Genetic incompatibility

Peter has lipoprotein(a), or Lp(a), a genetic pattern shared by 11% of Americans.

It means that Peter inherited a gene that codes for a protein, called apoprotein(a), that attaches to LDL particles, forming the combined particle Lp(a). It also means that his overall pattern responds well to a high-fat, high-protein, low-carbohydrate diet: The small LDL particles that accompany Lp(a) over 90% of the time are reduced, Lp(a) itself is modestly reduced, other abnormalities like high triglycerides (that facilitate Lp(a)'s adverse effects) are corrected. Small LDL particles are, by the way, part of the genetic "package" of Lp(a) in most carriers.

Peter also has another gene for Apo E4, another genetically-determined pattern shared by 19% of Americans. (Another 2% of Americans have two "doses" of Apo E4, i.e., they are homozygotes for E4.) This means that the Apo E protein, normally responsible for liver uptake and disposal of lipoproteins (especially VLDL), is defective. In people with Apo E4, the higher the fat intake, the more LDL particles accumulate. (The explanation for this effect is not entirely clear, but it may represent excessive defective Apo E-enriched VLDL that competes with LDL for liver uptake.) People with Apo E4 therefore drop LDL (and LDL particle number and apoprotein B) with reductions in fat intake.

This is a genetic rock-and-a-hard-place, or what I call a genetic incompatibility. If Peter increases fat and reduces carbohydrates to reduce Lp(a)/small LDL, then LDL measures like LDL particle number, apoprotein B, and LDL cholesterol will increase. Paradoxically, sometimes small LDL particles will even increase in some genetically predisposed people.

If Peter decreases fat and increases carbohydrates, LDL particle number, apoprotein B, and LDL cholesterol will decrease, but the proportion of small LDL will increase and Lp(a) may increase.

Thankfully, such "genetic incompatibilities" are uncommon. In my large practice, for instance, I have about 5 such people.

The message: If you witness paradoxic responses that don't make sense or follow the usual pattern, e.g., reductions in LDL particle number, apoprotein B, and small LDL with reductions in their dietary triggers (i.e., carbohydrates, especially wheat), then consider a competing genetic trait such as Apo E4.

Comments (29) -

  • Anonymous

    1/10/2011 5:57:47 PM |

    How do you test for it?


  • Anonymous

    1/10/2011 7:35:25 PM |

    I am APOE 3/4.

    1. When you say fat is not good, do you mean all fats, or does the research indicate that MUFA's are helpful? Or PUFA's

    2. Does Niacin affect the negative impact of the APOE 4?

    3. Is it wise with APOE 4 to eat low fat, high carb? And take the niacin, and increase exercise? Or better to stay low carb higher fat and use the niacin?

    Thank you.

  • Anonymous

    1/10/2011 8:35:06 PM |

    General question. For the past year I've been trying to correct my lipid levels. One thing i've done for lunch every day is to make a shake with an apple, banana and orange, plus add a scoop of protein powder from Sam's Club. My triglycerides have skyrocketed even with taking 2 grams fish oil, healthy diet, etc. Should I not each so much fruit every day? Thanks.

  • David

    1/10/2011 9:30:59 PM |


    That's a lot of fruit. Add it up, and assuming that you're eating medium/average sizes of those three fruits, you're drinking down almost 50 grams of sugar at every lunch (not including the starch in the banana, which also breaks down into glucose). The fructose alone adds up to about 24 grams, which is excessive, in my view, and I don't think there's any mystery as to why your triglycerides have skyrocketed. Back off on the fruit. Eat it only occasionally, and/or pick low-fructose varieties like berries.


  • David

    1/10/2011 9:38:32 PM |

    P.S. As a point of reference, a can of Coca-Cola has 23 grams of fructose.

  • Travis Culp

    1/10/2011 10:40:45 PM |

    If those were the only carbs that he's eating for the entire day, it's not that bad, although I would split it up so that he's eating a piece of fruit with each meal. There's no way someone would go from the SAD to paleo with 3 pieces of fruit and have triglycerides shoot up as a result. It would be a dramatic decrease in average blood glucose and carb intake.

