A Slippery Subject: Fish Oil and Alzheimer’s

A Slippery Subject: Fish Oil and Alzheimer’sA recent study published in JAMA indicated that eating more fish appears to reduce the probability of developing Alzheimer’s. However, that association was only significant for those individuals with high ApoE4 levels in the blood.

What is ApoE4? It’s protein that’s an integral part of circulating lipoproteins.

What’s the connection with Alzheimer’s? Those individuals who have a certain genetic mutant of this protein (know as ApoE4) are at much higher risk for developing Alzheimer’s. In fact, about 14 times higher. That’s a lot, but why? And what do levels of lipoproteins high in ApoE have to do with Alzheimer’s?

With Fish Oil, It’s Easier to Fight Alzheimer’s

In the past, lipoproteins (like LDL or bad cholesterol) were usually associated only with heart disease. The first insight of the relationship with Alzheimer’s comes with a recent study that indicated those with high levels of ApoE4 in their lipoproteins have difficulty in transferring omega-3 fatty acids into the brain. Without adequate levels of omega-3 fatty acids being supplied to the brain, you will have a limited chance to reduce neuroinflammation that is the underlying cause of Alzheimer’s. This explains why it was only in the subjects that had high levels of ApoE4 had any benefits by consuming more fish in reducing the development of Alzheimer’s.

And here’s another important point that seems to be lost on Alzheimer’s researchers: there is a big difference between the anti-inflammatory actions of omega-3 fatty acids and the pro-resolution activity of the same fatty acids.

The resolution of inflammation remains the Holy Grail of medicine because it is only this resolution response that brings the inflammatory response back to equilibrium. However, the resolution response can only be optimized with adequate levels of EPA and DHA in diet in order to supply the building blocks to make the pro-resolution hormones known as resolvins.

Even more importantly, the key fatty acid for resolution in the brain appears to be EPA, not DHA.

Don’t Forget: You Need EPA in Your Blood

You need EPA in your blood to make pro-resolution hormones. The best marker for your ability to resolve inflammation is the AA/EPA ratio. This was supported in a study that demonstrated that AA/EPA ratio in both Alzheimer’s patients and cognitively impaired patients was significantly elevated compared to age-matched subjects with normal cognitive functioning.

That observation from 16 years ago was extended by recent work demonstrating the resolution response in older individuals is reduced. The only way to increase that resolution response regardless of age is to increase your intake of EPA and DHA

Brain Trauma: It’s Like an Accelerated Form of Alzheimer’s

I view severe brain trauma as an accelerated form of Alzheimer’s. I demonstrated several years ago in animal studies that giving high-dose omega-3 fatty acids would reduce the production of amyloid precursor proteins (APP) in the brain induced by severe head trauma.

Appearance of APP in the brain is the first step toward the development of an Alzheimer’s plaque in the brain. As I demonstrated in that article, the blood marker that was the best correlated with the reduction of APP formation was a reduced AA/EPA ratio.

Applying the same protocol to humans with severe brain trauma has shown when you reduce the AA/EPA ratio to less than two, then seemingly “miraculous” recoveries become commonplace.

Danger: Fish vs. Fish Oil

One of the problems of consuming adequate levels of fish to generate the resolution benefits from omega-3 fatty acids is that all fish contain some levels of a known neurotoxin called poly chlorinated biphenyls (PCBs). PCBs are known neurotoxins. So eating a lot of fish to reduce neuroinflammation may have unintended consequences like increased PCB levels.

This problem can be overcome by supplementing with purified omega-3 supplements, but only if they are suitable for long-term use. This is because omega-3 fatty acids have to be consumed at levels sufficient to induce a sufficient resolution response.

This is why Zone Labs is the only company that provides the levels of PCBs in every lot we sell. There are general industry standards for max PCB levels, and then there are Zone Labs standards on max PCB levels, which are nearly 20 times lower.

You need adequate levels of omega-3 fatty acids to achieve adequate blood levels of omega-3 fatty acids necessary to promote resolution of neuroinflammation in the brain.

Don’t Guess, Test Your Blood

How do you know if you are taking enough? The blood will tell you. In other words, “don’t guess, always test.” Your goal is achieve an AA/EPA ratio between 1.5 and 3. There are several sources for such testing that requires only a drop of blood. I recommend you try the most inexpensive source to test your blood through Zone Diagnostics.

Are higher intakes of omega-3 fatty acids your only dietary approach to reduce the likelihood of Alzheimer’s? Not by a long shot. Recent studies by the same authors of the recent article on fish oil and Alzheimer’s published a study on the ability of the MIND diet to reduce Alzheimer’s.

What is the MIND diet? It is simply the DASH diet with extra polyphenols, especially those coming from blueberries. Furthermore, high levels of purified cocoa polyphenols also have demonstrated the ability to improve cognitive function. The hypothesized mechanism for polyphenols is their reduction of insulin resistance.

