I feel like the below is very likely outdated at this point. Does the Generational Study address this? I'm wondering what this means for 2/4 and 3/4 carriers, too.
This case involves the APOE gene on chromosome 19. This has gotten considerable attention since roughly the mid-1990s. There are six variants of this gene that are known. These are the 4/4, 3/4, 2/4, 3/3, 2/3, 2/2 alleles. The 4/4 allele has gotten the most attention because it is associated with earlier onset Alzheimer’s disease [AD]. To be precise, the 4/4 allele is associated with an average age of onset of Alzheimer’s in the mid to late 60s. The lifetime risk for Alzheimer’s of a person with the 4/4 allele is about 30%. But there is also a 94% probability that such an individual will have Alzheimer’s by age 80. This may seem statistically incongruous with the prior sentence. But there is a clinical explanation. The 4/4 allele of APOE is also associated with very early onset heart disease, typically in the late 30s or early 40s. That means many individuals with this genotype die well before they get into their 60s. [To avoid confusion, we will note that there are forms of early-onset Alzheimer’s known as Familial Alzheimer’s Disease [FAD]. This is associated with symptom onset in the late 30s to early 50s. Different chromosomes and genes are associated with this distinct disorder.]
https://msu.edu/course/hm/546/apoe.htm
"Lifetime risk for APOE4/4 carriers is 30% because they'll likely die from heart disease" - is this research outdated?
Re: "Lifetime risk for APOE4/4 carriers is 30% because they'll likely die from heart disease" - is this research outdate
If it weren't potentially (emotionally) harmful, the information would be kind of laughable. This looks more like an exercise for genetic counselors than conveyance of accurate ApoE4 info... although they probably need accurate information as much as anyone! 
Many of us are E4 homozygotes, in midlife and beyond, with no sign of heart disease. I'm currently 57 and my CAC (few years ago) was zero. Please don't worry about this. -xo
Many of us are E4 homozygotes, in midlife and beyond, with no sign of heart disease. I'm currently 57 and my CAC (few years ago) was zero. Please don't worry about this. -xo
Re: "Lifetime risk for APOE4/4 carriers is 30% because they'll likely die from heart disease" - is this research outdate
I agree with JulieG, especially because the numbers are so variable when you look up articles about the risk of AD for 4/4, as I have been doing recently. I think some of the higher risk numbers come from studies of families with late onset Alzheimer's, in those families the AD risk is > 90% if they are 4/4, but they may have other genes that contribute to their disease frequency.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
Corder EH1, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA.
Author information
1
Department of Medicine, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710.
Abstract
The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80." (italics are mine)
In large population studies it is more like 30%:
"Five-year risk was highly variable across the four samples within each group; for APOE-e4/e4 individuals, it ranged from 0% to 23% in those entering the study at age 60–64 years, 9% to 35% in those entering at 65–69 years, and 19% to 38% in those entering at 70–75 years.
Lifetime risk was more consistent across the two samples in which it could be estimated, and did not vary as much with age, ranging from 31% to 40% for those with APOE-e4/e4."
Here is the whole article: As far as CV risk from 4/4 it is supposed to be slightly increased due to higher LDL and TG levels. The very early onset heart disease in the late 30s and early 40s is more typical of other inherited dyslipidemias, such as familial hypercholesterolemia.
JAMA. 2007 Sep 19;298(11):1300-11.
Association of apolipoprotein E genotypes with lipid levels and coronary risk.
Bennet AM1, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J.
Author information
1
Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
Abstract
CONTEXT:
Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases.
OBJECTIVE:
To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk.
DATA SOURCES:
We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies.
STUDY SELECTION:
Eighty-two studies of lipid levels (86,067 healthy participants) and 121 studies of coronary outcomes (37,850 cases and 82,727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes.
DATA EXTRACTION:
Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators.
RESULTS:
In the most extreme comparison, people with the epsilon2/epsilon2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the epsilon4/epsilon4 genotype. There were approximately linear relationships of apoE genotypes (when ordered epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon3, epsilon3/epsilon4, epsilon4/epsilon4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the epsilon2/epsilon2 genotype. Compared with epsilon3/epsilon3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in epsilon2 carriers and was 1.06 (95% CI, 0.99-1.13) in epsilon4 carriers.
CONCLUSIONS:
There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the epsilon3/epsilon3 genotype, epsilon2 carriers have a 20% lower risk of coronary heart disease and epsilon4 carriers have a slightly higher risk.
I am really glad to see that those really really high risks previously reported are not holding up in the large population studies.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
Corder EH1, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA.
Author information
1
Department of Medicine, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710.
