View source for Fats, Omega -3(ω-3) & -6(ω-6), DHA and More

There are three macronutrients: 
# protein  
# carbohydrates 
# '''fats''' 
We all need fat in our diet, in fact there are fatty acids that are essential.   Fats provide energy, balance hormones, and help the body absorb vitamins.  Yet fat almost seems to be a dirty word when it comes to advice on healthy eating.   Searching the internet to gather clarity on dietary fat only seems to make the subject more confusing.  Plus there are still many unknowns that need further research.   This wiki endeavors to offer a simplified tutorial on fats and their known health nuances for ApoE4s.


== A short history regarding contemporary attitudes about fat ==

Fats, specifically saturated fats, are said to contribute to cardiovascular disease. This is largely as a result of research conducted in the 1950s by Dr Ancel Keys called [https://www.sevencountriesstudy.com/about-the-study/ The Seven Countries Study].  At the time, this was an interesting study opening the door to an intriguing hypothesis regarding heart disease.  But this doorway became a foundation upon which we stand on today. 

How this came to be is the result of the US Senate’s Select Committee on Nutrition and Human Needs, more commonly known as the McGovern Committee.  In the 1970s they were tasked with defining what constitutes a balanced diet and producing a national nutrition policy.  Despite expert testimony suggesting that an endorsement of a low-fat diet was based on inadequate evidence, the committee supported the low-fat theory.  These 1977 dietary goals eventually lead to the 1981 US dietary guidelines, and as the US went, so did many other countries and saturated fat has had a bad name ever since.

The data in the Seven Countries Study has subsequently come under criticism for being associational, inadequate, and cherry-picked.  For a deeper dive into this, [http://www.zoeharcombe.com/lcbreck17/ Should Dietary Fat Guidelines have been Introduced?] offers a 35 minute presentation by Dr Zoë Harcombe and includes a .pdf of the slides.  Or you can refer to her paper, [http://bjsm.bmj.com/content/51/10/769 Dietary Fat Guidelines have No Evidence Base:  Where Next for Public Health Nutritional Advice?]  

Today the US dietary guidelines and prevailing medical opinion continues to advocate that saturated fats should be avoided, although there are indications the tide may be changing based on recent studies that  indicate saturated fats can be part of a healthy diet and not contribute to cardiovascular disease.  However, these studies have not separated ApoE ε status to evaluate consequences of genetics to specific fat consumption.  Contemporary medical observations do indicate that the ε4 allele doesn’t process saturated fats as well as the other genotypes.  ApoE is both a genetic allele (ApoE ε) and a protein (ApoE) that binds to lipids (fats) in the body. The ApoE ε produces the ApoE protein in the body.  Dr Bredesen has referred to this ApoE protein as a “fat bucket” [https://www.youtube.com/watch?v=s86wpaF-7XI&list=PLbhWKPDKXIEBBybYcY_jUQGE7S0KLgH5S&index=47 AHS16 Dale Bredesen - ApoE4 Mechanistics]  Given this, it does seem to be reasonable that the different genotypes (ApoE ε2, ε3, 4ε) might react differently to dietary fats.  But again, this is mostly observational data.  

= Fats - SFA, MUFA and PUFA = 
There are different classifications of fat, or more precisely, fatty acids:
:•Saturated (SFA)
:•Unsaturated
:::–Monounsaturated (MUFAs)
:::–Polyunsaturated (PUFAs)
::::·Omega-3
::::::ALA (alpha-linolenic acid) – an essential fatty acid
::::::DHA (docosahexaenoic acid) – important for ApoE ε4s
::::::EPA (eicosapentaenoic acid)
::::::DPA (Docosapentaenoic Acid)
::::·Omega-6
::::::Arachidonic Acid 
::::::Linoleic Acid – an essential fatty acid
:::–Trans fats (rare in nature, mostly a man made fat)


Food that contains fat contains all three fats: Saturated, Monounsaturated, and Polyunsaturated.  So for example, one cannot say that meat is saturated fat and plants are unsaturated fat. One can say meat contains a high percentage of saturated fat, recognizing that it also contains some monounsaturated and polyunsaturated fat.  
As an example, here are three common oils used for cooking with widely different fat compositions.  

