Minor Alleles for all TOMM40, APOE and APOC1

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cdaniel
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Minor Alleles for all TOMM40, APOE and APOC1

Post by cdaniel »

I'm a woman in her mid 30s and have posted here once before about supplements for APOE4/4 at my age. I recently got results back from Nebula and have now found out I am homozygous for minor alleles in TOMM40 and APOC1 as well. I checked Klothos and have no copies of the helpful gene. I've read different things about TOMM40 not really adding on to APOE4/4 diagnosis, but it seems that APOC1 in fact does. I'm looking for any guidance on what the research says about earlier LOAD with multiple of these [potentially] damaging genes. It feels like there's no escaping my ultimate fate and looking for a glimmer of hope. Thanks in advance to anyone who responds!
NF52
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Re: Minor Alleles for all TOMM40, APOE and APOC1

Post by NF52 »

cdaniel wrote: Fri May 05, 2023 8:31 am I'm a woman in her mid 30s and have posted here once before about supplements for APOE4/4 at my age. I recently got results back from Nebula and have now found out I am homozygous for minor alleles in TOMM40 and APOC1 as well. I checked Klothos and have no copies of the helpful gene. I've read different things about TOMM40 not really adding on to APOE4/4 diagnosis, but it seems that APOC1 in fact does. I'm looking for any guidance on what the research says about earlier LOAD with multiple of these [potentially] damaging genes. It feels like there's no escaping my ultimate fate and looking for a glimmer of hope. Thanks in advance to anyone who responds!
Hi cdaniel,

You may have seen this, but for those who have not, here's what Snpedia has to say about rs4402638, the APOC1 gene:
ApoE status is technically defined by two different SNPs, rs429358 and rs7412. This SNP, rs4420638, is situated about 14kb away in the adjacent ApoC1 gene and is co-inherited with ApoE and thus associated with late-onset Alzheimer's disease.[PMID 17192785]...
These two SNPs are correlated with each other and it's believed that most of the association with AD at rs4420638 is due to its proximity to rs429358....
The (G;G) form of this SNP indicates increased risk of Alzheimer's disease, however the probability and amount of increased risk is subject to some disagreement. ...The initial report concerning this SNP indicated a high likelihood that rs4420638(G;G) homozygotes were predictably ApoE4/ApoE4 homozygotes
https://www.snpedia.com/index.php/Rs4420638

Here's some research info on TOMM40 from a study of donated brains and blood samples from almost 19000 people, of whom 1500 had ApoE 4/4. Based on other research comparing differences between typical populations and those in brain research cohorts, this probably skews too pessimistic.
rs2075650 was nominally associated with AD among ε4 homozygotes
Association of Uncommon, Noncoding Variants in the APOE Region With Risk of Alzheimer Disease in Adults of European Ancestry

"Nominally associated" just barely reaches statistical significance, and since this is looking solely at data from people recruited in Alzheimer's research, is likely skewed differently than population data. Even in that population (of donated brains) there was large variation of between no increase (1.0 risk= the same as ApoE 4 risk) to 1.33 risk (increasing risk by 1/3).

Like you, I have both ApoE 4/4 and the G/G variant of Rs4420638. I have a history of high LDL-C and LDL-P cholesterol and take a statin to bring them down into the normal range. That and lifestyle changes in the last 15 years have made a big difference in both my brain and cardiac health. My resting heart rate is in the 60's; my blood pressure is normal, my EKG (taken 2 days ago) shows no sign of any cardiac problems and I had a zero score on a coronary artery calcium in 2017. And as a clinical trial participant for a drug (lecanemab) to remove elevated levels of amyloid plaque from my brain, I also got a perfect score two days ago on a test of free and cued recall, prompting the neuropsychologist to say "I've never had anyone get a perfect score." I'm 71, and far from perfect in all of my habits.

So when I say you have reason to have buckets full of hope, I sincerely mean it.
In 20 years, you will look back and realize you were like me in 1969, when I suddenly realized humans didn't just have to look at the moon, they could walk on it. We don't have to just look at our gene reports; we can act on them!
4/4 and still an optimist!
cdaniel
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Re: Minor Alleles for all TOMM40, APOE and APOC1

Post by cdaniel »

NF52 wrote: Fri May 05, 2023 10:11 am
cdaniel wrote: Fri May 05, 2023 8:31 am I'm a woman in her mid 30s and have posted here once before about supplements for APOE4/4 at my age. I recently got results back from Nebula and have now found out I am homozygous for minor alleles in TOMM40 and APOC1 as well. I checked Klothos and have no copies of the helpful gene. I've read different things about TOMM40 not really adding on to APOE4/4 diagnosis, but it seems that APOC1 in fact does. I'm looking for any guidance on what the research says about earlier LOAD with multiple of these [potentially] damaging genes. It feels like there's no escaping my ultimate fate and looking for a glimmer of hope. Thanks in advance to anyone who responds!
Hi cdaniel,

You may have seen this, but for those who have not, here's what Snpedia has to say about rs4402638, the APOC1 gene:
ApoE status is technically defined by two different SNPs, rs429358 and rs7412. This SNP, rs4420638, is situated about 14kb away in the adjacent ApoC1 gene and is co-inherited with ApoE and thus associated with late-onset Alzheimer's disease.[PMID 17192785]...
These two SNPs are correlated with each other and it's believed that most of the association with AD at rs4420638 is due to its proximity to rs429358....
The (G;G) form of this SNP indicates increased risk of Alzheimer's disease, however the probability and amount of increased risk is subject to some disagreement. ...The initial report concerning this SNP indicated a high likelihood that rs4420638(G;G) homozygotes were predictably ApoE4/ApoE4 homozygotes
https://www.snpedia.com/index.php/Rs4420638

Here's some research info on TOMM40 from a study of donated brains and blood samples from almost 19000 people, of whom 1500 had ApoE 4/4. Based on other research comparing differences between typical populations and those in brain research cohorts, this probably skews too pessimistic.
rs2075650 was nominally associated with AD among ε4 homozygotes
Association of Uncommon, Noncoding Variants in the APOE Region With Risk of Alzheimer Disease in Adults of European Ancestry

"Nominally associated" just barely reaches statistical significance, and since this is looking solely at data from people recruited in Alzheimer's research, is likely skewed differently than population data. Even in that population (of donated brains) there was large variation of between no increase (1.0 risk= the same as ApoE 4 risk) to 1.33 risk (increasing risk by 1/3).

Like you, I have both ApoE 4/4 and the G/G variant of Rs4420638. I have a history of high LDL-C and LDL-P cholesterol and take a statin to bring them down into the normal range. That and lifestyle changes in the last 15 years have made a big difference in both my brain and cardiac health. My resting heart rate is in the 60's; my blood pressure is normal, my EKG (taken 2 days ago) shows no sign of any cardiac problems and I had a zero score on a coronary artery calcium in 2017. And as a clinical trial participant for a drug (lecanemab) to remove elevated levels of amyloid plaque from my brain, I also got a perfect score two days ago on a test of free and cued recall, prompting the neuropsychologist to say "I've never had anyone get a perfect score." I'm 71, and far from perfect in all of my habits.

So when I say you have reason to have buckets full of hope, I sincerely mean it.
In 20 years, you will look back and realize you were like me in 1969, when I suddenly realized humans didn't just have to look at the moon, they could walk on it. We don't have to just look at our gene reports; we can act on them!
Thank you for this very thoughtful and kind response. It's good to hear from someone who has done a lot of research on it and which sources of information you trust.
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