Reduce Your Risk and Improve Your Odds

If you want to reduce the likelihood of developing Alzheimer’s, your best choice is to follow an anti-inflammatory diet such as the Zone Diet. Then, supplement that anti-inflammatory diet with refined omega-3 fatty acids and polyphenols.

How do you determine your success? Make sure you are in the Zone. The blood will tell you that with precision. As I described in The Mediterranean Zone, the clinical markers you are looking to achieve are the following:

  1. AA/EPA ratio between 1.5 and 3
  2. TG/HDL ratio less then 1
  3. Glycosylated hemoglobin (HbA1c) of 5.0%

This is not a multiple-choice test. All of these clinical markers have to be in the correct ranges or you are simply not in the Zone. If your blood says you aren’t in the Zone, then maybe you will be lucky when it comes to developing Alzheimer’s. Personally, I would rather be in the Zone than simply hoping to be lucky.


  1. Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O. “Association of seafood consumption, brain mercury level, and APOEε4 status with brain neuropathology in older adults.” JAMA 315:489-497 (2016).
  2. Vandal M, Alata W, Tremblay C, Rioux-Perreault C, Salem N, Calon F, and Plourde M. “Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.” J Neurochem 129:516-526 (2014).
  3. Georgiou T, Neokleous A, Nikolaou D, and Sears B. “Pilot study for treating dry age-related macular degeneration (AMD) with high-dose omega-3 fatty acids.” PharmaNutrition 2:8-11 (2014).
  4. Conquer JA, Tierney MC, Zecevic J, Bettger WJ, and Fisher RH. “Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment.” Lipids 35:1305-1312 (2000).
  5. Wang X, Zhu M, Hjorth E, Cortes-Toro V, Eyjolfsdottir H, Graff C, Nennesmo I, Palmblad J, Eriksdotter M, Sambamurti K, Fitzgerald JM, Serhan CN, Granholm AC, and Schultzberg M. “Resolution of inflammation is altered in Alzheimer’s disease.” Alzheimers Dement 11:40-50.e2 (2015).
  6. Mills JD, Bailes JE, Sedney CL, Hutchins H, and Sears B. “Omega-3 dietary supplementation reduces traumatic axonal injury in a rodent head injury model.” J Neurosurgery 114:77-84 (2011).
  7. Sears B, Bailes J, and Asselin B. “Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PharmaNutrition 1: 86-89 (2013).
  8. Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, and Aggarwal NT. “MIND diet associated with reduced incidence of Alzheimer’s disease.” Alzheimers Dement 11:1007-1014 (2015).
  9. Mastroiacovo D, Kwik-Uribe C, Grassi D, Necozione S, Raffaele A, Pistacchio L, Righetti R, Bocale R, Lechiara MC, Marini C, Ferri C, and Desideri G. “Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects.” Am J Clin Nutr 101:538-548 (2015).
  10. Sears, B. The Mediterranean Zone. Ballantine Books. New York, NY (2014).

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About Dr. Barry Sears

Dr. Barry Sears is a leading authority on the impact of the diet on hormonal response, genetic expression, and inflammation. A former research scientist at the Boston University School of Medicine and the Massachusetts Institute of Technology, Dr. Sears has dedicated his research efforts over the past 45 years to the study of lipids. He has published 40 scientific articles and holds 14 U.S. patents in the areas of intravenous drug delivery systems and hormonal regulation for the treatment of cardiovascular disease. He has also written 14 books, including the New York Times #1 best-seller, The Zone, which have sold more than 6 million copies in the U.S. and have been translated into 22 different languages.


  1. blair

    Hello Dr. Sears, I’m hoping you can help–I’m a little confused about the data. The majority of the studies I’ve run across say the benefit is only seen in the non APOE4 carriers. Also, what would your recommendation be for a homozygous APEO4 individual? You are appreciated!

  2. raulmitin

    However, that association was only significant for those individuals with high ApoE4 levels in the blood. Where did you get this information?

  3. Manya

    Dr. Sears,

    I’ve followed your dietary approach for two years and continue trying to stay in the Zone, and I have great results – I’ve lost 50 lb, I’m full with energy, some of my health problems disappeared (no more pain in my knees, ankles, back, shoulders and neck, improved breathing (despite my COPD). But living in Bulgaria I can’t use your test for AA/EPA ratio. I’ve reached TG/HDL ratio 1.16 and HbA1c of 5.5%. I hope these are pretty good results and hope to reach better in the next months.
    Thank you for you hard research work and sharing it with your books and website with the world. I hope some day and in my country will be possible to take an AA/EPA ratio test to be absolutely sure that as your follower am in the Zone.

