I am a preventive Cardiologist with a strong research interest in lipids, diet and brain health. This data, and yoiur superb article in particular Karin, is a major step forward in the field of Apo E4. I have one apoE4 allele, so this is personal for me. This data around the benefits of very low LDL and apoB are very strong for coronary disease, multi infarct demential, and peripheral artery disease. Ideal apo B levels are about 30 to 40, which is what our levels were when we were born. All wild mammals including hunter gatherer humans had apo B in the range, so it is in the evolutionarily normal range. I virtually never use a statin without ezetimibe, as these drugs are synergistic. I often add PCSK9i (Repatha or Praluent) to the mix. I personally follow a pristine diet and lifestyle but still take ezetimibe 10 mg d, Repatha 140 mg every two weeks and pitavastatin 1 mg Mon, Weds, Fri. Pitavastatin is a VERY cool statin, as it is neutral on glucose metabolism (most statins increase A1c sltightly), and has fewer side effects. This keeps my apoB about 30 to 40. High omega-3 is also key for apo E4 carriers, as the latest data from our group shows these people get outsize benefits from high omega-3 levels. Also agree with you Karin that high fiber, like added psyllium fiber, beta glucan are helpful. Finally, my version of the old adage is that an avocado a day keeps the doctor away. James O'Keefe, MD, FACC.
Thank you so much for the additional information and your perspective! I've noticed an 0.1 increase in my own A1C since starting Pravastatin which could be related...so I'll look into the Pitavastatin now! One thing I didn't include in the article, (but will do an addendum for others who might read it later), is lp(a). Many folks have never even been tested and an elevated lp(a) presence makes lipid control that much more important.
Is NAD also something worthy of adding to a statin and ezetimbe? I have upcoming appoint with a preventative cardiologist and feel a sense of urgency to know all I can! Thoughts on rapamycin vs or with NAD and statin etc…. Sounds like a lot of meds. Thanks in advance I really redirect your research and appreciate the way you explain!
I take NAD regularly but I pulse it.... month on, month off. (see Nick Norwitz' recent post https://staycuriousmetabolism.substack.com/p/never-get-alzheimers-disease-the). I also take once weekly rapamycin. You can take either NMN or NR supplement or opt for NAD injections. I chose injections since I'm older and want to be assured full absorption. If you haven't had lp(a) test, get that done and also ask for ApoB and homocysteine level which are also not routinely checked. Good luck!
@jameshokeefemd. I was just researching the Pitavastatin and see it's lipophilic. Dr. Alan Green, who had over 500 patients with APOE4, always said that APOE4s should only take hydrophilic statins...., any thoughts on this?
Yet again Karin you have blown me away with your extremely helpful and maybe life changing information! Thank you so much! I’m sending this to my Dr. so I can get on low dose statin stat!
I resisted statins for many years. My deeper dive into the lipid altering effects of APOE4 changed my mind as the research is pretty clear and unambiguous.
Thank you so very much for this! Statins are something I am wanting to try, and this piece is very helpful as I prepare for an upcoming doctor's visit.
This is a very thoughtful and balanced synthesis. The relationship between APOE4 and statins is one of those contexts where biology and clinical evidence both matter. APOE4 carriers do have distinct lipoprotein metabolism and a higher baseline cardiovascular and Alzheimer’s risk, but the best trial data we have doesn’t suggest withholding statins in this group; if anything, the absolute risk reduction for atherosclerotic events tends to be greater in those at higher baseline risk.
Where nuance matters is recognizing that risk profile is what drives benefit, not genotype alone. APOE4 may influence LDL response and lipoprotein particle distribution, but statins still reduce cardiovascular events consistently across genotype strata, and they remain a foundational therapy when indicated by risk. I also appreciate the distinction you make between mechanistic plausibility vs clinical outcomes. It’s exactly the type of careful interpretation that helps patients and clinicians move beyond headlines into decisions that actually improve longevity and quality of life.
ApoE4 is not one of the considerations I've honestly ever had around statins. I do think overall benefits of statins, even in the realm of primary prevention of CV events in low risk groups, is surprisingly strong. I'm sure we'll continue to learn about it's influence on the incidence of dementia as the population continues to age. Hopefully that comes with even more data on the ApoE4 populations.
