Dr. Rhonda Patrick recently published a paper on the Role of Phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease.
Here's a Very Brief Summary:
- DHA is an essential omega-3 fatty acid and plays a vital role in the prevention and reversal of cognitive decline and Alzheimer’s Disease
- The form of DHA found in fish, fish roe, and krill oil is primarily in phospholipid form and this form is broken down to DHA-lysoPC
- The form of DHA found in DHA/fish oil supplements is not in phospholipid form and is primarily broken down to free DHA
- APOE4 carriers have impaired free DHA transport into the brain because of APOE4-mediated degradation of the
blood brainbarrier, but this degradation does not impair how DHA-lysoPC enters the brain
- Dr. Rhonda Patrick proposes that consuming DHA in phospholipid form may be a strategy for APOE4 carriers to get DHA into the brain and prevent APOE4-associated Alzheimer’s Disease, which is found in fish, fish roe, and krill oil but not in fish oil supplements
What is Alzheimer’s Disease? Alzheimer's Disease is a neurodegenerative disorder. Key Characteristics: memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes.
Alzheimer's Disease and Age: Risk for AD doubles every 5 years, following the age of 65, and around 1/3 of people over 85 have AD.
Genetic Risks: Three common isoforms of the APOE(2, 3, 4) gene, each associated with different AD risks. In regard to AD, APOE4 is what we are concerned about. We carry two alleles of one single gene, meaning we can carry either one or two APOE4 alleles. About 1/4 of the population has at least one APOE4 allele. ~65–80% of people with AD have at least one APOE4 allele.
- APOE4 allele increases your risk for AD ~2–3-fold
- APOE4 alleles
increasesyour risk for AD ~15-fold
However, APOE4 does not guarantee you will get AD and not having APOE4 doesn’t mean you won’t get AD. Interestingly, APOE4 is associated with better cognition and intelligence early in life but earlier decline as we age (an example of antagonistic pleiotropy).
What is APOE?
The APOE gene codes for the APOE protein. This protein is made in the brain and peripheral tissues but plays similar roles for both in lipid and cholesterol transport.
In peripheral tissue, APOE is synthesized in the liver and regulates lipid and cholesterol transport to tissues and reverse cholesterol transport (from peripheral tissues back to the liver first via the lymphatic system, then the bloodstream).
- APOE3: baseline/normal
- APOE2: increased APOE protein expression and decreased plasma cholesterol
- APOE4: decreased APOE protein expression and increased plasma cholesterol
In the Brain, APOE is synthesized by astrocytes and regulates lipid and cholesterol transport to neurons. APOE2 and APOE3 are expressed 2–4 times more in neurons than APOE4, therefore APOE4 has reduced lipid and cholesterol transport to neurons.
Three Primary Pathological Hallmarks of Alzheimer's Disease:
1. Extracellular Amyloid-ß Plaques
As we age, reactive oxygen species (ROS) and inflammation
Two ways we clear amyloid-ß plaques from the brain:
1. Glymphatic System: activated when we sleep and removes waste products from the brain, including amyloid-ß plaques. A lack of sleep = less glymphatic activation = less amyloid-ß plaque clearance.
2. APOE-mediated Mechanism: APOE binds amyloid-ß42 and removes it from the cell. The APOE4 isoform, besides producing less APOE protein, also binds amyloid-ß42 with a 20-fold lower affinity than APOE3. This mechanism is therefore very ineffective for APOE4 carriers.
Sleep matters more for APOE4 carriers since they must rely on only one clearance system (
In short: chronic activation of our brain’s immune cells leads to amyloid-ß plaque build up, and clearance is impaired in APOE4 carriers.
2. Intracellular Neurofibrillary Tangles:
If that looks like gibberish to you, don’t worry that’s what I felt I was typing. These are also referred to as tau
In short: aggregates of tau proteins form tau tangles inside neurons and result in long-term memory loss and neuronal cell death.
3. Reduced Brain Glucose Uptake:
Between our blood and the brain is the
APOE4 carriers typically have downregulation of GLUT transporters, and therefore reduced brain glucose uptake is more prevalent in these individuals.
A lack of glucose to the brain also contributes to the formation of tau tangles. After a tau protein is translated (produced from its associated mRNA), it is modified in a glucose-dependent manner, and once modified, negatively regulates its phosphorylation. Without this modification, which occurs with reduced brain glucose uptake, tau proteins are hyperphosphorylated (since it has nothing negatively regulating this now), and this renders tau proteins pretty useless in addition to promoting their aggregation and formation of tau tangles.
In short: APOE4 carriers have reduced brain glucose uptake (which is more pronounced as we age) because APOE4 downregulates the transport of glucose into the brain.
How DHA acts on all three of these pathologies?
Docosahexaenoic acid (DHA) is one of the essential omega-3 fatty acids (the other important one is EPA and to a lesser extent, ALA). It accounts for just shy of 1/3 of the brain’s lipids, so it’s presence is pretty critical. Unfortunately, the body cannot produce DHA on its own, and it must be acquired through the diet.