  • Dr. William Davis

    1/10/2011 11:23:05 PM |


    Apoprotein E needs to be specified, usually (though not necessarily) with lipoprotein analysis.

    Anonymous with apo E questions--

    We will be covering this issue in more detail on the Track Your Plaque website near-future (

  • Patricia

    1/11/2011 3:12:40 AM |

    @Travis Culp

    Concerning Anonymous you say, "If those were the only carbs that he's eating for the entire day, it's not that bad."

    Apparently for Anonymous it *is* that bad or his trigs would not have "skyrocketed."  Clearly what he means by "healthy diet" is suspect if he believed a fructose bomb for lunch was a good idea whilst "trying to correct my lipid levels."  So, perhaps he is eating oatmeal and whole wheat bread as part of the "healthy diet" as well, thus contributing even more to said skyrocketing triglycerides.  

    However, given what he actually wrote, IMHO David's comments are spot on.

    Fruit is often and easily given a pass as "healthy" when it is definitely not, particularly vis-a-vis triglycerides.

  • Anonymous

    1/11/2011 3:56:06 PM |

    This last post by Dr. Davis leads to a question about the genetic profile of our blog community?

    And I would love to be wrong about my logic.

    Here we go.

    Fats are apparently not good for APOE 4's which Dr Davis offers is about 19 per cent of general population. Fats make an APOE 4 worse.

    But isn't the reader of this blog more likely to be an APOE 4 than 1 in five, since they are far more likely to have lipid disorders and heart plaque?

    Is it not more likely our blog population has a higer percentage of APOE 4's or 2's than the general population?  So, the advice should tilt toward those genetics not the cardio protected 3/3 who should eat more fats?

    Is this blog's "eat more fats, more nuts"  advice  targeted at the least likely patients to be here--meaning the APOE 3/3 who really dont have as much plaque? The ones who lipids genetics are normal and cardio protective anyway.

    So should not the advice be tilted the other way around, and not toward the rarer reader and blogger who is normal 3/3 who should eat more fats? But toward the rarer (in general population) but more likely reader in a lipid disordered population who should not eat more fats?

    Would it be more helpful to presume that the reader is a APOE 4or AOPE 2?

    And shouldn't every one here get tested because if we are APOE 4 then we could be making ourselves worse by eating more fats? Our attempts at self protection could be hurting us badly?

    Is this a good question? Or two?

    Does this make sense?

  • Onschedule

    1/11/2011 5:10:52 PM |

    @Anonymous regarding APOE 4 and this blog population:

    Dr. Davis writes: "Thankfully, such "genetic incompatibilities" are uncommon. In my large practice, for instance, I have about 5 such people."

    I would expect the population of Dr. Davis blog readers who have this genetic incompatibility to be less, not more, than this ratio. Certainly Dr. Davis's patients are "more likely to have lipid disorders and heart plaque" than the more random pool of readers. Dr. Davis's patients are his patients because they have heart-related issues. The population of blog readers, on the other hand, likely includes people interested in avoiding future heart problems, people with a general interest in health, etc. - all of which would tend to lower the ratio of people with these genetic incompatibilities who read this blog...

  • Anonymous

    1/11/2011 6:05:26 PM |

    Dear Onschedule:

    But if 19 per cent have APOE 4 and it causes plaque issues, why would Dr Davis have only  5 patients in many years in such a huge patient population?  

    Why wouldn't he have at least 19 per cent? 1 in 5?

    Why would it be rare in a heart doctor's office...... and 19 per cent, which is not rare at all, in the general population?

    Am I misunderstanding this?

    Does Dr. Davis test every patient for APOE ?  

    If APOE 4 causes lipids issues and plaque, I tend to think there would be lots of heart patients with APOE 4 genes, not less in his pool.  But either way, at least somewhere near 19 per cent, right?

    Unless I misunderstand the math?