What a great breakdown of the data and personal comments which make for a better post. As a PA/prescriber, I am a fan of properly prescribed medications and some advanced testing such as Lp(a). I appreciate the content you created and am sharing this post.
Maybe you can mention this to the very interesting, energetic, popular, but still young 4/4 Dr. Nick Norwitz. He can obviously read, but maybe he has not yet seen some of what you mention. I, too, found the Boston Heart Test to be very comprehensive, and indicating heavy production and retention. I'll take a another look at statins, though ezetimibe, diet, and trail jogging lowered my LDL to 82. Wherever I see your name, I check to see if there is something new and important to read. Thank you!
LDL of 82 sounds good to me. What about your ApoB and hsCRP? Keep an eye on them to decide if statins might be indicated and don't underestimate how fiber can help address LDL.... apart from feeding those butyrate producing gut bacteria we need! As for Nick, he is performing a lot of N=1 experiments on himself and as young as he is, I don't believe he's doing any lasting damage. He doesn't claim his 500+ LDL levels are healthy nor that he is going to keep them there.. it's simply not known where LMHR are positioned on the risk scale.
Thanks for this very informative. My question is- having an HDL of 95 and LDL of 150 along with being heterozygote Apoe4- are there still benefits in taking a statin?
The LDL number is less important than looking at the bigger picture which includes: your ApoB number, HDL/Trig. ratio, whether or not you have genetically determined elevated lp(a) and if you are dealing with inflammation (hsCRP). If those aren't pristine, I would look at ways to adjust that number. Ezetimibe (blocking cholesterol absorption) and increased fiber intake would be a good place to start.
A good perspective for the practitioners and I do hope they will be able to translate it for the benefit of their patients. Still, I would request the author to provide a small commoner’s summary here in the comments. Statins have been around for 40-50 years, they are no longer the big pharma’s golden goose. They are bulk manufactured and offered by hundreds of small companies. If there are government schemes for affordable drugs, as in India here (nearly a few hundred drugs and formulations are on offer), they can cost a pittance. For example, under this scheme, a 10 mg Atorvostatin tablet just costs a cent. Like all drugs we have known, statins have their pluses and minuses and the doctors need to be well informed. But their potential in other physically and financially crippling diseases ( cancer, Alzemeirs) should not be missed and must be brought to the table - as prophylactic or therapeutic. Research minded small companies and doctors have a large role here.
The point I’m making is narrower and APOE-specific: APOE4 carriers have distinct lipid transport and neuroinflammatory biology, and responses to statins — particularly regarding cognition — may differ meaningfully from the general population.
I agree that statins have potential pleiotropic effects and may play roles beyond LDL lowering. But in APOE4, the question isn’t access or cost — it’s whether benefits outweigh risks at the brain level, and that’s where more genotype-aware discussion and research are needed.
If you consume ancestrally raised eggs, raw dairy, pastured chicken and modest amounts of fatty steaks your lipoproteins become so healthy you don't need statins... And when you do that your cravings for carbohydrates drop and you do less damage that the lipoproteins don't have to fix as often...
Statins are still a distraction from the truth no matter how you put it.
No. A belief system is universal application without stratification. Statins are useful for some, unnecessary for others. The mistake is dogma in either direction.
Maybe... maybe for a double 4 carrier... but i think even a double 4 and certainly a single 4 can make dietary and lifestyle eliminations that will drastically cut the risk of Alzheimer's.
Metal exposure is the single leading cause of Alzheimer's from these sources: (AND SPECIFICALLY Aluminum and Fluoride Combination)
🦷 Amalgam dental fillings (mercury vapors)
🐟 Large predatory fish (tuna, swordfish, shark, king mackerel → methyl mercury
🌾 Rice (arsenic → esp. brown rice & grown in flooded fields)
🫚 Root vegetables grown in polluted soil (arsenic, lead, cadmium)
😬 Braces and Permanent retainers (Nickel)
🧪 Lead pipes, solder, or old plumbing fixtures
🍳 Impure Cheap Stainless Steal Pans → Nickel
🍳 Cast Iron Skillet → Iron Oxide
🛠️ Welding & construction dust (chromium, nickel, lead)
🚿 Well water contaminated with arsenic, cadmium, or uranium
🎭 Cheap jewelry/toys (lead, cadmium)
🍵 Herbal teas & supplements grown in contaminated soil
🎨 Old paint (lead-based, esp. pre-1978) even painted glass kitchen items.
