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.

If interested in this subject of saturated fat and dietary guidelines, this book is a good reference '''''The Big Fat Surprise: Why Butter, Meat and Cheese Belong in a Healthy Diet''''' by Nina Teicholz or refer to her website [https://www.nutritioncoalition.us/ Nutrition Coalition]

=== Deeper Dive into the science ===
Some recent studies with findings challenging the current dietary guidelines on fat consumption
::* [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32252-3/fulltext Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study] Dehghan, et al, 2017, The Lancet
:::'''Conclusions:''' (N=135,335, 30-70 years old, 667 urban/rural communities, 18 countries)  “High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.”
:::Augmenting this study is this '''video''' where one of the principal investigators, Associate Professor Andrew Mente presents findings from the PURE Study: [https://denversdietdoctor.com/assoc-prof-andrew-mente-dietary-fats-and-cardiovascular-disease-in-pure-a-more-complete-picture/ Dietary Fats and Cardiovascular Disease in PURE: A More Complete Picture]

::* [https://www.ncbi.nlm.nih.gov/pubmed/27697938 Evidence from prospective cohort studies does not support current dietary fat guidelines: a systematic review and meta-analysis] Harcombe, et al, 2016, British Journal of Sports Medicine 
:::'''Conclusions:''' “Epidemiological evidence to date found no significant difference in CHD [Coronary Heart Disease] mortality and total fat or saturated fat intake and thus does not support the present dietary fat guidelines. The evidence per se lacks generalisability for population-wide guidelines.”

::* [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0065649/ Dietary fatty acids in the secondary prevention of coronary heart disease: a systematic review, meta-analysis and meta-regression] Schwingshackl and Hoffman, 2014, BMJ
:::'''Conclusions:''' (looking only at subjects with existing Cardiovascular Disease) “The present systematic review provides no evidence (moderate quality evidence) for the beneficial effects of reduced/modified fat diets in the secondary prevention of coronary heart disease. Recommending higher intakes of polyunsaturated fatty acids in replacement of saturated fatty acids was not associated with risk reduction.”

= Fats - SFA, MUFA and PUFA = 
There are different classifications of fat, or more precisely, fatty acids:
:•Saturated Fatty Acid (SFA)
:•Unsaturated Fatty Acid
:::–Monounsaturated Fatty Acid (MUFAs)
:::–Polyunsaturated Fatty Acid (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.

== Deeper Dive into the Science ==

Studies on '''<big>Fat intake and Alzheimer's Disease</big>''' 
* [https://www.ncbi.nlm.nih.gov/pubmed/16710090 '''Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study'''] Laitinen, et al, 2006, Dement Geriatr Cogn Disord

:::CONCLUSION:  Moderate intake of unsaturated fats at midlife is protective, whereas a moderate intake of saturated fats may increase the risk of dementia and AD, especially among ApoE epsilon4 carriers. Thus, dietary interventions may potentially modify the risk of dementia, particularly among genetically susceptible individuals.

* [https://www.ncbi.nlm.nih.gov/pubmed/12580703 '''Dietary fats and the risk of incident Alzheimer disease'''] Morris, et al, 2003, Arch Neurol 
:::CONCLUSION: High intake of unsaturated, unhydrogenated fats may be protective against Alzheimer disease, whereas intake of saturated or trans-unsaturated (hydrogenated) fats may increase risk.


Studies on '''<big>Saturated fat intake and ApoE4</big>''' 
The different forms of ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, they do so with different efficiencies, and saturated fat appears to play a role in this.  Studies have shown a link between higher amyloid in the brain of patients with ApoE4 and diets high in saturated fat increasing the risk of developing Alzheimer’s.  Some of these studies:

* [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828889/ '''Apolipoprotein E ε4 magnifies lifestyle risks for dementia: a population-based study'''] Kivipelto, et al, 2008, J Cell Mol Med
:::Furthermore, low–moderate intake of polyunsaturated, and moderate–high intake of saturated fats were associated with an increased risk of dementia/AD more pronouncedly among apoE ε4 carriers.