Low levels of DHA promote all three pathological hallmarks of AD
Normal/high levels of DHA prevent or reverse all three pathological hallmarks of AD
- DHA has been shown to reduce amyloid-ß plaques and their associated toxicity
- DHA has been shown to promote amyloid-ß plaque clearance from the brain
- DHA has been shown to decrease tau tangles
- DHA regulates GLUT transporters; high levels upregulate GLUTs and low levels downregulate GLUTs
Decreases risk of AD in APOE4 carriers:
- Healthy diet
- Adequate sleep
Increases risk of AD in APOE4 carriers:
- Unhealthy diet
- Alcohol consumption
- Sedentary lifestyle
- Lack of sleep
Regardless of APOE status, dietary fish and seafood intake slows AD progression and improves all three pathological characteristics of AD. Interestingly, DHA supplementation does not show these effects in APOE4
Why would fish improve cognitive function in APOE4carriers but supplementing with DHA does not? Dr. Rhonda Patrick suggests that the reason for this is because DHA in fish is in phospholipid form, whereas in a DHA supplement it is not.
The form of DHA consumed dictates how it is metabolized:
- Phospholipid form of DHA (found in fish) is metabolized to lysophosphatidylcholine (DHA-lysoPC) Non-phospholipid form of DHA (found in DHA supplements) is metabolized to
non- esterfiedDHA (free DHA)
- The transport of these two types of DHA
usedifferent transport mechanisms for entry into the brain. Therefore, Dr. Patrick suggests that the transport of free DHA into the brain of APOE4 carriers is impaired, but the transport of DHA-lysoPC,is not.
Dr. Rhonda Patrick’s proposal: Providing the brain of APOE4 carriers with DHA-lysoPC may be a way to bypass defective free DHA transport into the brain.
In short: the type of DHA found in fish, fish roe, and krill oil has a better chance of getting into the brain of APOE4 carriers.
How APOE4 Impacts Free DHA Transport:
APOE4 in the brain breaks down the integrity and permeability of the BBB through multiple different mechanisms ultimately rendering free DHA transport into the brain very limited. It also decreases cerebral vascularization (i.e. blood supply to the brain). Specifically, APOE4 degrades the tight junctions of the BBB which disrupts the outer membrane leaflet used by free DHA to enter the brain.
Free DHA improves cognitive function in young APOE4 carriers, but not in older individuals, indicating that age is a factor in the APOE4-mediated deterioration of the BBB.
In short: the type of DHA in fish oil supplements
How APOE4 Impacts DHA-LysoPC Transport:
Trick question, it doesn’t. DHA-LysoPC bypasses the tight junctions of the BBB and enters the brain via the inner membrane leaflet, therefore regardless of APOE status, DHA-LysoPC should enter the brain despite any degradation caused by APOE4.
The form of DHA becomes very critical for APOE4
Sources of Phospholipid DHA:
- Fish contain ~1–1.5% of their omega-3 fatty acids in phospholipid form but fish oil
- Fish roe from salmon, herring, pollock, and flying fish contain high amounts (~38–75%) of their omega-3 fatty acids in phospholipid form (mostly as phosphatidylcholine)
- Krill oil contains ~35% of DHA in phospholipids
- Supplements do not contain any
Metabolism of DHA in phospholipid form (fish, fish roe, krill oil):
In phospholipid form, whether DHA is attached to the first or second carbon of the glycerol backbone dictates its break down.
DHA at carbon 2 (sn2):
- Metabolized by pancreatic enzyme PLA2 which releases DHA as a free fatty acid
- This free fatty acid (DHA) is resecreted into both LDL and HDL
- Only the portion that binds to HDL generates DHA-LysoPC
- The portion in LDL will generate the free form of DHA.
DHA at carbon 1 (sn1):
- Bypasses pancreatic enzyme PLA2
thereforeretaining its phospholipid form
- This has a much greater chance of accumulating in HDL than LDL, therefore a much greater chance of generating DHA-lysoPC
Metabolism of DHA in ethyl ester and triglyceride form (DHA & Fish oil supplements):
These forms are broken down by pancreatic lipases in the intestines and can both generate free DHA and DHA-lysoPC depending on whether it is resecreted into LDL or HDL, respectively. Compared to the fate of DHA at the sn1 position in phospholipid form, these forms do not generate DHA-lysoPC (the end product we want!) to the same extent. Dr. Patrick suggests the possibility that high dose DHA supplementation could increase the generation of DHA-lysoPC.
Phospholipid form ends up in circulation as DHA-lysoPC more rapidly than consumption in triglyceride form
DHA is delivered to the brain in greater abundance when consumed in phospholipid form versus triglyceride
In summary, APOE4 limits the transport of free DHA (from DHA supplements) into the brain, therefore consuming DHA in phospholipid form to generate DHA-lysoPC (e.g. fish, fish roe, and krill oil) may bypass this faulty transport in APOE4 carriers.