggests that a Mediterranean-style diet could decrease Alzheimer’s disease risk in ApoE4s as it contains natural compounds that inhibit the CypA-MMP9 inflammatory pathway ( 2). Such biochemical mechanisms agree with the epidemiological data that shows Mediterranean-style diets are associated with lower rates of AD ( 3).

Specifically, polyphenols found in extra virgin olive oil (oleuropein and hydroxytyrosol) (2) and red onions and capers (quercetin) ( 2), and glucosinolates-derivatives found in cruciferous vegetables such as broccoli, cauliflower, and Brussels sprouts (sulforaphane) ( 4) have been shown to inhibit the CypA-MMP9 pathway.

Inflammation leads to blood-brain barrier damage and Alzheimer’s disease. A new study suggests a new mechanism by which an increased AD risk associated with ApoE4 may be largely due to inflammation - a modifiable risk factor!

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Dr. Nicholas Norwitz
PhD in Ketogenics and Metabolism, Oxford University

Nicholas Notwitz

Dr. Nicholas Norwitz is a new shining star in nutrition science. This 25-year-old Ivy League Valedictorian obtained his PhD at Oxford University in just two years and is now pursing his MD at Harvard Medical School. His research expertise is ketosis and brain aging; however, he has published scientific papers on topics ranging from neuroscience to heart disease to gastrointestinal health to genetics to bone health to diabetes.

You can find Nick on Twitter at @nicknorwitz.

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Comments (6)

Hi Dr. Norwitz. I love the article, but I'm doing a carnivore diet. Is that okay for inflammation, since it's not Mediterranean? Could you suggest any tips to help me decrease my inflammation in my brain. I'm worried about dementia. I'm a 58-year-old woman with one ApoE4. Thanks in advance.

Dear Grecia, I love the question. Believe it or not, I'm experimenting with a carnivore diet myself too, although I'm historically Mediterranean Keto. My main tips for you regard food quality. It's very important to get "100% grass-finished" red meat or "only grass-fed." Fish should always by wild and salmon is best if it's wild alaskan sockeye. Get eggs that are "pastured" (US) or "organic and free-range" (UK) and chicken that's labeled the same.
Because animals' fat profiles are influenced by the foods they themselves eat, you should tend towards animals who eat a natural diet. When you feed animals soy, corn, or grain, they end up with more inflammatory fat in their own fat! This is particularly true of chicken and pork. This isn't inflammation-related, per se, but if you're eating lots of seafood (which is great!) don't eat big fish high on the food chain like tuna or swordfish too often. Those fish are high in heavy metals, like mercury. The best fish/shellfish for carnivore are wild alaskan salmon, whole sardines, mackerel, oysters, and mussels. The reasons for this are manifold, but include the fact that they are, with the exception of the mackerel, whole organisms such that you're effectively eating nose-to-tail and getting a full range of nutrients. For example, the mussels are packed with manganese and the oysters with zinc. You want to eat nose-to-tail to make sure you're nutrient replete.
Finally, I have a preference for incorporating in more MUFA and Omega-3 fat sources on carnivore, which I suppose makes it less carnivore but whatever. I like macadamia nut oil to make homemade mayo with egg yolks, and also enjoy high quality extra virgin olive oil on omelets. I fry my feta and halloumi in avocado oil, etc. This helps me personally feel my healthiest. What you do it up to you and many carnivores would be strictly against this practice, but I feel these oils are harmless, if not beneficial.
Hope that helps and let me know if you have any more questions.

Very interested in this topic in the Keto App Blog.  
Alzheimers disease and inflammation, by Nicholas Norwitz  Oxford PHD etc etc , it is IMPERATIVE that  the reference and/or a link to his prestigious article in Nature be provided, in order that this topic can be reviewed.
I know it sounds nerdy, but for me and other highly educated PHD candidates it is important that this reference, and/ or  be provided
Thank you Sally

It's there. Click on the "(1)" in the first line of the above.

Very good article. I would like to know your opinion on the 2 weeks diet.
Thank you!

Andrea, could you please give more details on what the two weeks diet is? Neither I nor Martina have ever heard of it.