    • Dr. Sears

      You continue to do an excellent job. Pushing the HbA1c closer to 5.0% will make a lot of difference. Here is a good approximation for estimating your AA/EPA ratio. 2.5 grams of EPA and DHA per day will bring the AA/EPA ratio to under 5, 5 grams of of EPA and DHA per day will bring it under 2.5, and 7.5 grams of EPA and DHA will bring the AA/EPA to about 1.5.

  4. Jorge Villarroel

    Thank Dr. Sears for your research for all mankind.
    Im from Ecuador and just recieve a seminar abour the Diet Zone, so Im a beginner.

    1) i followed the zone diet. And got good results with glucose, ldl, uric acid and hdl, sgot, sgpt. All of them started in danger zone.
    2) however..the Triglicerids (TG?) are still in 670….althought they started at 800!
    3) ensym GGT hepatic, is still high 20 times.

    I was taking omga 3 not purified, i just realize th i portance of this.



    • Dr. Sears

      Elevated triglycerides is usually the first clinical marker to fall if you are using adequate levels of refined fish oils like OmegaRx. I would recommend at least 5 grams of EPA and DHA per day to see a significant drop in triglyceride levels within 30 days.

  5. Michael L Burt

    I have type 2 diabetes and saw a video a few weeks ago indicating that High Intensity Interval Training (HIIT) done daily or every other day can lower blood sugar levels. Sense then I have been practicing short (2 to 4 min – on a stationary bicycle pedaling as fast as I can for 20 sec and a slow for 20 sec alternating for either 2 or 4 min) HIIT sessions every other day and found positive results – between 20 to 40 points lower before breakfast. The improved results so far have been consistent. Does this make sense? Do you think the improved numbers should last?

    • Dr. Sears

      HIIT is very effective but long term benefits will be dramatically enhanced by following an anti-inflammatory diet such as the Zone Diet. The combination becomes a very powerful approach to managing type 2 diabetes on a lifetime basis.

      • Michael L Burt

        I’m sorry I should have mentioned in my previous post that I do follow the zone diet – it works wonders for me. I also workout in the gym 3 times a week.

        Just to report: it’s 4 weeks so far and the added daily 4 minute HIIT sessions continue work.

        Thank you,


        • Dr. Sears

          Once you set the hormonal foundation by the Zone Diet, exercise becomes much more effective especially if you are following a HIIT routine.

  6. Edward J. Bernhart DDS

    Dr. Sears, There is considerable speculation that all disease is an eschemic event. Could you relate to me an ultimate echemic event on the sub cellular level where the cell mitochondria are interfered with and neutralized by the rise of the AA/EPA ratio? I will refer you to a novel and very interesting piece. Thank you, EJB


    • Dr. Sears

      I do believe that cancer is metabolically driven disease, but not due to the reasons outline in the Mercola article. The three metabolic drivers of cancer are (1) increased insulin, (2) increased inflammation, and (3) increased mTOR activation. While increased glucose will increase insulin, it is only when you develop insulin resistance that both insulin and blood glucose stay continually elevated. Insulin is a powerful growth factor, yet is also necessary for maintenance of normal metabolism. In other words you need a zone. This is why I like to keep glucose low as indicated by maintaining HbA1c of 5.0%. Inflammation is far stronger driver of metastasis than is elevated glucose or insulin. This is why high-dose fish oil is important for increasing the resolution of inflammation. I should point out that increased hypoxia is a driver of inflammation. Thus keeping an AA/EPA ratio of 1.5 is the best way to induce resolution of inflammation. Finally, reducing mTOR activity can achieved by increasing AMP kinase activity. The best is calorie restriction or high-dose polyphenols, and ideally a combination of both. Although a ketogenic diet will reduce insulin, it has also been shown to increase cortisol levels. That cortisol increase results in the depression of the immune system. That’s not a good thing for managing cancer.

  7. John Kraus

    I have smoldering multiple myeloma. The disease began as mugs about eight years ago. I have been on Zone fish oil about eight capsules daily or 15 cc,s liquid oil. I would like to keep the disease from progressing. I also take about 5000 mg of curcumin daily. Should I change anything. Try to stay in the zone with my diet. Thank You, John Kraus

    • Dr. Sears

      I would consider getting an AA/EPA ratio test to see if you are taking adequate levels of omega-3 fatty acids. Ideally you want the AA/EPA ratio to be 1.5 with your EPA levels being at least 4%. This should provide high enough levels of both EPA and DHA to make more resolvins that are a key to managing any chronic disease. Although the levels of curcumin are OK, I would consider adding about 4 MaquiRx capsules per day (1.2 grams) since unlike curcumin polyphenols, the maqui polyphenols are much more water-soluble and thus can enter the blood to activate AMP kinase that suppresses mTOR activity. It is increased mTOR activity that drives tumor growth.