* [https://jamanetwork.com/journals/jamaneurology/fullarticle/1697444?fbclid=IwAR23CHEVsPebiXhey4D6KRr-qoJoO7L9IG5dwSiADEekLgGKm8IS0L4eqFI '''Effect of Apolipoprotein E Genotype and Diet on Apolipoprotein E Lipidation and Amyloid Peptides''' Randomized Clinical Trial] (Angela J. Hanson, MD, et al, Aug 2013) The results of this study suggest that the lipidation states of apolipoproteins and amyloid peptides might play a role in Alzheimer’s pathology as influenced by saturated fats decreasing ApoE’s ability to remove beta-amyloid from the brain and that these AD pathological processes are influenced by APOE genotype, thus explaining the higher incidences in ApoE4s.  
:::Herein we provide preliminary evidence that E4+ adults have higher basal levels of LD [Lipid-depleted] ApoE and that adults with mild cognitive impairment (MCI), particularly E4+ adults, have higher levels of LD Aβ. We also show that a High diet [45% of energy from fat (>25% saturated fat), 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein] increases LD Aβ levels and that a Low diet [25% of energy from fat (<7% saturated fat), 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein] has opposing effects. Furthermore, diet-induced changes in LD Aβ levels inversely correlate with changes in CSF insulin levels. These findings may provide insight into the mechanisms through which ApoE4 and unhealthy diets impart risk for developing AD. 

*[https://www.sciencedirect.com/science/article/pii/S0197458014003558 '''Saturated and trans fats and dementia: a systematic review''' ] Barnard et al, https://doi.org/10.1016/j.neurobiolaging.2014.02.030
:::Conclusion:  Several, although not all, prospective studies indicate relationships between saturated and trans fat intake and risk of cognitive problems.

:::Given the the divergence in findings, the discussion section addressed different factors including ApoE4. '''From discussion section''': APOE status: in the WHICAP and CAIDE studies, the Alzheimer's risk related to saturated fat intake was largely confined to individuals with the APOE ε4 allele (Laitinen et al., 2006; Luchsinger et al., 2002). In CHAP, APOE ε4 status had no significant effect on this relationship (Morris et al., 2003). APOE status was not reported in the Rotterdam Study. If the relationship between saturated fat intake and AD risk is influenced by APOE status, it might be obscured in studies that do not account for genetic variability.

:::Also from the discussion section  '''4.1. Mechanisms'''  Some studies have suggested that the effect of saturated fat intake on Alzheimer's risk may be most evident in (or even limited to) carriers of the APOE ε4 allele. The ApoE protein produced by the APOE gene is a major plasma apolipoprotein and the primary cholesterol carrier in the brain (Puglielli et al., 2003). As a group, APOE ε4 carriers have higher plasma total and LDL concentrations compared with APOE ε3 homozygotes (Bennett et al., 2007). Moreover, APOE status may influence the relationship between dietary intake and plasma lipid concentrations; a greater effect of dietary saturated fat on LDL cholesterol concentrations has been observed among APOE ε4 carriers (Rubin and Berglund, 2002). In a substudy of the European Prospective Investigation of Cancer and Nutrition (EPIC), saturated fat intake correlated significantly with serum LDL cholesterol concentrations only in individuals carrying the ε4 allele (Loktionov et al., 2000).

More on ApoE4 Saturated Fat sensitivity can be found in the ApoE4.info wiki '''[[ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s]]'''

= 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 from fish oil come with a caveat'''. Higher Omega-3 levels appear to be beneficial for all genotypes, however, ApoE4s (especially males) with male family history of stroke, may want to avoid fish oil supplements since it thins the blood and stick to wild-caught seafood for a source of Omega-3s instead.  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 (see the discussion on Cerebral Amyloid Angiopathy (CAA) in '''[[ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s]]'''. 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.) There's also this paper [https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2821809 '''ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults A Randomized Clinical Trial'''](Lynne H. Shinto et al, 1 Aug 2024) published in JAMA Open Network which found, "In this randomized clinical trial of 102 participants, ω-3 treatment failed to significantly reduce WML progression and neuronal integrity breakdown among all participants; however, '''apolipoprotein E ε4 allele (APOE*E4) carriers who received ω-3 had significant reductions in neuronal integrity breakdown over 3 years'''."(bold font added.)

::•  '''A higher omega-3 index is associated with better asbtract reasoning and a lower white matter hyperintensity burden in ApoE4s'''  According to the results of this study [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9754651/ '''Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife:  The Framingham Heart Study'''] (Claudia L. Satizabal, 6 Dec 2022)  "Results: We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers."

::•	'''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.

