Dr. Rhonda Patrick on DHA in Phospholipid Form for Alzheimer's Prevention in APOE4 Carriers

Dr. Rhonda Patrick 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 brain barrier, 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.

A Not-So-Brief-Summary:

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 increase your 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 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 accumulate in the brain, which is taken care of via the activation of microglial cells (brain’s immune cells). Acutely, microglial cell activation is good, and chronic activation is bad.In AD, microglial cells are chronically activated by a protein called amyloid-ß42, which is a product of full-length amyloid-ß cleavage. This triggers a vicious cycle because microglial activation leads to further production of amyloid-ß plaques and, thus, more amyloid-ß42 product. When amyloid-ß plaques form these aggregations, they interfere with neuronal communication, disrupting or destroying it.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 (glymphatic system)

In short: chronic activation of our brain’s immune cells leads to amyloid-ß plaque buildup, and clearance is impaired in APOE4 carriers.

1. 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 tangles because they are aggregates of tau proteins. These are inside the neurons of patients with AD, whereas the amyloid-ß plaques are outside the cell.Tau tangles interfere with how cellular components are transferred inside neurons, limiting energy to the cell needed to form new synapses and maintain those previously formed. Eventually, neurons succumb to this energy deficit resulting in long-term memory loss and neuronal cell death.In short: aggregates of tau proteins form tau tangles inside neurons and result in long-term memory loss and neuronal cell death.

1. Reduced Brain Glucose Uptake:

Between our blood and the brain is the blood brain barrier (BBB). Within the BBB are transporters that shuttle glucose into our brain; these are called GLUT transporters (specifically GLUT1 and GLUT3). Neurons rely on GLUT transporters because they cannot store or produce glucose themselves.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 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.

APOE4 carriers have reduced brain glucose uptake (which is more pronounced as we age) because APOE4 downregulates the transport of glucose into the brain.

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 its 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 have been linked to the development of the three main pathological hallmarks of AD, which include the accumulation of beta-amyloid plaques, the formation of neurofibrillary tangles, and neuroinflammation. These hallmarks are associated with the degeneration and cognitive decline observed in AD.Conversely, maintaining normal or high levels of DHA in the body is suggested to have a protective effect against AD. Studies have indicated that DHA at adequate levels may help prevent or even reverse the three pathological hallmarks of the disease, potentially slowing down or mitigating its progression.

• 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:

   

  Following a healthy and balanced diet, such as the Mediterranean diet, has been associated with a decreased risk of AD in individuals with the APOE4 gene variant. This diet typically includes fruits, vegetables, whole grains, lean proteins (such as fish and poultry), and healthy fats (such as olive oil and nuts).

• Adequate sleep:

   

  Getting sufficient and restful sleep is important for overall brain health and may help reduce the risk of AD in APOE4 carriers. Sleep plays a crucial role in memory consolidation and brain function.

• Exercise:

   

  Regular physical exercise has been shown to have a protective effect against AD in APOE4 carriers. Engaging in aerobic exercise, such as brisk walking or jogging, as well as strength training, can contribute to overall brain health and reduce the risk of cognitive decline.

Increases risk of AD in APOE4 carriers:

• Unhealthy diet:

   

  Consuming an unhealthy diet, characterized by a high intake of processed foods, sugary snacks, and saturated fats, has been associated with an increased risk of AD in individuals carrying the APOE4 gene variant.

• Smoking:

   

  Smoking tobacco has been linked to an increased risk of AD in APOE4 carriers. Smoking is known to be detrimental to overall health, including brain health, and can contribute to cognitive decline.

• Alcohol consumption:

   

  Excessive alcohol consumption is associated with an increased risk of AD in APOE4 carriers. Heavy and prolonged alcohol use can lead to brain damage and impair cognitive function.

• Sedentary lifestyle:

   

  Leading a sedentary lifestyle, characterized by a lack of physical activity and prolonged sitting, has been shown to increase the risk of AD in APOE4 carriers. Regular exercise and staying physically active are important for maintaining brain health.

• Lack of sleep:

   

  Chronic sleep deprivation or poor sleep quality can raise the risk of AD in APOE4 carriers. It's important to prioritize adequate sleep to support brain function and reduce the risk of cognitive decline.

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 carriers, but does in non-carriers.Why would fish improve cognitive function in APOE4 carriers but supplementing with DHA does not? Dr. Rhonda Patrick suggests that this is because DHA in fish is in phospholipid form, whereas in a DHA supplement, it is not.

