I have APOE 3/4, MTHFR c667t homozygous, PEMT homozygous also MTR and my mother was diagnosed with vascular dementia at 70 and died from dementia at 77. My father is turning 90 this year and is cognitively good. Do you think the same protocol applies for preventing vascular dementia as preventing alzheimers? My mother took no prescribed medication had no diabetes, normal blood pressure and didnt have high cholesterol. She had an angiogram of her heart and was told her arteries were as clean as a whistle, yet died from vascular dementia. She didnt smoke or drink, exercised, played sport all her life and was not overweight. She had a healthy diet. The only thing other than her genetics that I can see that could have impacted her brain health was she did have shingles and h pylori.
Hi Julie, sorry about your mom. What makes stories like hers so difficult is that vascular dementia is often far more complex than just cholesterol, blood pressure, weight, or lifestyle. In many people, the line between vascular dementia and Alzheimer’s is also blurry - there is often overlap. So yes, I personally think the core prevention strategies overlap substantially: reducing inflammation, protecting vascular health, supporting mitochondrial and metabolic function, optimizing methylation, sleep, exercise, glucose control, and maintaining cognitive engagement. Your shingles and H. pylori observations are insightful too - chronic infections and immune activation are increasingly being looked at as contributors to neurodegeneration in genetically susceptible people. I absolutely recommend the shingles shot, and with PEMT variant, phospholipids/choline supplementation are a must (in my book!).
I would be interested in reading your book. How do I get a copy? I asked my functional practitioner about choline supplementation however she was concerned about over-methylation as I already take TMG, and methylated Bs and had a severe over methylation incident last year after a GP insisted I stop taking my supplements due to slightly raised AST. After I stopped all suplements, over a period of about 6 weeks my sleep deteriorated, I began feeling burning sensations in my back and feet and escalating anxiety. After a repeat blood test that showed perfectly normal liver function I resumed my supplements other than tumeric as that was the suspected cause. I didnt realise I needed to titrate all the methylated vits and had a severe reaction. Raised blood pressure, over the top anxiety, constant headache, inability to sleep at all wired and tired, burning sensations extended to whole body and came in waves at night and reactions to food, never had food intolerances ever before. My electrolytes became unbalanced and I was hospitalized with life threatening low sodium and low magnesium and potassium despite have resumed taking 450mg magnesium citrrate a day. After my electrolytes were returned to normal via infusions I was discharged however symptoms didnt disappear and eventually I had an acute admission to a psychiatric hospital where they gave me mirtazapine at a very low dose which acts as a histamine blocker. The burning sensations disappeared at night and I was able to get some sleep no real impact on the anxiety. To cut a long story short 12 months since the over methylation incident I have now regained my health and have no anxiety and rarely experience any burning sensations. Btw during this time my homocysteine went up to 17 previously was always 7. I had to titrate methylated B vits and TMG to bring it down again. Anxiety remained an issue until I started taking saffron and lemon balm I have no anxiety now. I also suffered daily headaches during this time and my memory was not good. Thankfully I no longer have headaches and my memory has returned the brain fog lifted. Understandably I am now cautious regarding methylated vits/supplements. I do eat eggs daily. Is there a way to test whether the eggs are providing enough choline before supplementing? Btw I live in Australia so testing is different here.
I haven't written a book - not sure who you have mixed me up with. I'm simply a 4/4 deeply interested in the research of this gene and its risk factors. Choline isn't a direct methyl donor but converts to TMG - so indirect. But with PEMT variant you will want to make sure you have sufficient choline/PC and PS. How old are you? Post-menopause?
Ah.. I took your comment "in my book" literally apologies. I am 63 years young, post menopausal, went through menopause at 51 no real issues Usual hot flushes after drinking hot drinks which abated after my functional dr advised me to take 1 tablespoon of flaxseed freshly ground every day which I did. I also drank soy milk and ate soy products until this histamine issue came up.
Such an important expansion of the conversation around Alzheimer’s risk as APOE4 has become so dominant in public discourse that people sometimes forget neurodegeneration is profoundly polygenic, multifactorial, and environmentally modulated. I appreciated that the piece moved beyond a deterministic “gene equals destiny” framework and instead emphasized the complexity of personalized risk biology.
What stood out to me most is the recognition that genetics likely functions more as a landscape of susceptibility rather than a singular predictive switch. APOE4 may alter lipid transport, neuroinflammation, synaptic repair, amyloid handling, and vascular vulnerability, but its expression is deeply influenced by sleep quality, metabolic health, insulin resistance, cardiovascular function, exercise, inflammation, environmental exposures, and possibly even microbiome and immune dynamics. Two individuals carrying similar genetic variants can experience dramatically different aging trajectories depending on the biologic environment surrounding those genes.
I also appreciated the broader implication that precision neurology is evolving from single-marker thinking toward integrated systems profiling. Polygenic risk scores, metabolomics, inflammatory signatures, retinal imaging, sleep metrics, vascular biomarkers, and longitudinal cognitive assessment may eventually work together to characterize brain aging far more accurately than any one gene alone. That systems-level direction feels much more aligned with how neurodegeneration actually develops over decades.