::• '''Omega-3s can aid muscle health'''.  Maintaining muscle mass is important for cognitive health, for references, see [[Exercise - Types, Lengths, and Benefits]].  This study [https://www.mdpi.com/1660-3397/21/7/399 '''The Effect of Omega-3 Fatty Acids on Sarcopenia: Mechanism of Action and Potential Efficacy'''] (Atiporn Therdyothin et al, 13 Jul 2023) suggests Omega-3s also improves muscle health.   
:::Proposed mechanisms by which n-3 PUFA supplementation improves muscle health include 1. anti-inflammatory properties, 2. augmented expression of mechanistic target of rapamycin complex 1 (mTORC1) pathway, 3. decreased intracellular protein breakdown, 4. improved mitochondrial biogenesis and function, 5. enhanced amino acid transport, and 6. modulation of neuromuscular junction activity. In conclusion, n-3 PUFAs likely improve musculoskeletal health related to sarcopenia, with suggestive effect on muscle mass, strength, physical performance, and muscle protein synthesis.

::• '''Omega-3s support a longer lifespan.'''  ApoE4s seem to have decreased longevity in comparison to non-carriers.  According to the conclusions of this paper [https://www.mayoclinicproceedings.org/article/S0025-6196(23)00603-1/fulltext '''Circulating Docosahexaenoic Acid and Risk of All-Cause and Cause-Specific Mortality'''](Evan L. O’Keefe et al, 20 Mar 2024) higher DHA levels were associated with significant risk reductions in all-cause mortality, as well as reduced risks for deaths due to cardiovascular disease, cancer, and all other causes. The findings strengthen the hypothesis that DHA may support cardiovascular health and lifespan.

::• '''May protect menopausal APOE4s.'''  Finding from this research, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103304/ '''DHA-Enriched Fish Oil Ameliorates Deficits in Cognition Associated with Menopause and the APOE4 Genotype in Rodents'''](Matthew G. Pontifex et al, 19 Apr 2022), "In conclusion, supplementation with a physiologically relevant dose of DHA-enriched fish oil appears to offer protection against the detrimental effects of menopause, particularly in “at-risk” APOE4 female carriers."

::• '''Omega-3 DHA in phospholipid form from dietary sources vs fish oil supplements may be best for ApoE4s'''  That’s what Dr Rhonda Patrick proposes in her paper, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338661/ '''Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease'''](Rhonda Patrick, 5 Oct 2018).  From the abstract of the paper:
::::I propose that APOE4 carriers have impaired brain transport of free DHA but not of DHA-lysoPC, as a consequence of a breakdown in the outer membrane leaflet of the BBB, putting them at increased risk for AD. …I posit that the difference is that fish contain DHA in phospholipid form, whereas fish oil supplements do not. This influences whether DHA is metabolized to nonesterified DHA (free DHA) or a phospholipid form called lysophosphatidylcholine DHA (DHA-lysoPC)….Dietary sources of DHA in phospholipid form may provide a means to increase plasma levels of DHA-lysoPC, thereby decreasing the risk of AD.  I propose that APOE4 carriers have impaired brain transport of free DHA but not of DHA-lysoPC, as a consequence of a breakdown in the outer membrane leaflet of the BBB, putting them at increased risk for AD. Dietary sources of DHA in phospholipid form may provide a means to increase plasma levels of DHA-lysoPC, thereby decreasing the risk of AD.

::•'''More effective when homocysteine is normalized''' Maintaining homocysteine levels of ≤7μmol/L to reduce brain tissue loss with aging is a prudent practice for ApoE4s.  Since trials of supplementation with omega-3 fatty acids in patients with mild cognitive impairment or Alzheimer’s disease (AD) have produced inconsistent effects on cognitive decline, this paper [https://content.iospress.com/articles/journal-of-alzheimers-disease/jad181148 '''Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study'''] (Fredrika Jernerén et al, 07 May 2019) sought to explore if homocysteine levels influenced results of Omega-3 fatty acid supplementation.  They found that cognitive measures after taking Omega-3 supplementation is effected by baseline homocysteine, suggesting that adequate B vitamin status and keeping foods containing the amino acid methionine moderated is required to obtain beneficial effects of Omega-3 supplementation.  There's also this slightly older paper, [https://www.sciencedirect.com/science/article/pii/S1279770723000891?via%3Dihub '''Cross-sectional associations of total plasma homocysteine with cortical β-amyloid independently and as a function of omega 3 polyunsaturated fatty acid status in older adults at risk of dementia'''] (Claudie Hooper et al, Dec 2017) that found similar results, "Exploratory analysis showed that homocysteine was however significantly associated with cortical Aβ in subjects with low baseline omega-3 index (< 4.72 %) after adjustment for Apolipoprotein E ε4 status (B-coefficient 0.041, 95 % CI: 0.017,0.066, p = 0.005, n = 10), but not in subjects with a high baseline omega-3 index (B-coefficient -0.010, 95 % CI: -0.023,0.003, p = 0.132, n = 66)."