[[File:Oil fat composition comparison smaller.JPG|framed|center|Comparing fat composition in three common cooking oils.   Source:   http://chartsbin.com/view/1961]]

It’s the chemical structure that differentiates fats.  Fats with fewer open binding sites are more stable,  they’re less likely to let a free radical oxidize them by stealing an electron. 


'''Saturated fats.'''  Saturation refers to the number of hydrogen atoms and double bonded carbon atoms.  If a fatty acid has only single carbon bonds, then it has the maximum number of hydrogen bonds, so it’s "saturated" with hydrogen atoms.  A free radical can’t get in anywhere to grab an electron and oxidize the fat.  Saturated fats are solid at room temperature, representative of their tight chemical bond composition.

[[File:Saturated-fat-molecule annotated bigger.jpg|framed|center|Saturated fat molecule]]


Common sources of foods high in saturated fats:  Meat and dairy products.  Also butter, tallow, suet, lard - what we largely cooked with before the 1900s.


'''Monounsaturated fats''' have one double bond.  This indicates that there is one place for a free radical to enter. 

[[File:Monounsaturated-fat-molecule annotated bigger.jpg|framed|center|Monounsaturated fat molecule]]

Common sources of foods high in monounsaturated fats:  Nuts, avocados, olive oil.



'''Polyunsaturated fats''' have more than one double bond.  Polyunsaturated fats have multiple binding sites exposed, making them particularly open to oxidation.
[[File:Polyunsaturated-fat-molecule annotated bigger.jpg|framed|center|Polyunsaturated fat molecule]]

Common sources of foods high in polyunsaturated fats:  Oils, particularly corn oil, soybean oil, safflower oil.  Also walnuts, sunflower seeds, flax seeds or oil, fish.

Because they are susceptible to oxidation, foods high in polyunsaturated fats need to be handled properly to make sure they don’t spoil.  Sources of polyunsaturated fats should come from natural sources and be consumed in healthy Omega 6 to Omega 3 ratios. 


'''Trans fats.'''    These are a form of fat that are found in very small amounts in nature and were developed by the food industry through an industrial process called '''hydrogenation'''   to stabilize polyunsaturated fats.  They are "trans" because the hydrogen atoms that are on either side of the double bond oppose each other.  Beginning in the 1950s, trans fats were introduced in packaged foods, shortening, and margarine.  They offered a hardened source of fat with stability so foodstuffs such as cookies could be stocked in grocery stores for a period of time and not be greasy, mushy, or rancid when it came time to eat them.  

Artificial trans fats is one fat that everyone seems to agree that can be classified as genuinely bad. In 2015, the US Food and Drug Administration (FDA) required elimination of trans fats from all food prepared in the United States.  Many other countries also have legal limits to trans fat content. 

When faced with having to replace trans fats, the food industry, recognizing that saturated fats are still perceived as “bad,” have produced genetically modified, chemically manipulated, industrially processed alternative solutions.  The health effects of these are as yet unknown, but given that humans have no history of ingesting such substances, the odds are not favorable that they are healthy.

= Omega -3s and Omega -6s =
The polyunsaturated fats component of fat can be further differentiated to their Omega-3 and Omega-6 content.  Omega−3 fatty acids are also called '''ω−3''' fatty acids or '''n−3''' fatty acids.  Omega-6 fatty acids are also referred to as '''ω-6''' fatty acids or '''n-6''' fatty acids.

Both omega-3 and omega-6s are important, each contain an '''essential fatty acid''':
* '''Alpha-linolenic acid''' (ALA or α-linolenic acid) which is an Omega-3 
* '''Linoleic Acid''' (LA) which is an Omega-6 
They’re “essential” because the body can’t synthesize them, they must be obtained from food.  But essential doesn’t equate to rare, at least not in the case of Omega-6s, specifically linoleic acid.  Omega-6s are very common in most diets, arguably too common.  The body can only use a certain amount of the Omega-3 and Omega-6 in combination and too much Omega-6 consumption will crowd out beneficial Omega-3 intake.

