Dr Rhonda Patrick's ApoE4 Paper Summarized - How Omega-3 DHA Phospholipids May Help Prevent Alzheimer's in ApoE4 Carriers

When I first heard about Rhonda’s paper on ApoE4, Alzheimer’s & Omega-3 Phospholipids – it sounded important, but I had no idea what it was about. For a start, I didn’t know my ApoE4 allele’s from my MSFD2A transporters – so it was an uphill challenge to understand.

In this post I’d like to cover what I’ve learnt from it, and hopefully, make it seem more digestible for others who are also new to the subject.

Table of Contents

Who does this apply to?

This research only applies to ApoE4 carriers, which may make up 20% of the general population.*

The only way to know if you carry ApoE4, is to perform a genetic test (saliva sample based), to sequence your SNPs. The most commonly used for this purpose are 23andMe & Ancestry. At the time of writing it’s noted on the SNPedia ApoE4 page that Ancestry misreports rs429358 (which is relevant to ApoE4), so it may be worth using 23andMe until that is resolved.

*It’s not clear exactly how many people carry the ApoE4 allele. Rhonda’s paper quotes ~25% of the population, citing this paper as the source¹. But looking at the paper, and I could be wrong, it doesn’t appear their sample size is enough to draw any conclusions on prevalence of ApoE4. A better source appears to be the Corbo and Sacchi paper² (see Table 1) which shows a large variance in ApoE4 prevalence, based on geography. For example in Europe, the prevalence is largely 16% or lower.

Why is Rhonda’s paper important?

Rhonda with her freshly published paper in Oct 2018 (source).

Having 1 ApoE4 allele confers a 2-3x increase in Alzheimer’s disease risk, and having 2 ApoE4 allele’s confers up to a 15x risk (the most one can have is 2 allele’s).

I don’t need to tell you that this is very undesirable. Alzheimer’s sucks for all involved. It currently makes up ~70% of all dementia cases³.

Rhonda’s paper proposes a way to reduce this risk through the consumption of fish, fish roe (fish eggs) and/or phospholipid DHA supplements (rather than regular DHA supplements).

Which would be fantastic.

For Rhonda, her ApoE4 research is close to home. She reportedly carries at least one ApoE4 allele herself.

How does the solution work?

It would be wrong to pretend we fully understand how Alzheimer’s develops. But we do know that there are 3 hallmarks:

Extracellular amyloid-beta plaques (extracellular in this context means that the plaques build up outside of the cells, vs intracellular, which would be inside)
Intracellular neurofibrillary tangles (commonly referred to as tau tangles)
Reduced glucose uptake in the brain

Something that affects all 3 of these hallmarks is DHA levels in the brain. DHA being the essential omega-3 fatty acid that comprises ~30% of the fat (lipids) in the brain. Higher levels ameliorate the above 3 hallmarks, lower levels increase them.

An illustration from Rhonda’s paper showing the 3 hallmarks of Alzheimer’s disease in one picture. (1) Reduced glucose uptake in the brain. (2) Tau tangles inside of neurons. (3) Amyloid-beta plaques in the space between neurons. With (1) & (2) disrupting neuronal synaptic transmission.

So the next question becomes… how do we get more DHA into the ApoE4 carrier brain?

Typically, we would eat fish or, consume fish oil supplements, in order to achieve adequate amounts of DHA. There are plant sources of DHA, but the absorption pathway is unfortunately inefficient in humans.

In ApoE4 carriers, it appears that fish oil supplements are not effective, but fish itself is. Why might that be? What does the fish have that the fish oil does not?

Rhonda proposes that this is due to the following:

Fish contains DHA in phospholipid form, whereas fish oil supplements do not.
When consuming fish oil supplements, the DHA gets metabolized to nonesterified DHA (free DHA). ApoE4 carriers have impaired brain transport for free DHA.
When consuming fish, the phospholipid DHA is metabolized to a specific form called lysophosphatidylcholine DHA (that is not a word you want coming up in a spelling test! DHA-lysoPC for short)
This DHA-lysoPC may bypass the defective transport of free DHA in ApoE4 carriers – allowing them to uptake DHA into the brain.

Another excellent illustration from Rhonda’s paper, showing how low DHA reduces the GLUT1 transporters. These are key for glucose transport through the blood brain barrier. With reduced brain glucose, we get more tau phosphorylation (the green Ps in the right image), resulting in more tau tangles (not good). Reduced glucose also results in more amyloid beta plaques – but the image above doesn’t show the mechanism.

So, what’s the upshot?

The upshot of all this is that ApoE4 carriers can potentially reduce their Alzheimers risk by consuming more omega-3 phospholipids. In practice, this means eating things like:

Fish
In particular cold water fish like salmon, sardines, anchovy, herring and mackerel. Fish contain between 1%–1.5% phospholipids⁴. Tinned sardines are a nice go-to option. For things like salmon and mackerel, you’ll ideally want to source wild varieties, as farmed fish often have their fatty acid ratios affected by the unnatural fish feed used.
Fish Roe
Fish roe (fish eggs) from herring, salmon, pollock, and flying fish contain between 38%–75% of their lipids in the form of phospholipids⁵. Wild Salmon Roe is Rhonda’s go-to choice these days for omega-3 phospholipids. For example see this and this Instagram post on the subject. She bulk buys direct from Vital Choice , who offer 2.2lbs in quarters, that can be frozen and taken out when needed.
Fish Oil
“Regular” fish oil primarily contains the triglyceride form of omega-3 fatty acids, rather than the phospholipid form we’re discussing in this article. This is the motivation behind Rhonda including fish roe (mentioned above), because it contains the phospholipid form. That said, Rhonda continues to take the triglyceride form of omega-3s, due to them having many other benefits. For more on that, see this post on the fish oil she takes.