🍄 Wild mushrooms (can absorb cadmium, mercury)
🚛 Exhaust & brake dust (cadmium, lead)
⚡ Power plants (coal-burning → mercury, arsenic, lead released)(Affect fresh water fish and many crops)
🏭 Industrial runoff in rivers & lakes
We cannot underestimate exposure to mold mycotoxins, microplastics, PFAS, glyphosate and seed oils either these are all potent CVD, Alzheimer's, insulin resistance and Cancer.
agreed, aware of all of that and more. Believe me, as a 4/4 I look at everything possible that could impact my brain health both negatively and positively.
I am a preventive Cardiologist with a strong research interest in lipids, diet and brain health. This data, and yoiur superb article in particular Karin, is a major step forward in the field of Apo E4. I have one apoE4 allele, so this is personal for me. This data around the benefits of very low LDL and apoB are very strong for coronary disease, multi infarct demential, and peripheral artery disease. Ideal apo B levels are about 30 to 40, which is what our levels were when we were born. All wild mammals including hunter gatherer humans had apo B in the range, so it is in the evolutionarily normal range. I virtually never use a statin without ezetimibe, as these drugs are synergistic. I often add PCSK9i (Repatha or Praluent) to the mix. I personally follow a pristine diet and lifestyle but still take ezetimibe 10 mg d, Repatha 140 mg every two weeks and pitavastatin 1 mg Mon, Weds, Fri. Pitavastatin is a VERY cool statin, as it is neutral on glucose metabolism (most statins increase A1c sltightly), and has fewer side effects. This keeps my apoB about 30 to 40. High omega-3 is also key for apo E4 carriers, as the latest data from our group shows these people get outsize benefits from high omega-3 levels. Also agree with you Karin that high fiber, like added psyllium fiber, beta glucan are helpful. Finally, my version of the old adage is that an avocado a day keeps the doctor away. James O'Keefe, MD, FACC.
Thank you so much for the additional information and your perspective! I've noticed an 0.1 increase in my own A1C since starting Pravastatin which could be related...so I'll look into the Pitavastatin now! One thing I didn't include in the article, (but will do an addendum for others who might read it later), is lp(a). Many folks have never even been tested and an elevated lp(a) presence makes lipid control that much more important.
Is NAD also something worthy of adding to a statin and ezetimbe? I have upcoming appoint with a preventative cardiologist and feel a sense of urgency to know all I can! Thoughts on rapamycin vs or with NAD and statin etc…. Sounds like a lot of meds. Thanks in advance I really redirect your research and appreciate the way you explain!
I take NAD regularly but I pulse it.... month on, month off. (see Nick Norwitz' recent post https://staycuriousmetabolism.substack.com/p/never-get-alzheimers-disease-the). I also take once weekly rapamycin. You can take either NMN or NR supplement or opt for NAD injections. I chose injections since I'm older and want to be assured full absorption. If you haven't had lp(a) test, get that done and also ask for ApoB and homocysteine level which are also not routinely checked. Good luck!
@jameshokeefemd. I was just researching the Pitavastatin and see it's lipophilic. Dr. Alan Green, who had over 500 patients with APOE4, always said that APOE4s should only take hydrophilic statins...., any thoughts on this?
Yet again Karin you have blown me away with your extremely helpful and maybe life changing information! Thank you so much! I’m sending this to my Dr. so I can get on low dose statin stat!
I resisted statins for many years. My deeper dive into the lipid altering effects of APOE4 changed my mind as the research is pretty clear and unambiguous.
I think this is one of the most important messages an APOE4/4 carrier can receive. Thank you for sharing.