Abstract
The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80." (italics are mine)
In large population studies it is more like 30%:
"Five-year risk was highly variable across the four samples within each group; for APOE-e4/e4 individuals, it ranged from 0% to 23% in those entering the study at age 60–64 years, 9% to 35% in those entering at 65–69 years, and 19% to 38% in those entering at 70–75 years.
Lifetime risk was more consistent across the two samples in which it could be estimated, and did not vary as much with age, ranging from 31% to 40% for those with APOE-e4/e4."
Here is the whole article: As far as CV risk from 4/4 it is supposed to be slightly increased due to higher LDL and TG levels. The very early onset heart disease in the late 30s and early 40s is more typical of other inherited dyslipidemias, such as familial hypercholesterolemia.
JAMA. 2007 Sep 19;298(11):1300-11.
Association of apolipoprotein E genotypes with lipid levels and coronary risk.
Bennet AM1, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J.
Author information
1
Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
Abstract
CONTEXT:
Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases.
OBJECTIVE:
To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk.
DATA SOURCES:
We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies.
STUDY SELECTION:
Eighty-two studies of lipid levels (86,067 healthy participants) and 121 studies of coronary outcomes (37,850 cases and 82,727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes.
DATA EXTRACTION:
Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators.
RESULTS:
In the most extreme comparison, people with the epsilon2/epsilon2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the epsilon4/epsilon4 genotype. There were approximately linear relationships of apoE genotypes (when ordered epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon3, epsilon3/epsilon4, epsilon4/epsilon4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the epsilon2/epsilon2 genotype. Compared with epsilon3/epsilon3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in epsilon2 carriers and was 1.06 (95% CI, 0.99-1.13) in epsilon4 carriers.
CONCLUSIONS:
There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the epsilon3/epsilon3 genotype, epsilon2 carriers have a 20% lower risk of coronary heart disease and epsilon4 carriers have a slightly higher risk.
I am really glad to see that those really really high risks previously reported are not holding up in the large population studies.
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Re: "Lifetime risk for APOE4/4 carriers is 30% because they'll likely die from heart disease" - is this research outdate
Thanks for the info @karolena
The conclusion is, it might happen or it might not. No one really knows if it’ll happen to you
The remedy is to make sensible life choices but above all enjoy the life you have now to the full. The chances are, it might probably never happen to you
The conclusion is, it might happen or it might not. No one really knows if it’ll happen to you
The remedy is to make sensible life choices but above all enjoy the life you have now to the full. The chances are, it might probably never happen to you
Re: "Lifetime risk for APOE4/4 carriers is 30% because they'll likely die from heart disease" - is this research outdate
And here I am at age 59 in the 99th percentile for coronary calcium for women my age. But my LDL and TG have always been fine (with one exception, when I was pigging out on coconut products). I believe my issues have been inflammation from longstanding mold toxicity and gut dysbiosis. But per my last coronary calcium scan, my coronary artery disease is stable due to the interventions I’m doing. I don’t plan on dying from CVD. Or from dementia.
ApoE 4/4 - When I was in 7th grade, my fellow students in history class called me "The Brain" because I had such a memory for detail. I excelled at memorization and aced tests. This childhood memory helps me cope!
Re: "Lifetime risk for APOE4/4 carriers is 30% because they'll likely die from heart disease" - is this research outdate
Sometimes I can absorb data like this objectively and scientifically. Sometimes my first response is a wave a dread and worry. Depends on the day. My calcium score was zero - which was reassuring. But I have had close relatives have early life heart attacks too. I try to use statements like this to our advantage - to stress the importance and urgency of aggressive of research trials.
As for these specific statistics, not everyone will live into their 60s, 70s, and 80s for a whole range of reasons. Car accidents. Cancer. Whatever. Not all those 4/4s who don't reach these ages died from CVD. I think that's a weakness in their argument. Put another way, if everyone who had a heart attack in their 40's had one or two E4 alleles I think society would be paying it far more attention. It would be the very first thing cardiologists would ask about and test for. So, yes, the fact the not everyone lives into their 6s, 70s, or 80s does explain the apparently contradictory statistics but not all of these early deaths are from 4/4-induced heart attacks.
As for these specific statistics, not everyone will live into their 60s, 70s, and 80s for a whole range of reasons. Car accidents. Cancer. Whatever. Not all those 4/4s who don't reach these ages died from CVD. I think that's a weakness in their argument. Put another way, if everyone who had a heart attack in their 40's had one or two E4 alleles I think society would be paying it far more attention. It would be the very first thing cardiologists would ask about and test for. So, yes, the fact the not everyone lives into their 6s, 70s, or 80s does explain the apparently contradictory statistics but not all of these early deaths are from 4/4-induced heart attacks.