== Omega-3 fatty acids ==
Research has shown that Omega-3s, and especially DHA, are critical contributors to cell structure and function in the nervous system, and deficits in DHA are associated with cognitive decline during aging and in neurodegenerative disease. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666388/ Docosahexaenoic Acid and the Aging Brain] Walter J. Lukiw, Nicolas G. Bazan, 2008, Pomponi M, et al., 2008))

A study of older adults at risk of late-onset Alzheimer's disease found that those who consumed more omega-3 fatty acids did better than their peers on tests of cognitive flexibility - the ability to efficiently switch between tasks - and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439554/ Anterior cingulate cortex mediates the relationship between O3PUFAs and executive functions in APOE e4 carriers] Zamroziewicz, MK, et al., 2015)

While a review of observational and clinical trials that assessed supplementation with Omega-3 fatty acids such as docosahexaenoic acid (DHA) showed that it was not beneficial in symptomatic AD, several did show benefit in the pre-dementia stage of AD, suggesting supplementation may slow early memory decline in E4 carriers. ([https://jamanetwork.com/journals/jamaneurology/article-abstract/2597293 Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers] Yassine HN, et al., 2017)

We also know that in general population studies, Omega-3s have a positive effect in coronary heart disease (CHD) outcomes. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698844/ Plasma Phospholipid Long-Chain Omega-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: the Cardiovascular Health Study]  Dariush Mozaffarian, et al., 2013) ApoE4 carriers are at a higher risk of developing CHD.

=== Why Omega-3s are important for ApoE4s ===

::•	'''Omega-3s come with a caveat'''. Higher Omega-3 levels appear to be beneficial for all genotypes, however, '''Dr. Bredesen generally warns males, with a 4/4 status and family history of stroke, to be cautious with fish oil supplementation.''' If you are a 4/4 male with a personal or male family history of stroke, talk to your doctor about using supplements (like fish oil) that thin the blood. If you have a male relative who suffered a stroke, be suspicious that it may have been Cerebral Amyloid Angiopathy (CAA.) There's a link between ApoE4 and CAA primarily in males. This is a very rare risk, but important to be aware of if you are taking ANY medication or supplement that thins the blood. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947445/ Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease] Mitsuru Shinohara, M, et al., 2016)

::•	'''Evidence is mounting that E4 carriers actually need more Omega-3s than other APOE genotypes''' to reach similar Omega-3 blood levels, which are positively correlated with cognition. This paper ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210928/ Fatty Acid Metabolism in Carriers of Apolipoprotein E Epsilon 4 Allele: Is It Contributing to Higher Risk of Cognitive Decline and Coronary Heart Disease?] Chouinard-Watkins R, Plourde M, 2014) demonstrates that E4 carriers preferentially metabolize omega-3s suggesting E4s may actually need higher levels. Their novel hypothesis suggests that perturbed fatty acid metabolism, as opposed to elevated LDL-C, leads to both cognitive decline and coronary heart disease. The authors establish that E4 carriers preferentially metabolize DHA whereas the other APOE genotypes conserve it. (If you read this article, bear in mind that β-oxidation is NOT the same as lipid peroxidation, which is bad for you. β-oxidation (beta-oxidation) is the catabolic process in which fatty acids are used by the body as a source of energy. Lipid peroxidation refers to the oxidative degradation of lipids.)

::•	'''Omega-3s can increase blood flow in the brain'''. Research compared brain images to the corresponding Omega-3 Index of participants and found a statistically significant correlation between higher blood flow and higher Omega-3 Index. In addition, they evaluated the neuropsychological functions of the subjects and found that omega-3 levels also correlated with various psychological feelings using a standardized test battery (WebNeuro). ([https://www.ncbi.nlm.nih.gov/pubmed/28527220|Quantitative Erythrocyte Omega-3 EPA Plus DHA Levels are Related to Higher Regional Cerebral Blood Flow on Brain SPECT.] Amen DG, et al., 2017) This might be of particular importance to E4s given that a reduction in blood flow is the first visible difference in E4 carrier's brains via imaging.