  • Anonymous

    1/11/2011 6:13:49 PM |


    I amend my own comment about how common the "APOE 4 dont eat fats" patients ought to be in this blog population. It is even less rare than we thought !

    I was thinking that the APOE 4 was at 19 per cent....but Dr. Davis actually states 21 per cent.

    So, my argument has more weight, not less, with the corrected percentage. APOE 4 is not rare if 21 per cent have it.

    Now I am confused by this.

    Any help?

    Why wouldnt this reader blog have the same 21 per cent as the general population, and actually more if we figure that lipid disorders ( very high in APOE 4's) drive more to this site than general.

    " Peter also has another gene for Apo E4, another genetically-determined pattern shared by 19% of Americans. (Another 2% of Americans have two "doses" of Apo E4, i.e., they are homozygotes for E4.)"

  • David

    1/11/2011 6:57:16 PM |

    Dr. Davis wasn't saying that he only has 5 patients who are ApoE4. He was saying that he only has 5 patients who have the specific combination of ApoE4 with this particular kind of Lp(a) pattern.

  • Gene K

    1/12/2011 4:50:46 AM |

    I would like to hear what other people with ApoE 4 have to eat. I am now both low carb and low fat. Still consuming a handful of almonds a day, hummus, and natto - these are not low-fat foods, so my next NMR won't be pretty. Also, should fish oil be counted towards daily fat intake?

  • Anonymous

    1/12/2011 6:49:30 PM |

    Gene asks a great question.

    I too would love to know what ApoE 4's should eat. Pufa, mufa, no fats?

    No carbs?

    Does post exercise mitigate the harm after eating offending foods?


  • Gene K

    1/13/2011 5:04:58 AM |

    My understanding is that PUFA or MUFA makes no difference in this case as long as it is fat (I am talking about those with ApoE 4 here). I would rather see somebody more qualified to comment on this, though.

    As to mitigating the effect of offending foods after exercise, you'll have to prick your finger to find out. At least it is what I have gathered from posts and discussions on this blog.

    In my pre-TYP life, I absorbed all existing advice on diet and exercise for people with risk factors for heart disease. It is commonly believed that there is a 30-40 min-long carbohydrate window after an intensive exercise session, during which you can and should consume carbohydrates. I am not qualified to argue this point, but to know your specific response, you should check your BG.

    For one, I checked my BG to see whether I can eat a spaghetti squash dinner. One night (I), I did it after gym, and next night (II) without gym, but after a 25-min walk from the train station. The meal was the same both nights. Results:

    (I) Before dinner: 84, 1hr PP: 114
    (II) 88 and 129 respectively.

    My conclusion: Although exercise helps, I should avoid this food.

  • Anonymous

    1/13/2011 2:27:53 PM |

    Wow! anonymous of Jan 11, 2011.  I totally get you! I was thinking the same.  I have had high cholesterol since my eary 20's (now in my 40's)at times >350 with my ldl always high triglycerides never too bad. That puzzled my doctors.  All my doctors have said that I need to take statins or I will die basically. Thought I ate well.  But now I know I could have been eating wrong all these yrs!? Tried a McDougall 2 months ago, but thought it was way too much carbs. No nuts, oils or fish. Felt ok then, crappy as time went on.. Put fish/nuts back in my diet and Surprise, I felt better. But now, after reading @ that APOE stuff, I wonder should I go back to strick vegetarian or not?? I guess I have to get some test first to determine what my break down is, right? I have always wondered since my 20's if this is going to b the year of the big one?  I have a 2 yr old and want to b around for a long time.  My grandfather and Great grandfather live into 90's. Grandma, @78-80. But on my other side, My mom 1st husband(my biological dad) had quadrupal bybass at 42. What test should i get it seems you could be screwed either way you eat, depending on your genetics. thanks

  • Anonymous

    1/13/2011 6:09:09 PM |

    Dear Anon Said:

    With high levels so early, a good idea to ask MD about niacin, statins dont work on ApoE 4.s very well. I dont take them.

