Higher Red Blood Cell EPA and DHA Levels Corresponds with Larger Total Brain and Hippocampal Volumes Plus Preserves Cognitive Function

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Brain Atrophy or Shrinkage

Brain atrophy, or brain shrinkage, is the opposite of neurogenesis. Brain atrophy describes a loss of neurons and the connections between them.

Brain atrophy can be categorized as either general or focal. With general brain atrophy, all of the brain shrinks. With focal brain atrophy, shrinkage of the brain affects a limited area of the brain which often results in decreased functions in the area that area controls. For example, if the cerebrum atrophies, then conscious thought and voluntary processes may be impaired.

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Figure 1.  Atrophic brain and Normal brain

Even if you do not have a chronic disease, you may be losing as much as 0.4% of your brain mass every year.   1  The rate of brain shrinkage increases with age and is a major factor in early cognitive decline and premature death.  Age related cognitive decline occurs in tandem with the physical degradation of brain structure.

By the age of 60, approximately .5 to 1% of brain volume is lost per year. By the time you reach age 75, your brain is on average of 15% smaller than it was when you were in your mid-20’s.

In fact, it has been shown that older adults with significant brain shrinkage are much more likely to have cognitive disorders than similarly aged people with normal brain size and are at an increased risk of vascular death and ischemic stroke.  2 

The good news is that brain atrophy and shrinkage can be slowed or even reversed by utilizing and managing the consumption of dietary marine source omega-3 fatty acids. 

The Importance of Marine Source Omega-3 Fatty Acids in Maintaining Brain Structure and Function

Marine sourced omega-3 fatty acids have been shown to have a positive role in maintaining brain structure and functioning.

The presence of docosahexaenoic acid (DHA) represents approximately 30% to 40% of fatty acids in gray matter of the cortex and is also highly concentrated in the synaptic membranes.  3 

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Figure 2.  The importance of omega-3 fatty acids and brain function  (Source)

In two studies from 2014 and 2016, researchers have shown that higher red blood cell levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA):

  • preserves brain volume and cognitive function

  • corresponds with larger total brain and hippocampal volumes

In a third study, researchers demonstrated that lower levels of docosahexaenoic acid (DHA) are:

  • associated with smaller brain volumes

Higher RBC EPA and DHA preserves brain volume and cognitive function

The aim of this study from 12 April 2016 was to investigate whether the use of fish oil supplements (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) is associated with concomitant reduction in cognitive decline and brain atrophy in older adults.  4

Older adults (229 cognitively normal individuals, 397 patients with mild cognitive impairment, and 193 patients with Alzheimer’s disease) were assessed with neuropsychological tests and brain magnetic resonance imaging every 6 months. Primary outcomes included:

  • global cognitive status and
  • cerebral cortex gray matter and hippocampus and ventricular volumes

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) use during follow-up was associated with significantly lower mean cognitive subscale of the Alzheimer’s Disease Assessment Scale and higher Mini-Mental State Examination scores among those with normal cognition.

In addition, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) use during the study was also associated with less atrophy in one or more brain regions of interest.  5

Higher EPA and DHA corresponds with larger total brain and hippocampal volumes

This objective of the second study from 4 February 2014 was to test whether red blood cell (RBC) levels of marine omega-3 fatty acids measured in the Women’s Health Initiative Memory Study were related to MRI brain volumes measured 8 years later.  6

The researchers assessed 1,111 the red blood cell (RBC) levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of postmenopausal women from the Women’s Health Initiative Memory Study.  MRI brain volumes were tested in all 1,111 participants.

In fully adjusted models, a 1 SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm3 larger brain volume (p = 0.048). DHA was marginally correlated (p = 0.063) with total brain volume while EPA was less so (p = 0.11). There were no correlations between ischemic lesion volumes and EPA, DHA, or EPA + DHA. A 1 SD greater omega-3 index was correlated with greater hippocampal volume (50 mm3, p = 0.036) in fully adjusted models. Comparing the fourth quartile vs the first quartile of the omega-3 index confirmed greater hippocampal volume (159 mm3, p = 0.034).

A higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured 8 years later.

Researchers concluded that:

“While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy. Future studies should examine whether maintaining higher RBC EPA + DHA levels slows the rate of hippocampal or overall brain atrophy.”  7

Lower levels of docosahexaenoic acid (DHA) are associated with smaller brain volumes

In this third study from 28 February 2012, researchers examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.  8

Researchers related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1,575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI.

Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2–4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = −0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs Q2–4) also had lower scores on tests of visual memory (β ± SE = −0.47 ± 0.18; p = 0.008), executive function (β ± SE = −0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = −0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.

Lower RBC DHA levels are associated with smaller brain volumes and a “vascular” pattern of cognitive impairment even in persons free of clinical dementia.  9


Higher RBC EPA and DHA:

  • preserves brain volume and cognitive function
  • corresponds with larger total brain and hippocampal volumes

Lower RBC DHA:

  • associated with smaller brain volumes

Marine Sourced EPA and DHA is Superior

It is widely accepted that the best way to obtain dietary EPA and DHA is to consume marine animals and/or to supplement with EPA/DHA rich fish oil or algae oil. Consuming plant based omega-3 fatty acids will provide a limited amount of EPA and DHA.

Omega-3 fatty acids are polyunsaturated fatty acids and consist of:

  • alpha-linolenic acid (ALA)
  • eicosapentaenoic acid (EPA)
  • docosahexaenoic acid (DHA)

The are two primary sources of omega-3 fatty acids, animal and plant sources.  Marine animals such as fish and krill provide eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  Plant foods, such as flaxseed and chia seed provide alpha-linolenic acid (ALA).  When consuming plant-based omega-3 fatty acids, the body has to convert the ALA into EPA and DHA, which can be limited.

ALA is converted into EPA and DHA in your body through desaturations (addition of a double bond) and elongation (addition of two carbon atoms) enzymes.  However, this process results in a very low ratio of EPA and DHA.

This means that even when consuming large quantities of ALA (e.g., flaxseeds/oil or chia seeds), the body can only convert a relatively small amount into EPA and DHA, and only when there are sufficient enzymes.

Linoleic Acid (LA), (which is also called omega-6 fatty acid) and ALA compete for the same elongase and desaturase enzymes in the synthesis of longer polyunsaturated fatty acids, such as Arachidonic acid (AA) and EPA.

Figure 3. Desaturation and Elongation of Essential Fatty Acids. Humans can synthesize longer omega-6 and omega-3 fatty acids from the essential fatty acids LA and ALA through a series of desaturation (addition of a double bond) and elongation (addition of two carbon atoms) reactions. Delta-6 desaturase (FADS2) is considered the rate-limiting enzyme in this metabolic pathway. Retroconversion of DHA to EPA in peroxisomes occurs at low basal rates and following DHA supplementation.

Figure 3.  Desaturation and Elongation of Essential Fatty Acids  (Source)

In addition to the fact that LA and ALA compete for the same elongase and desaturase enzymes in the synthesis of longer polyunsaturated fatty acids, namely AA and EPA, there are two other factors that influence the ability to generate long-chain polyunsaturated fatty acids (LC-PUFA).   These two factors include:

  • Gender
  • Genetic variability

The capacity to generate DHA from ALA differs based on gender.  The capacity is higher in women than men:

  • Women  10
    • 21% of ALA converted to EPA
    • 9% of ALA converted to DHA
  • Men  11
    • 8% of ALA converted to EPA
    • 0-4% of ALA converted to DHA

Estrogens cause higher DHA concentrations in women than in men, probably by upregulating synthesis of DHA from vegetable precursors.  12

The two key enzymes in fatty acid metabolism include:

  • delta-6 desaturase (FADS2)
  • delta-5 desaturase (FADS1)

The single nucleotide polymorphisms (SNPs) in the FADS gene differ dramatically in their ability to generate Long Chain Polyunsaturated Fatty Acids (LC-PUFA), which include AA, EPA and DHA.  With these FADS polymorphisms there may be up to 30% of the variability in blood levels of omega-3 and omega-6 fatty acids among individuals.

The FADS2 gene converts the omega-3 fatty acid ALA to EPA and downstream to DHA.  FADS2 is responsible for elongating ALA and converting it into eicosapentenoic acid (EPA).

The minor “G” allele in the FADS2 gene is associated with a lower rate of ALA conversion to EPA and a decrease in the conversion of EPA to DHA.  As a result, only a small percentage of ALA can be changed via the enzymes produced by FADS1 and FADS2 genes into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).


To raise RBC EPA and DHA levels it is best to eat fresh wild caught fish and/or supplement with marine sourced EPA and DHA (fish oil) or if you are a vegetarian or vegan, consume algae oil high in EPA and DHA

Resources:

Testing for RBC EPA and DHA levels is administered by a number of laboratories.  Two reputable labs include:

Cleveland Heartlab, Inc. – Know Your Risk Program (Omega Check®)

Salveo Diagnostics, Inc.