The potential of phosphatidylcholine-DHA in mitigating APOE4-related Alzheimer’s disease

May 18, 2023

Consuming a type of omega-3 fatty acid called docosahexaenoic acid (DHA) has been found to lower the risk of Alzheimer’s disease (AD) and improve its symptoms. The apolipoprotein E (APOE)4 allele is known as the most influential risk factor for sporadic AD, excluding age. Interestingly, individuals carrying the APOE4 allele respond better to DHA obtained from fish, while their response to DHA dietary supplements is not as effective. The reasons behind this differing response are not yet understood.

One potential explanation is that fish naturally contain DHA in a form called phospholipid, whereas fish oil supplements lack this form. This disparity affects how DHA is processed in the body, leading to two primary forms: nonesterified DHA (free DHA) and a phospholipid form called lysophosphatidylcholine DHA (DHA-lysoPC). Free DHA can passively diffuse across the outer layer of the blood-brain barrier (BBB), while DHA-lysoPC requires a specific protein called major facilitator superfamily domain-containing protein 2A to transport it across the inner layer of the BBB.

Individuals with the APOE4 allele may have impaired transport of free DHA into the brain due to a breakdown in the outer layer of the BBB. This impaired transport mechanism increases their vulnerability to AD. However, the transport of DHA-lysoPC seems to remain unaffected in these individuals. Therefore, consuming dietary sources of DHA in the phospholipid form may raise the levels of DHA-lysoPC in the bloodstream, potentially reducing the risk of AD.

Obtaining DHA from dietary sources in the phospholipid form could play a significant role in preventing AD associated with the APOE4 allele. By increasing the levels of DHA-lysoPC, which can bypass the impaired transport mechanism seen in APOE4 carriers, the risk of developing AD could potentially be decreased.

Phosphatidylcholine-DHA: a promising approach to alleviate Alzheimer’s disease in APOE4 carriers

Here are our key takeaways from the study, Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease

Alzheimer’s disease overview


Alzheimer’s Disease (AD) is a neurodegenerative disorder characterised by memory loss, spatial disorientation, cognitive dysfunction, and behavioural changes.

The risk of developing AD increases with age, with around 1/3 of people over 85 years old having the disease.

Genetic factors, including the APOE gene, also play a role in AD risk. APOE4 carriers have an increased risk of developing AD, but it does not guarantee the disease, and non-carriers can still develop AD.

DHA for brain health


DHA is an essential omega-3 fatty acid that is important for brain health and has been linked to the prevention and reversal of cognitive decline and Alzheimer’s Disease.

Omega-3 fatty acids, including DHA, cannot be produced by the body and must be obtained through the diet.

DHA forms and sources


DHA can be found in different forms in various sources.

The form of DHA found in fish, fish roe, and krill oil is primarily in the phospholipid form, specifically as phosphatidylcholine (DHA-lysoPC).

On the other hand, DHA supplements usually provide non-phospholipid DHA, which is in the form of non-esterified or free DHA.

APOE4 gene and Alzheimer’s risk


APOE4 is a gene variant associated with an increased risk of developing Alzheimer’s Disease.

APOE4 carriers have impaired transport of free DHA into the brain due to the APOE4-mediated degradation of the blood-brain barrier (BBB). However, this degradation does not affect how DHA-lysoPC enters the brain.

Benefits of DHA-lysoPC


Consuming DHA in phospholipid form, such as DHA-lysoPC found in fish, fish roe, and krill oil, may be beneficial for APOE4 carriers.

This form of DHA can bypass the defective transport of free DHA into the brain, potentially improving cognitive function and reducing the risk of APOE4-associated Alzheimer’s Disease.

APOE gene and isoforms


APOE is a gene that codes for the APOE protein, which plays a role in lipid and cholesterol transport in the body.

There are three common isoforms of the APOE gene: APOE2, APOE3, and APOE4. APOE4 carriers have decreased APOE protein expression and impaired lipid and cholesterol transport to neurons in the brain.

Pathological hallmarks of AD


Alzheimer’s Disease is characterised by three primary pathological hallmarks: extracellular amyloid-ß plaques, intracellular neurofibrillary tangles (tau tangles), and reduced brain glucose uptake.

These hallmarks contribute to the degeneration and cognitive decline observed in AD.

DHA’s impact on AD hallmarks


DHA acts on all three pathological hallmarks of Alzheimer’s Disease.

Adequate levels of DHA have been associated with a reduced risk of AD and have shown benefits in reducing amyloid-ß plaques, decreasing tau tangles, and regulating glucose transport in the brain.

Lifestyle factors and AD risk


Lifestyle factors can influence the risk of developing Alzheimer’s Disease in APOE4 carriers.

Following a healthy diet, such as the Mediterranean diet, getting sufficient sleep, engaging in regular physical exercise, avoiding unhealthy habits like smoking and excessive alcohol consumption, and maintaining an active lifestyle can help reduce the risk of AD.

Importance of DHA form


The form of DHA consumed is crucial for APOE4 carriers because it affects how DHA is metabolised and transported into the brain.

The phospholipid form of DHA, such as DHA-lysoPC, found in fish, fish roe, and krill oil, can enter the brain more effectively than the non-phospholipid form of DHA in supplements.


DHA-lysoPC and APOE4 transport


APOE4 carriers have impaired transport of free DHA into the brain, but they can still benefit from DHA-lysoPC, which is not affected by this impairment.

Therefore, consuming sources of DHA in the phospholipid form may be particularly advantageous for APOE4 carriers to ensure sufficient DHA levels in the brain.

Reference: Patrick RP. Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease. FASEB J. 2019 Feb;33(2):1554-1564. doi: 10.1096/fj.201801412R. Epub 2018 Oct 5. PMID: 30289748; PMCID: PMC6338661