::• '''May protect against age-related neurodegeneration'''  Although a mouse study, [https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.690410/full?fbclid=IwAR04uCa-nUzVojBl5VV0WwPAJABHU-_a9z0YKA3DbMV_ajar3mBPNfXWm2A '''LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4'''] (Sarah B. Scheinman et al, 30 Jun 2021) wrote, "In conclusion, our data demonstrate that LPC-DHA/EPA-enriched krill oil [LPC is lysophosphatidylcholine] can increase brain DHA and improve memory-relevant behavior in mice that express APOE4. Therefore, long-term use of LT-krill oil supplements may on some level protect against age-related neurodegeneration.

=== 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)
::• '''Obtain DHA in Phospholipid form - krill oil, fish roe and fish.'''  Krill oil has a high content of long-chain omega-3 fatty acids, antioxidants, and choline, an essential nutrient that aids healthy brain development and function.  Krill oil also typically contains a high percentage of phospholipids (vs triglycerides in fish oil).  Phospholipids improve tissue absorption and can cross the blood-brain barrier, whereas triglycerides cannot cross the blood-brain barrier.  Dr Rhonda Patrick, cell biologist, researcher, educator, and fellow E4, says the phospholipid form of DHA (an omega-3) is especially important for us because ApoE4s aren’t able to get DHA where it needs to go unless it is in phospholipid form. ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338661/ '''Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease'''] Rhonda P. Patrick, Feb 2019).  Another article, [https://www.medicalnewstoday.com/articles/krill-oil-can-it-protect-the-brain-from-age-related-degeneration?fbclid=IwAR1AahG_B5B_QnOXJ9yOJj8fd-Notfudriw1uMD2L9rFlrsN1ES6zHea6JI '''Krill oil: Can it protect the brain from age-related degeneration?'''](Annie Lennon, 30 Nov 2022, Medical News Today) includes a discussion of Krill oil vs Fish oil. 
::• '''Omega-3s if vegan'''  From this Dr Rhonda Patrick article,  [https://www.foundmyfitness.com/topics/omega-3?fbclid=IwAR14V00p9kU2BwNbeszRtZEDGvfH2tecvQwrasGwiw3c87-g_uB1FyAx0E0#apoe-4-and-alzheimer-39-s-disease '''Omega-3 fatty acids'''] "Algal sources of EPA and DHA are suitable for people following a vegan (non-gelatin capsules only) or vegetarian diet or for those who do not eat fish.[21] However, these products generally provide lower concentrations of omega-3s than similarly priced fish oil products."
::•	'''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)
::•	'''Keep a healthy gut''' According to this paper, [https://journals.lww.com/co-clinicalnutrition/fulltext/2024/03000/can_the_gut_microbiome_inform_the_effects_of.6.aspx '''Can the gut microbiome inform the effects of omega-3 fatty acid supplementation trials on cognition?'''] (Kerman, Bilal E.; Self, Wade; Yassine, Hussein N., Mar 2024) "The composition of the gut microbiota can help define the effects of n-3 PUFA supplementation on the brain and lead to more personalized nutritional interventions."  For more information on gut health and microbiota see '''[[Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs)]]'''
::• '''Take fish oil supplement with fat and low fiber meal'''   Omega-3s are fat-soluble, so it's best to consume them with a fat-containing meal to enhance their bioavailability. Consuming immediately before a meal that includes healthy fats avoids floating oil in the stomach and promotes mixing with the meal for better digestion.  Avoid taking omega-3 supplements with high-fiber meal because fiber can make it harder for the body to absorb these nutrients, by binding with the omega-3s or reducing how well the body absorbs them. For the best results, it’s recommended to take these supplements with meals that contain moderate to high levels of fat, but lower levels of fiber.
::•	'''Get an Omega-3 Index test''' done and adjust diet accordingly until a minimum of 10% Red Blood Cell (RBC) count of EPA+DHA is achieved.  Home testing kits are available.