=== Strategies for increasing Omega-3s ===
Omega 3 fats are relatively rare in our food system which means we need to specifically focus on ways to incorporate them into our diet.
::•	'''Eat more fish''', such as salmon, sardines, mackerel and herring, but to be safe, reduce your consumption of fish that might have higher mercury loads, such as tuna or swordfish. Individuals who were E4 positive and consumed at least 1 seafood meal per week or had higher intakes of long-chain Omega-3s had less Alzheimer disease neuropathology compared with those who consumed lower amounts. ([https://jamanetwork.com/journals/jama/fullarticle/2484683 Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults] Morris MC, et al., 2016) With regards to mercury, they also found although seafood consumption was correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology. However, they do note that their "findings cannot be generalized to populations with higher seafood consumption or with high mercury exposure."
::•	'''Take fish oil supplements'''. Eating fish alone might not be enough for E4 carriers, and supplementation might be necessary to raise Omega-3 index levels in the blood. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891213/ APOE ε4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline] van de Rest O, et al., 2016) The two Omega-3s that are most brain-healthy are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The MAPT study has found that 800 mg of DHA and 200 mg of EPA, as well as the multidomain intervention (exercise, nutrition, socialization) have the most benefit. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652787/ MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER’S DISEASE: DESIGN AND BASELINE DATA] Vellas B, et al., 2014)
::•	'''Watch your levels of B vitamins'''. Using data from the VITACOG study, these researchers showed when omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. ( [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927899/ Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment] Oulhaj A, et al., 2016)
•	'''Get an Omega-3 Index test''' done. Both Dr. Bredesen and Dr. Gundry suggest a minimum of 10% RBC EPA+DHA.

=== A deeper dive into the science on Omega-3s ===
::•	This study ([https://www.frontiersin.org/articles/10.3389/fnagi.2015.00087/full Anterior cingulate cortex mediates the relationship between O3PUFAs and executive functions in APOE e4 carriers] Marta K. Zamroziewicz1, et al., 2015) is groundbreaking in that it examined omega-3 levels in an exclusively ε4+ data set. Rather than comparing the ε4+ population to the general population (which typically results in ε4 carriers demonstrating no benefit) researchers compared HIGH omega-3 levels (mean: 216.00 nmol/mL) vs. LOW omega-3 levels (mean: 102.30 nmol/mL) among ε4 carriers using both cognitive testing and brain imaging. These older adults at risk of late-onset Alzheimer's disease, who consumed more omega-3 fatty acids, did better than their peers on tests of cognitive flexibility, the ability to efficiently switch between tasks, and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility.
::•	A recent paper ([https://www.ncbi.nlm.nih.gov/pubmed/27005961/ Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention] Matualatupauw JC, et al., 2016) reveals that the increased expression of interferon (IFN) signaling and cholesterol biosynthesis pathways might explain part of the association between APOE-ε4 and cardiovascular disease. Fish-oil supplementation may particularly benefit ε4+ individuals by decreasing expression of IFN signaling related genes.

== Omega-6 fatty acids ==

Omega-6s are important for general health, but are inflammatory with most diets because they are '''overconsumed'''.
   
Quoting from  this article,  [https://chriskresser.com/how-too-much-omega-6-and-not-enough-omega-3-is-making-us-sick/ How too much omega-6 and not enough omega-3 is making us sick]by Chris Kresser:

::"The short answer is that elevated n-6 intakes are associated with an '''increase in all inflammatory diseases''' – which is to say virtually all diseases. The list includes (but isn’t limited to):
:::•	cardiovascular disease
:::•	type 2 diabetes
:::•	obesity
:::•	metabolic syndrome
:::•	irritable bowel syndrome & inflammatory bowel disease
:::•	macular degeneration
:::•	rheumatoid arthritis
:::•	asthma
:::•	cancer
:::•	psychiatric disorders
:::•	autoimmune diseases"

=== Why reducing Omega-6s is important for ApoE4s ===
Reducing Omega-6 consumption is important because the ApoE ε4 allele is already associated with a heightened inflammatory response in comparison to those with the ε2 or ε3 allele.  

In addition to the above incomplete list of inflammatory diseases, one can also add Alzheimer’s disease.  In the paper [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586104/ Metabolic profiling distinguishes three subtypes of Alzheimer's disease]“Metabolic profiling distinguishes three subtypes of Alzheimer's disease”  Dr Dale Bredesen writes, “It has been well documented via numerous methods and observations that inflammation plays an important role in AD [Alzheimer’s Disease] pathogenesis”  

While inflammation can come from numerous sources, not just Omega-6s, all sources of inflammation should be kept to a minimum, since minimizing inflammation minimizes threats that allow amyloid to accumulate.  