    I do exercise after meals, and use pysillium, 1k niaspan, and increase vegetable sources of Omega 3, since some research says that fish oil is not as useful with ApoE 4's either, but I still take fish 2k, and D3 2k daily. Ground flax seed is good source of veg omega3.

    My brother is not just 4/3 but 4/4.

    Would love to see others comment, since we are 21per cent of population.

    Good luck,


  • Anonymous

    1/13/2011 9:14:07 PM |

    Thanks. In my 20s...My Dr said he had never seen someone so young with my #'s.  Said he would not give Statins because they didnt know the effects on young persons.  
      In 30's...Have been on Lipitor in the past. My Drs said Niacin wouldnt lower it enough.  Lipitor did not do much. It < my ldl at first then it started to lower my hdl too. Remember my triglycerides were never high normal or lower even.  I felt weird/achy on it with brain fog or general stupor feeling. I stopped in my 30's.  Felt better. Found tons of info against statins on internet.
      Also told them a long time ago, my great aunt, my mother and my uncle(moms bro)had a < thyroid.  But as long as my numbers come out ok, thats as far as they go here.  I think I have always been "tweeked" a bit low. Have cold hands/feet, dry hair/skin, hard to very lose weight,tired ect...

    In my 40's...Had my daughter @2yrs ago and Drs wanted me to try Crestor after delivery. I Said No. I know there is a better way. So, I have been trying to do a cross between Asian/Medittarean/Jen's common sense. Here it is...

      I eat fruit/veggies with almost fish exclusively. Occasionally some turkey/chicken real lean.
      Stopped all coffee, drink tea black/green brewed only.
      Stopped all the phoney crap.No artificial sweetners. No hydrogenated oils ect..
      Stopped eating quick oats yrs ago, now trying coarse grind or the steel cut. I mix it with barley adn rye flakes. Use lots of flaxseed in anything I can.
      For a snack I eat a handful of nuts w/o salt mixed with fruit like raisens/cranberries no sugar or the least I can find.
      In the process of stopping wheat products. Almost impossible to find though. Switched to rice/potatoes but exclusively but now I am confused, Dr. Davis says that might b taboo too? Thought rice is a staple in Japan? Hmm..
      Take 1 fishoil High omega3 Sams club daily. And 2-3 times a week starting this winter, a couple 1-3tsp of cod liver oil every other day.
       Bought a bottle of Sloniacin to try if all this doesnt work. I just have to find a doc that will do the right test for lipids. That is the APOE Correct?? Please tell me if I am wrong.  They don't do particle size, always just the basic cholesterol test.  
      Jen in Minnesota

  • sailormom

    1/14/2011 1:53:18 AM |

    very interesting!  My endo thinks I have some genetic cause for high ldl  (ldl particle # > 2000, but HDL  is 90 and trig around 40).  On low carb high fat diet and my ldl just goes up and dr wants me on a statin.  so far I have resisted as I want to try diet/exercise (my weight is at the high range of normal).  I have no wheat, potatoes, rice, sugar etc -- basically fish, fowl, vegetables and dairy (minimal fruit) and nothing proocessed but have not seen any change in lipid profile.  lp(a) is normal so does this sound like  an APOE variant?  What is the best diet?

  • Onschedule

    1/14/2011 1:56:09 AM |

    @Jen in Minnesota

    Have you had a recent heart scan? If not, getting one would give you a baseline with which to compare the effects of future dietary strategies. It will also give you peace of mind when you find that your calcium score (if any) is holding steady or decreasing. Tracking lipids without the scan, IMHO, is less satisfying and less useful.

  • Dr. William Davis

    1/14/2011 3:08:33 AM |

    I hear the several frustrated comments here.

    The key is to:

    1) be armed with information when talking with your healthcare provider. Just asking about apo E raises the bar considerably.

    2) Start to think about individualized health, i.e., diet fine-tuned to your genetic susceptibilities. There is not a true one-size-fits-all diet approach. Some tweaking is required for various genetic patterns, largely determined by apo E genetic type.

