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

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By Dr. Nicholas Norwitz, updated May 8 20226
Expert Article Evidence Based

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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