=== A deeper dive into the science on Omega-3s ===

Some references, not a complete list:

•This Dr Rhonda Patrick article [https://www.foundmyfitness.com/topics/omega-3?fbclid=IwAR14V00p9kU2BwNbeszRtZEDGvfH2tecvQwrasGwiw3c87-g_uB1FyAx0E0#apoe-4-and-alzheimer-39-s-disease '''Omega-3 fatty acids''']is a comprehensive overview of Omega-3s and includes a discussion of ApoE4 and Alzheimer's Disease.

•	This paper, [https://link.springer.com/article/10.14283/jpad.2023.77 '''Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia'''] (Hussein Yassine et al, 19 June 2023) addresses APOE4 and brain DHA metabolism. 
::This study investigates the effects of high dose DHA supplementation (2 grams per day) on DHA brain delivery following 6 months of supplementation in cognitively healthy participants with limited omega-3 consumption and CVD risk factors. It also measures the subsequent effects of DHA supplementation on brain structure and function and cognition over a period of 24 months. The study investigates interaction effects of DHA brain delivery and brain structure and function by APOE4 carrier status. We hypothesize that high-dose DHA supplementation will increase DHA and EPA and their ratio to AA in CSF. We also hypothesize that a lower increase in DHA and EPA levels and their ratio to AA will be observed in APOE4 carriers compared to non-carriers: signifying either lower brain DHA transport across the blood-brain barrier (BBB) or greater brain DHA consumption with APOE4. We expect that a lower increase in CSF DHA/AA will correlate with greater measures of inflammation (such as plasma and CSF eicosanoids and other oxylipins), loss of BBB function (indicated by elevated CSF/plasma albumin or platelet-derived growth factor β (PDGF-β)) or amyloidosis (CSF Aβ42, or plasma Aβ 42/40). This in turn can have implications for understanding the effect of DHA supplementation on brain structure and function to guide future prevention strategies using ω-3 supplements.

• [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.

•	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.

•	[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917688/ '''Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes'''] (James V. Pottala, et al., 2014) from journal ''Neurology'' found that a higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured 8 years later.

== 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] 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.  

[[File:Vegetable oil consumption over time.JPG|framed|center|While this was taken from a website addressing diet and Age-related Macular Degeneration (AMD) the data is relevant.  Note the red line showing a marked upward trend in harmful vegetable oil.   Total vegetable oil consumption went from about 2 grams a day/person to about 80 grams a day/person,  and most of that is from harmful vegetable oils. Source: http://www.cureamd.org/introduction-is-age-related-macular-degeneration-amd-preventable-and-treatable-with-diet/]]

These vegetable oils 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. From this paper [https://www.tandfonline.com/doi/abs/10.1080/21551197.2012.752335 '''The Omega-6/Omega-3 Ratio and Dementia or Cognitive Decline: A Systematic Review on Human Studies and Biological Evidence'''] (Martin Loef and Harald Walach, 1 Mar 2013) "Our review of the 14 studies in humans that fulfilled the selection criteria (7 prospective studies, 3 cross-sectional studies, 1 controlled trial, 3 case-control studies) provided evidence, albeit limited, supporting an association between the n-6/n-3 ratio, cognitive decline, and incidence of dementia. This review supports growing evidence of a positive association between the dietary n-6/n-3 ratio and the risk of Alzheimer's disease."

'''Just supplementing with Omega-3 Fish Oil is not enough if maintaining a diet high in Omega-6''' 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 Kresser  “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 [https://draxe.com/canola-oil-gm/ Stop Using Canola Oil Immediately! 6 Canola Oil Dangers]   


''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] 

'''Other strategies to reduce Omega-6s'''
* '''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'''.  

* '''Keep consumption of meat and dairy products to moderate to low levels'''.'''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 to 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.

[[File:Omega 6 to 3 of nuts.JPG|framed|center|Source:  Wikipedia, article  "Ratio of fatty acids in different foods" accessed Apr 14, 2018]]

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

::* [https://www.jci.org/articles/view/142883/pdf '''The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection'''](Hildur Arnardottir, et al, October 26, 2021) This paper addresses a receptor activated by substances formed from omega-3 fatty acids to play a vital role in preventing inflammation in blood vessels and reducing atherosclerosis. The discovery can pave the way for new strategies for treating and preventing cardiovascular disease using omega-3 fatty acids.

::* [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'''] Blasbalg, et al, 2011, The American Journal of Clinical Nutrition
:::'''Conclusion''': The apparent increased consumption of LA [Lineoleic Acid], which was primarily from soybean oil, has likely decreased tissue concentrations of EPA and DHA during the 20th century.