Thank you so very much for this! Statins are something I am wanting to try, and this piece is very helpful as I prepare for an upcoming doctor's visit.
This is a very thoughtful and balanced synthesis. The relationship between APOE4 and statins is one of those contexts where biology and clinical evidence both matter. APOE4 carriers do have distinct lipoprotein metabolism and a higher baseline cardiovascular and Alzheimer’s risk, but the best trial data we have doesn’t suggest withholding statins in this group; if anything, the absolute risk reduction for atherosclerotic events tends to be greater in those at higher baseline risk.
Where nuance matters is recognizing that risk profile is what drives benefit, not genotype alone. APOE4 may influence LDL response and lipoprotein particle distribution, but statins still reduce cardiovascular events consistently across genotype strata, and they remain a foundational therapy when indicated by risk. I also appreciate the distinction you make between mechanistic plausibility vs clinical outcomes. It’s exactly the type of careful interpretation that helps patients and clinicians move beyond headlines into decisions that actually improve longevity and quality of life.
Fantastic work and helpful in the fight against misinfo that runs rampant among APOE4 community. Fear makes an unfortunate friend of misinformation.
ApoE4 is not one of the considerations I've honestly ever had around statins. I do think overall benefits of statins, even in the realm of primary prevention of CV events in low risk groups, is surprisingly strong. I'm sure we'll continue to learn about it's influence on the incidence of dementia as the population continues to age. Hopefully that comes with even more data on the ApoE4 populations.
What a great breakdown of the data and personal comments which make for a better post. As a PA/prescriber, I am a fan of properly prescribed medications and some advanced testing such as Lp(a). I appreciate the content you created and am sharing this post.
Thanks, Karin, as always for sharing helpful and accurate information!
Great article! Thanks for sharing the data!
Maybe you can mention this to the very interesting, energetic, popular, but still young 4/4 Dr. Nick Norwitz. He can obviously read, but maybe he has not yet seen some of what you mention. I, too, found the Boston Heart Test to be very comprehensive, and indicating heavy production and retention. I'll take a another look at statins, though ezetimibe, diet, and trail jogging lowered my LDL to 82. Wherever I see your name, I check to see if there is something new and important to read. Thank you!
LDL of 82 sounds good to me. What about your ApoB and hsCRP? Keep an eye on them to decide if statins might be indicated and don't underestimate how fiber can help address LDL.... apart from feeding those butyrate producing gut bacteria we need! As for Nick, he is performing a lot of N=1 experiments on himself and as young as he is, I don't believe he's doing any lasting damage. He doesn't claim his 500+ LDL levels are healthy nor that he is going to keep them there.. it's simply not known where LMHR are positioned on the risk scale.
Thanks for this very informative. My question is- having an HDL of 95 and LDL of 150 along with being heterozygote Apoe4- are there still benefits in taking a statin?
The LDL number is less important than looking at the bigger picture which includes: your ApoB number, HDL/Trig. ratio, whether or not you have genetically determined elevated lp(a) and if you are dealing with inflammation (hsCRP). If those aren't pristine, I would look at ways to adjust that number. Ezetimibe (blocking cholesterol absorption) and increased fiber intake would be a good place to start.
A good perspective for the practitioners and I do hope they will be able to translate it for the benefit of their patients. Still, I would request the author to provide a small commoner’s summary here in the comments. Statins have been around for 40-50 years, they are no longer the big pharma’s golden goose. They are bulk manufactured and offered by hundreds of small companies. If there are government schemes for affordable drugs, as in India here (nearly a few hundred drugs and formulations are on offer), they can cost a pittance. For example, under this scheme, a 10 mg Atorvostatin tablet just costs a cent. Like all drugs we have known, statins have their pluses and minuses and the doctors need to be well informed. But their potential in other physically and financially crippling diseases ( cancer, Alzemeirs) should not be missed and must be brought to the table - as prophylactic or therapeutic. Research minded small companies and doctors have a large role here.
The point I’m making is narrower and APOE-specific: APOE4 carriers have distinct lipid transport and neuroinflammatory biology, and responses to statins — particularly regarding cognition — may differ meaningfully from the general population.