  8. JoAnn Forrester

    I have been along time advocate of the Zone diet and I have encouraged family and employees to read and subscribe to various programs. We get a monthly shipment of Omega 3 and Sea Health Plus for over three years now. I have a question that is important to me as well as one of my employees. s Due to life threatening injury of an employee who now suffers from post concussion syndrome we have become very interested in various forms of treatment for TBI. Will you please share more about how the Zone diet and Omega 3 and any supplements could help our employee. She is an important part of our company and family and finding out whatever we can do to help to important to us. I would greatly appreciate any information you can share.

    • Dr. Sears

      The long-term symptoms of TBI are a result of ongoing neuroinflammation. High-dose omega-3 fatty acids are in the best way to reduce that neuroinflammation since they can easily pass the brain-blood-barrier whereas anti-inflammatory drugs cannot. However you need enough in the blood to drive them into the brain. I have always used the AA/EPA ratio as the best indicator of the amount of omega-3 fatty acids that are need for resolution of existing neuroinflammation. The ideal AA/EPA ratio for that is about 1.5. For the average American this requires about 7.5 to 10 grams of highly refined EPA and DHA on a daily basis.

  9. Hank Simon

    1. My Physician told me that research had showed that Fish oil supplements were not effective; only food sources were effective. He could not provide references, and I don’t consider it prudent to argue with my doctor … So, I don’t discuss my Zone supplements with him. Could you address these issues, because I’m sure other readers run into similar situations.

    2. I’ve read the recent summaries ‘debunking’ the 50 year studies vilifying ALL saturated fats. There’s still caution about animal fats, but recommendations for greatly increasing medium chain triglycerides (MCT), especially coconut oil. Please advise.

    3. I understand about Olive oil, but I’ve been using Macadamia nut oil for years, because it’s similar and stable at high temperatures. Opinions? But, Olive oil decreases N- nitroso amines (DMN), which may increase chances for Alzheimer’s and for prostate cancers – How does Macadamia nut oil affect DMN ?

    4. My son is in college and one of his nutritional professors discussed research about drinking 30 grams of whey isolate protein four times a day, along with a normal diet and exercise. My son is a top computer engineering student and a normally active young man, but in 6 weeks with this one change in diet (and less alcohol), he looks like a lean bodybuilder! This seems like a lot more protein than recommended on the Zone Diet. Is there something similar that you can recommend, additional to the Zone Diet, for a middle aged man?

    • Dr. Sears

      All good questions.

      Relative to Question #1, omega-3 fatty acids are only effective if given in therapeutic doses to increase the resolution response to bring the levels of inflammation to a normal level. This usually requires at least 5 grams of EPA and DHA per day. A placebo dose of fish oil will always generate a placebo result.

      Relative to Question #2
      Palmitic acid is the most inflammatory of the saturated fats. It is very hard to reduce palmitic acid without reducing all saturated fats. However, replacing saturated fats with monounsaturated fats provides the taste of saturated fats without increasing inflammation.

      Relative to Question #3
      While both olive oil and macadamia nut oil both are rich in monounsaturated fats, but it is only the extra virgin olive oil that contains the polyphenols that are necessary to reduce the N-nitroso amines.

      Relative to Question #4
      You need about 30 grams of highly quality protein in a meal to provide enough leucine to activate the gene transcription factor mTOR that is essential in stimulating protein synthesis to make muscle in response to exercise.. Whey protein is a good source of leucine, but egg whites are an even better source. Your son is probably taking more whey protein than needed since any level of leucine greater than 3 grams per meal will no longer stimulate any additional increase in mTOR activity.

    • Dr. Sears

      The low cadmium cocoa extract has received GRAS status so it can be included into food products such as bars and shakes. The first prototypes are being developed, and we expect them to be available for sale in June.

  10. Susan Smuck

    Thanks Dr. Sears. My husband is 79 y.o When we heard U on Dennis Prager, we began OmegaRx, Maqui Rx, zone diet stat. Bill had a trauma that elevated some blood enzymes. MD’s rx’d cardiac catheterization. Bill told ’em he took omega Rx, Maqui Rx & to prove their efficacy he had the cath, thinking he was right, MD’s wrong. He had cardiac cath, carotid scan. Both studies revealed perfectly unplaqued coronary arteries, perfectly unplaqued carotids. MD’s said please keep taking the Omega Rx, Maqui Rx, stay on Zone diet!!! Know this is anecdotal, but we credit Dr. Barry Sears advice, nutritional products, Zone diet for the healthy state of Bill ‘s blood vessels. God bless Dr. Barry Sears for saving lives, enhancing quality of life for all who follow his sage advice, use his great nutritional supplements. N.B.: Bill’s had type II diabetes for 25 years. I, too, use your products. I’ve had insulin dependent diabetes for 52 years.


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