At the same time, I think these discussions benefit from careful communication around uncertainty. Expanding genetic testing without equally strong counseling and interpretive context risks creating unnecessary anxiety or false precision. Many people interpret elevated genetic risk as inevitability when the predictive power for individual outcomes remains probabilistic rather than deterministic. The psychological and ethical dimensions of predictive neurology are becoming just as important as the molecular science itself.
I have 3/4, homozygous PEMT, but my methylation is “compound heterozygous”, with one copy of the 1298 as well as 677. Not sure how that affects things. I limit my eggs because a majority of people with Epstein-Barr have problems with them, but I take lecithin for my PC supplement. Currently taking omega-3s, the Basic B and creatine, which can help with homocysteine levels too.
I think a few different pathways may be getting blended together here. PEMT and MTHFR affect different things. PEMT is more tied to choline/phosphatidylcholine production, while MTHFR relates to folate/methylation. Eggs make sense in the PEMT conversation because they’re such a rich choline source. The EBV/egg concern seems to come more from alternative-health theories than strong evidence. Since the vast majority of adults carry latent EBV, we’d expect eggs to be a widespread issue if that were truly the case. Individual sensitivities are of course possible, but that’s different from EBV-positive people broadly needing to avoid eggs. I don't avoid them.
Karin, I have the same genetic makeup as you on these three genes. In taking a methylated multivitamin, I have been able to get my homocysteine down to 6. Is there an additional benefit to adding TMG, if my homocysteine is already where I want it?
If/when my homocysteine gets to 6 (last check was 7), I'll probably stop using TMG regularly. However, even with exceptional methylation, the PEMT T/T variant leaves us struggling to synthesize PC.... so our need for PC and Choline supplementation is, and always will be, greater.
What does one do when very high Lpa and bad reaction to Methylfolate and folinic acid and intolerance to B vitamins due to interstitial cystitis doesn’t allow for these crucial intakes. Homocysteine always around 10.
Karin, as I always I appreciate your great explanations. I too have 4/4 and homozygous C677T and not sure on the last one. I like the Bodybio PC and I now eat 2 eggs every morning. I take methylated Bs in Qualia Mind most mornings. I also sometimes take krill oil, DHA, etc. I haven't done the Prodrome test. Is it expensive? thank you
Hi Karin
I have APOE 3/4, MTHFR c667t homozygous, PEMT homozygous also MTR and my mother was diagnosed with vascular dementia at 70 and died from dementia at 77. My father is turning 90 this year and is cognitively good. Do you think the same protocol applies for preventing vascular dementia as preventing alzheimers? My mother took no prescribed medication had no diabetes, normal blood pressure and didnt have high cholesterol. She had an angiogram of her heart and was told her arteries were as clean as a whistle, yet died from vascular dementia. She didnt smoke or drink, exercised, played sport all her life and was not overweight. She had a healthy diet. The only thing other than her genetics that I can see that could have impacted her brain health was she did have shingles and h pylori.
Hi Julie, sorry about your mom. What makes stories like hers so difficult is that vascular dementia is often far more complex than just cholesterol, blood pressure, weight, or lifestyle. In many people, the line between vascular dementia and Alzheimer’s is also blurry - there is often overlap. So yes, I personally think the core prevention strategies overlap substantially: reducing inflammation, protecting vascular health, supporting mitochondrial and metabolic function, optimizing methylation, sleep, exercise, glucose control, and maintaining cognitive engagement. Your shingles and H. pylori observations are insightful too - chronic infections and immune activation are increasingly being looked at as contributors to neurodegeneration in genetically susceptible people. I absolutely recommend the shingles shot, and with PEMT variant, phospholipids/choline supplementation are a must (in my book!).
Hi Karin
I would be interested in reading your book. How do I get a copy? I asked my functional practitioner about choline supplementation however she was concerned about over-methylation as I already take TMG, and methylated Bs and had a severe over methylation incident last year after a GP insisted I stop taking my supplements due to slightly raised AST. After I stopped all suplements, over a period of about 6 weeks my sleep deteriorated, I began feeling burning sensations in my back and feet and escalating anxiety. After a repeat blood test that showed perfectly normal liver function I resumed my supplements other than tumeric as that was the suspected cause. I didnt realise I needed to titrate all the methylated vits and had a severe reaction. Raised blood pressure, over the top anxiety, constant headache, inability to sleep at all wired and tired, burning sensations extended to whole body and came in waves at night and reactions to food, never had food intolerances ever before. My electrolytes became unbalanced and I was hospitalized with life threatening low sodium and low magnesium and potassium despite have resumed taking 450mg magnesium citrrate a day. After my electrolytes were returned to normal via infusions I was discharged however symptoms didnt disappear and eventually I had an acute admission to a psychiatric hospital where they gave me mirtazapine at a very low dose which acts as a histamine blocker. The burning sensations disappeared at night and I was able to get some sleep no real impact on the anxiety. To cut a long story short 12 months since the over methylation incident I have now regained my health and have no anxiety and rarely experience any burning sensations. Btw during this time my homocysteine went up to 17 previously was always 7. I had to titrate methylated B vits and TMG to bring it down again. Anxiety remained an issue until I started taking saffron and lemon balm I have no anxiety now. I also suffered daily headaches during this time and my memory was not good. Thankfully I no longer have headaches and my memory has returned the brain fog lifted. Understandably I am now cautious regarding methylated vits/supplements. I do eat eggs daily. Is there a way to test whether the eggs are providing enough choline before supplementing? Btw I live in Australia so testing is different here.