APOE4 Carriers Have Impaired Transport of DHA.

The explanation provided by Dr. Rhonda Patrick suggests that the difference in the cognitive effects between consuming fish (rich in DHA) and taking DHA supplements in APOE4 carriers lies in the different forms of DHA and how they are metabolized.According to Dr. Patrick, the DHA in fish is in the phospholipid form, specifically as phosphatidylcholine (DHA-lysoPC). On the other hand, DHA supplements typically provide non-phospholipid DHA, which is in the form of non-esterified or free DHA.The form of DHA consumed influences how it is metabolized in the body. The phospholipid form of DHA, found naturally in fish, is metabolized into lysophosphatidylcholine (DHA-lysoPC). However, the non-phospholipid form of DHA, as found in DHA supplements, is metabolized into non-esterified DHA or free DHA.Dr. Patrick suggests that the transport mechanisms for these two forms of DHA into the brain differ. In the case of APOE4 carriers, there may be impaired transport of free DHA into the brain, while the transport of DHA-lysoPC remains unaffected.Based on this understanding, Dr. Patrick proposes that providing APOE4 carriers with DHA in the form of DHA-lysoPC may offer a way to bypass the defective transport of free DHA into the brain. By consuming DHA in the phospholipid form (as DHA-lysoPC), it is hypothesized that APOE4 carriers may deliver DHA more effectively to the brain, potentially enhancing cognitive function.

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 can not adequately enter the brain in APOE4 carriers, especially in older individuals.

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 carriers because this dictates DHA’s entry into our brain.

Sources of Phospholipid DHA:

• Fish contain ~1–1.5% of their omega-3 fatty acids in phospholipid form

• 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 breakdown.The position of DHA on the glycerol backbone of the phospholipid molecule determines how it is broken down and processed in the body.When DHA is attached to the second carbon (sn2) of the glycerol backbone:

• It is metabolized by an enzyme called pancreatic phospholipase A2 (PLA2), which cleaves the DHA from the glycerol backbone, releasing it as a free fatty acid.

• This free form of DHA can be resecreted into both low-density lipoproteins (LDL) and high-density lipoproteins (HDL), which are two types of lipoproteins involved in transporting fats in the bloodstream.

• The portion of DHA that binds to HDL has the potential to generate DHA-lysoPC (lysophosphatidylcholine), a form of DHA linked to a lysophospholipid molecule.

• The portion of DHA associated with LDL will remain in the free form of DHA.

When DHA is attached to the first carbon (sn1) of the glycerol backbone:

• It bypasses the pancreatic enzyme PLA2 and retains its phospholipid form without being cleaved.

• This phospholipid form of DHA in the sn1 position has a higher likelihood of accumulating in HDL rather than LDL.

• As a result, there is a greater chance of generating DHA-lysoPC when DHA is in the sn1 position and associated with HDL.

The breakdown described here provides insights into the metabolism of DHA in its phospholipid form and the potential fate of the released DHA in different lipoproteins. The generation of DHA-lysoPC, specifically associated with HDL, is of interest as it relates to the potential cognitive benefits of consuming DHA in the phospholipid form found in certain marine sources.

Metabolism of DHA in ethyl ester and triglyceride form (DHA & Fish oil supplements):

When DHA is in the ethyl ester or triglyceride form:

• These forms are broken down by pancreatic lipases in the intestines. Pancreatic lipases are enzymes responsible for the digestion and hydrolysis of fats.

• The breakdown of ethyl ester or triglyceride form can lead to the generation of both free DHA and DHA-lysoPC, depending on whether the released DHA is resecreted into LDL or HDL, respectively.

• However, compared to the fate of DHA in the sn1 position of the phospholipid form, the ethyl ester and triglyceride forms do not generate DHA-lysoPC to the same extent. DHA-lysoPC is the desired end product due to its potential cognitive benefits.

Dr. Patrick suggests the possibility that high-dose DHA supplementation could increase the generation of DHA-lysoPC. However, further research is needed to establish the specific mechanisms and dosage requirements for achieving this effect.In terms of absorption and delivery to the brain:

• The phospholipid form of DHA, such as that found in fish or krill oil, is suggested to reach circulation as DHA-lysoPC more rapidly compared to the consumption of DHA in the triglyceride form.

• It is also noted that DHA consumed in the phospholipid form is delivered to the brain in greater abundance compared to when consumed in the triglyceride form.

Conclusion

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.