This overconsumption of Omega-6 in most diets is largely due to the development and increased usage of vegetable oils: corn oil, soybean oil, safflower oil, cottonseed oil, sunflower oil.  These didn’t even exist, much less consumed, until rather recently.  They were originally developed during the industrial revolution as lubricants for machinery.  They became especially popular after 1961 when the American Heart Association recommended eating polyunsaturated oils to fight heart disease. Yet since 1961, '''heart disease remains the number one cause of death in the United States and we’ve additionally experienced increased rates of obesity, Type 2 diabetes, cancer, and other health concerns''' source: https://www.cdc.gov/nchs/products/databriefs/db254.htm.  But these oils are cheap to produce, so they’re highly prevalent in processed food, fast food, and even fine restaurants.   In his book, The End of Alzheimer’s Dr Bredesen writes, “Therefore cheeseburgers and fries are on the dementogen list; they should be on our plates rarely if at all.”

=== Omega 6 to Omega 3 ratio ===

Improving the omega-6 to omega-3 ratio is widely regarded as important to reduce inflammation, optimize brain function, and enhance mental health. Just supplementing with Omega-3 Fish Oil while maintaining a diet high in Omega-6 is inadequate since the two compete for the same conversion enzymes.  From this article [https://chriskresser.com/how-much-omega-3-is-enough-that-depends-on-omega-6/ How much omega-3 is enough? That depends on omega-6] by Chris  “The important thing to remember is that any recommendation for n-3 intake that does not take the background n-6 intake into account is completely inadequate.”	

=== Strategies to reduce Omega-6 ===
*First and foremost, '''eliminate industrially processed oils that are a significant source of Omega-6s''':  Corn oil, Cottonseed Oil, Soybean Oil, Safflower Oil, Peanut Oil. 

[[File:Omega 6 to 3 ratio.JPG|framed|center|Omega-6 to Omega-3 ratios in cooking oils.  source https://theconsciouslife.com/omega-3-6-9-ratio-cooking-oils.htm]]

::A note about '''Canola Oil'''. Despite a low 2:1 Omega-6 to Omega 3 ratio it has often been categorized as one of the “bad” inflammatory oils.  This is because:
:::* 90% of the product is genetically modified 
:::* Canola is a refined oil that’s often partially hydrogenated to increase its stability, which increases negative health effects
::For more information, read “Stop Using Canola Oil Immediately! 6 Canola Oil Dangers”  https://draxe.com/canola-oil-gm/  

Hope to have a link to All about Oils as a future wiki article

Simply eliminating vegetable oils won’t adequately limit Omega-6s. From Chris Kresser, ”So chances are, if you’re eating foods that come out of a package or box on a regular basis, and you eat out at restaurants a few times a week, you are most likely significantly exceeding the recommended intake of n-6”   [https://chriskresser.com/how-much-omega-3-is-enough-that-depends-on-omega-6/ How much omega-3 is enough? That depends on omega-6] 

* '''Eliminate processed and packaged foods''', nearly all contain oils high in Omega-6s.   

* Eat fresh food at home, most '''restaurant foods are cooked with PUFA oils because they’re so cheap'''.  

* '''Eat grass-fed/grass-finished beef and dairy products, pastured chicken, and wild-caught fish'''.  Industrial farm raised poultry (including “free-range” poultry), livestock, and farm-raised fish are fed corn and other feed products that are full of omega-6s.

* Keep consumption of nuts, avocados, and eggs to moderate levels. You can still eat them, but they contain Omega-6s so be mindful when consuming them.  Nuts and seeds with high Omega-6 linoleic acid content include sunflower seeds at 10 grams per 1-ounce serving; pine nuts, 9 grams; pecans, 6 grams; and Brazil nuts, 6 grams. Avocados do present a generous serving of linoleic acid, but put things into perspective, the overwhelmingly predominant fat in an avocado is monounsaturated, followed by a small amount of saturated, and an even smaller amount of polyunsaturated.  So while the Omega-6 to Omega-3 ratio is high in an avocado, the total amount is small compared to the rest of the fat intake.  Similarly with eggs, of the 5 grams of fat in an egg, only .7 grams is polyunsaturated, the fat that contains the Omega-3s and Omega-6s.

=== A deeper dive into the science ===

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076650/ Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century]