I agree that statins have potential pleiotropic effects and may play roles beyond LDL lowering. But in APOE4, the question isn’t access or cost — it’s whether benefits outweigh risks at the brain level, and that’s where more genotype-aware discussion and research are needed.
This is an intriguing and great post. It continues to show the pleomorphic and beneficial effects of statins.
If you consume ancestrally raised eggs, raw dairy, pastured chicken and modest amounts of fatty steaks your lipoproteins become so healthy you don't need statins... And when you do that your cravings for carbohydrates drop and you do less damage that the lipoproteins don't have to fix as often...
Statins are still a distraction from the truth no matter how you put it.
Diet helps, but it doesn’t override genetics or lipid transport biology.
For some people, statins are a tool — not a belief system.
Fair counter, so for most people statins are a belief system?
That's a pretty big implied attack on statins.
It means most people should stop taking a statin.
Pharmaceuticals are mostly taken due to a dogmatic belief system not rational uncensored discourse.
No. A belief system is universal application without stratification. Statins are useful for some, unnecessary for others. The mistake is dogma in either direction.
Maybe... maybe for a double 4 carrier... but i think even a double 4 and certainly a single 4 can make dietary and lifestyle eliminations that will drastically cut the risk of Alzheimer's.
Metal exposure is the single leading cause of Alzheimer's from these sources: (AND SPECIFICALLY Aluminum and Fluoride Combination)
🦷 Amalgam dental fillings (mercury vapors)
🐟 Large predatory fish (tuna, swordfish, shark, king mackerel → methyl mercury
🍫 Cocoa/chocolate (cadmium, lead)
💉 Older Flu Vaccines + (H1N1 Multi-dose) (thimerosal → ethylmercury)
💉Current Vaccines (Direct Aluminum to Lymphatic System w Proven Brain Translocation)
Fluoride/PFAS in toothpaste, tooth floss and non stick cooking pans.
High Fructose Corn Syrup -> Mercury
🐓 Animal organs (especially liver & kidney → cadmium, lead)
🚬 Tobacco smoke (cadmium, lead, arsenic, thallium)
🧴 Some cosmetics (kohl eyeliner → lead; skin lightening creams → mercury)
🥬Leafy Greens (spinach, lettuce, kale, arugula) (lead, cadmium, thallium)
🐚 Shellfish (arsenic, cadmium)
🌾 Rice (arsenic → esp. brown rice & grown in flooded fields)
🫚 Root vegetables grown in polluted soil (arsenic, lead, cadmium)
😬 Braces and Permanent retainers (Nickel)
🧪 Lead pipes, solder, or old plumbing fixtures
🍳 Impure Cheap Stainless Steal Pans → Nickel
🍳 Cast Iron Skillet → Iron Oxide
🛠️ Welding & construction dust (chromium, nickel, lead)
🚿 Well water contaminated with arsenic, cadmium, or uranium
🎭 Cheap jewelry/toys (lead, cadmium)
🍵 Herbal teas & supplements grown in contaminated soil
🎨 Old paint (lead-based, esp. pre-1978) even painted glass kitchen items.
🍄 Wild mushrooms (can absorb cadmium, mercury)
🚛 Exhaust & brake dust (cadmium, lead)
⚡ Power plants (coal-burning → mercury, arsenic, lead released)(Affect fresh water fish and many crops)
🏭 Industrial runoff in rivers & lakes
We cannot underestimate exposure to mold mycotoxins, microplastics, PFAS, glyphosate and seed oils either these are all potent CVD, Alzheimer's, insulin resistance and Cancer.
agreed, aware of all of that and more. Believe me, as a 4/4 I look at everything possible that could impact my brain health both negatively and positively.
Do you get electrolytes like potassium etc and other essential minerals?
A multi mineral excluding iron?
Have you tested your response to 1mg of copper glycinate? Alone and in a full mineral complex?
It can indicate healthy metabolism.
I never take copper alone... i don't really isolate any minerals always in a mineral complex... because even organic soils these days are really bad.
Need to see if I’m 4-4. We’ll do lots of testing soon.