  • Anonymous

    1/14/2011 5:24:19 PM |

    Thanks all, and Dr. Davis...
       It's convincing the Docs that you should get specific tests, beyond the basics. (like total thyroid breakdown, APOE lipids testing, heart scan, Vit D testing).
      At a University Hosp I asked my gp 2-3 yrs ago if I could get a scan to clear up all this cholesterol business to check 4 plack? Said hosp wouldnt allow it. I would have had to private pay everything,(& u can't get one w/o recommendation anyway). Asked the same thing over 10 yrs ago to my clinic dr. Said same thing. It depends if your insurance will cover too. Cant get on partners insurance for family coverage, so I have to pay for all tests w/a high deductable too.
      No big deal though...It is great u can get tests on your own now. Will look into that more, maybe I will save up or join something like "Track your Plack".  Looks like I can maybe get some sort of test for lipids.
    If my breakdown comes out good, and I eat well already, plus take Vit D; then maybe they have had me worried unecessarily for 20 yrs!!HaHa...
    Take care Jen in Mn

  • Kurt

    1/16/2011 4:14:22 PM |

    You've written in the past about the failure of low fat diets to reduce plaque, so I was surprised to read that 19% of people benefit from eating less fat (assuming they don't replace fat with grains). I believe I'm one, because through trial and error - and multiple cholesterol tests - I've found that the less fat I eat, the lower my LDL reading.

  • Anonymous

    1/18/2011 2:01:10 AM |

    Kurt: and then Gene:

    Just wanted to point out---it's not 19 percent, it is 21. That means 1 in 5 should not follow the "increase your fats diet." And they may in fact not be harmed by diets that harm other gene profiles.

    Sure would like to know if niacin balances this all out?

    Keep in mind that ApoE 4 is a very controversial gene test---it is sometimes called the Alzheimers gene, mistakenly; and there is a lot of debate about the ethics of such a test for fear of marking people for a certain fate. Would suggest maybe discuss and research before checking, but it too is a rock and hard place choice.

    "Peter also has another gene for Apo E4, another genetically-determined pattern shared by 19% of Americans. (Another 2% of Americans have two "doses" of Apo E4, i.e., they are homozygotes for E4.)"

    Gene: Thank you so much for posting, I am grateful for freeback and input on this. Suggest trying the exercise after not before you eat. The science says the benefits are about post prandial exercise. I would love to see your results.

  • Lucy

    1/18/2011 2:26:36 AM |

    28 y/o ApoE 3/4 here.  Haven't been tested for Lp(a) yet, but my mom has it and she's also a 3/4.  Definitely frustrated with all the back and forth on whether I should do LC/HF or veg.  Started taking niacin last year, but I'd really like to know what to do with the diet.

    Dr. Davis-  Do you recommend ApoE 4's take fish oil, and if so how much?  I've heart conflicting info.

  • Anonymous

    1/18/2011 2:34:08 PM |


    Great question !

    Thank you for asking Dr. Davis about fish oil and ApoE 4's. I too take fish oil and wonder if I am making it worse.

  • Gene K

    1/23/2011 5:37:08 AM |


    The science says the benefits are about post prandial exercise.

    Immediate benefits will depend on the kind and amount of food consumed, the type, duration, and intensity of the exercise, and how soon after eating you exercise.

    There are also long-term benefits from regular exercise, and I am not sure you can reduce them to whether you eat and then exercise or exercise and then eat.

    I prefer to have a light meal within 1hr before a workout, and a good meal with lots of protein after my workout. My typical workout includes 30 min cardio + strength resistance the slow burn style.

    Disclaimer. The opinion is my own, and I am not an exercise scientist.

  • Dr. Daniel Chong

    1/24/2013 5:31:02 PM |

    In a case like this, I would continue on a plant based, low fat diet to combat Apo E4, then add in the following to combat the Lp(a) issue:
    Vitamin C titrated to bowel tolerance