I haven't written a book - not sure who you have mixed me up with. I'm simply a 4/4 deeply interested in the research of this gene and its risk factors. Choline isn't a direct methyl donor but converts to TMG - so indirect. But with PEMT variant you will want to make sure you have sufficient choline/PC and PS. How old are you? Post-menopause?
Ah.. I took your comment "in my book" literally apologies. I am 63 years young, post menopausal, went through menopause at 51 no real issues Usual hot flushes after drinking hot drinks which abated after my functional dr advised me to take 1 tablespoon of flaxseed freshly ground every day which I did. I also drank soy milk and ate soy products until this histamine issue came up.
Such an important expansion of the conversation around Alzheimer’s risk as APOE4 has become so dominant in public discourse that people sometimes forget neurodegeneration is profoundly polygenic, multifactorial, and environmentally modulated. I appreciated that the piece moved beyond a deterministic “gene equals destiny” framework and instead emphasized the complexity of personalized risk biology.
What stood out to me most is the recognition that genetics likely functions more as a landscape of susceptibility rather than a singular predictive switch. APOE4 may alter lipid transport, neuroinflammation, synaptic repair, amyloid handling, and vascular vulnerability, but its expression is deeply influenced by sleep quality, metabolic health, insulin resistance, cardiovascular function, exercise, inflammation, environmental exposures, and possibly even microbiome and immune dynamics. Two individuals carrying similar genetic variants can experience dramatically different aging trajectories depending on the biologic environment surrounding those genes.
I also appreciated the broader implication that precision neurology is evolving from single-marker thinking toward integrated systems profiling. Polygenic risk scores, metabolomics, inflammatory signatures, retinal imaging, sleep metrics, vascular biomarkers, and longitudinal cognitive assessment may eventually work together to characterize brain aging far more accurately than any one gene alone. That systems-level direction feels much more aligned with how neurodegeneration actually develops over decades.
At the same time, I think these discussions benefit from careful communication around uncertainty. Expanding genetic testing without equally strong counseling and interpretive context risks creating unnecessary anxiety or false precision. Many people interpret elevated genetic risk as inevitability when the predictive power for individual outcomes remains probabilistic rather than deterministic. The psychological and ethical dimensions of predictive neurology are becoming just as important as the molecular science itself.
Really thoughtful piece.
I have 3/4, homozygous PEMT, but my methylation is “compound heterozygous”, with one copy of the 1298 as well as 677. Not sure how that affects things. I limit my eggs because a majority of people with Epstein-Barr have problems with them, but I take lecithin for my PC supplement. Currently taking omega-3s, the Basic B and creatine, which can help with homocysteine levels too.
I think a few different pathways may be getting blended together here. PEMT and MTHFR affect different things. PEMT is more tied to choline/phosphatidylcholine production, while MTHFR relates to folate/methylation. Eggs make sense in the PEMT conversation because they’re such a rich choline source. The EBV/egg concern seems to come more from alternative-health theories than strong evidence. Since the vast majority of adults carry latent EBV, we’d expect eggs to be a widespread issue if that were truly the case. Individual sensitivities are of course possible, but that’s different from EBV-positive people broadly needing to avoid eggs. I don't avoid them.
Karin, I have the same genetic makeup as you on these three genes. In taking a methylated multivitamin, I have been able to get my homocysteine down to 6. Is there an additional benefit to adding TMG, if my homocysteine is already where I want it?
If/when my homocysteine gets to 6 (last check was 7), I'll probably stop using TMG regularly. However, even with exceptional methylation, the PEMT T/T variant leaves us struggling to synthesize PC.... so our need for PC and Choline supplementation is, and always will be, greater.
I have no problem with high dose sublingual methylcobalamin and TMG is the next thing on my list per my doc. I will microdose at first
What genetic testing did you do to find out your PEMT? Is there other genes that we should look more closely at as an APOE4/4? Thank you.
if you did Ancestry or 23andme, you can check raw data for rs7946.
What does one do when very high Lpa and bad reaction to Methylfolate and folinic acid and intolerance to B vitamins due to interstitial cystitis doesn’t allow for these crucial intakes. Homocysteine always around 10.
Have you tried lowering homocysteine with TMG or Hydroxocobalamin? I would dose very low and increase very slowly if you are having reactions.
I have no problem with B12 methylcobalamin and TMG was next on my list per doc. I will microdose
Karin, as I always I appreciate your great explanations. I too have 4/4 and homozygous C677T and not sure on the last one. I like the Bodybio PC and I now eat 2 eggs every morning. I take methylated Bs in Qualia Mind most mornings. I also sometimes take krill oil, DHA, etc. I haven't done the Prodrome test. Is it expensive? thank you
The Prodrome test is $499 plus third party blood draw.