APOE is the primary cholesterol carrier in the brain and plays a major role in packaging and transporting LDL cholesterol throughout the body.
APOE—The Single Most Important Gene for Longevity
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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
Though the genetic contribution to lifespan may be relatively minor, are there specific genes that have been associated with longevity? The leading method for complex genetic mapping is called genome-wide association analysis, which is essentially a massive game of Go Fish, comparing a million or more letters of DNA between groups of similar people, looking for a match. So, for example, if you stretch out the DNA of hundreds of centenarians, and compare those sequences to that of noncentenarians, is there a DNA letter at a certain position that centenarians share disproportionately? The problem is that hundreds of centenarians are all researchers are typically able to find.
Extremely long-lived individuals, such as centenarians, comprise only a tiny fraction of the population, on the order of one in 10,000 or so. As you can imagine, the more people you have in a genome-wide association study, the more likely you’ll be able to find a needle in the DNA haystack. With so few people available to study for extreme longevity research, it becomes much more difficult to identify trends. Some researchers have tried solving this problem by lowering the age requirement to 85. Then you can enroll thousands into your study, but making it to 90 is not the same as making it to 100. In fact, statistically, it’s as hard to get from 90 to 100 as it is to get to 90 in the first place. So, by using younger age brackets, we may miss out on discovering some secret centenarian sauce.
That brings us to the largest genome-wide association study of lifespan to date, based on data from a million people. How were researchers able to include so many subjects? By correlating the genetic fingerprints of half a million middle-aged individuals with the ages of both of their parents, they were able to find a dozen DNA regions linked to lifespan that appeared to account for up to five years difference between individuals. Twelve DNA markers is actually a surprisingly low number, compared to height, for example, which is determined by more than 400 different DNA spots. (Although, unlike lifespan, height is highly heritable.)
A review of all the genome-wide association studies for longevity put together only found one gene confirmed in multiple independent meta-analyses: the “Alzheimer’s gene” ApoE. Beyond just determining lower or higher dementia risk, ApoE is the single most important gene when it comes to longevity (though again, that’s not necessarily saying much). ApoE codes for a protein that is 299 amino acids long, called apolipoprotein E. Some people have ApoE genes that code for the protein with the amino acid cysteine at positions 112 and 158 (known as the ApoE2 variant), while others have an arginine in those spots (the ApoE4 variant of the protein). And ApoE3 is the third major type of variant, which has one of each. Having genes that code for the ApoE4 variant increases your risk of cognitive decline, full-blown Alzheimer’s disease, and premature death.
If you have one copy of the ApoE4 gene from your mother or father, your odds of becoming a centenarian are cut roughly in half, and if you have ApoE4 genes from both parents, your centenarian odds drop by more than 80 percent. What does this protein do to have such a powerful impact on our health and longevity?
ApoE is the primary cholesterol carrier in the brain, and plays a major role packaging and transporting LDL cholesterol throughout the body. The LDL cholesterol level in those with ApoE4 genes averages more than 40 points higher than those with ApoE2 genes, gunking up the arteries that feed both the heart and the brain. (LDL cholesterol is a risk factor not just for heart disease, but Alzheimer’s disease as well.) Switch people to a diet lower in animal fat and cholesterol, and those LDL differences can disappear—nearly a 60-point drop in LDL. The difference in cholesterol level caused by the different ApoE genes can simply disappear if you eat a diet low enough in saturated fat and cholesterol. So, diet can trump genetics.
This may explain the so-called Nigerian paradox. If you inherit one ApoE4 gene, your risk of getting Alzheimer’s may triple, and if you get ApoE4 genes from both parents—which occurs in about one in 50 people in the U.S.—you might end up with nine times the risk. The highest frequency of the ApoE4 variant occurs in Nigerians, but they also have some of the lowest rates of Alzheimer’s disease. How can that be? The population with the highest rate of the “Alzheimer’s gene” has one of the lowest rates of Alzheimer’s disease! This contradiction may be explained by Nigerians’ extremely low blood-cholesterol levels, thanks to a diet low in animal fat and consisting mainly of grains and vegetables.
Humans may have evolved to maintain an LDL level of about 25 mg/dL, but the average in the Western world is approximately 120 mg/dL. It’s no wonder that heart disease is the leading cause of death in high income countries, and Alzheimer’s disease, according to the World Health Organization, is killer #2.
Too often, doctors and patients have a fatalistic approach to chronic degenerative diseases, and Alzheimer’s is no exception. “It’s all in your genes,” they say, “and what will happen will happen.” But research shows that although you might have been dealt some poor genetic cards, you may be able to reshuffle the deck with diet.
Please consider volunteering to help out on the site.
- Milman S, Barzilai N. Dissecting the mechanisms underlying unusually successful human health span and life span. Cold Spring Harb Perspect Med. 2015;6(1):a025098.
- van den Berg N. Family matters in unraveling human longevity. Aging (Albany NY). 2020;12(22):22354-22355.
- Uffelmann E, Huang QQ, Munung NS, et al. Genome-wide association studies. Nat Rev Methods Primers. 2021;1(59):1-21.
- Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20(8):467-484.
- Broer L, van Duijn CM. Gwas and meta-analysis in aging/longevity. Adv Exp Med Biol. 2015;847:107-125.
- Zhang ZD, Milman S, Lin JR, et al. Genetics of extreme human longevity to guide drug discovery for healthy ageing. Nat Metab. 2020;2(8):663-672.
- Timmers PR, Mounier N, Lall K, et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. Elife. 2019;8:e39856.
- Wood AR, Esko T, Yang J, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014;46(11):1173-1186.
- Deelen J, Evans DS, Arking DE, et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat Commun. 2019;10(1):3669.
- Rea IM, Dellet M, Mills KI, ACUME2 Project. Living long and ageing well: is epigenomics the missing link between nature and nurture? Biogerontology. 2016;17(1):33-54.
- Hauser PS, Narayanaswami V, Ryan RO. Apolipoprotein E: from lipid transport to neurobiology. Prog Lipid Res. 2011;50(1):62-74.
- Sebastiani P, Gurinovich A, Nygaard M, et al. Apoe alleles and extreme human longevity. J Gerontol A Biol Sci Med Sci. 2019;74(1):44-51.
- Garatachea N, Marín PJ, Santos-Lozano A, Sanchis-Gomar F, Emanuele E, Lucia A. The ApoE gene is related with exceptional longevity: a systematic review and meta-analysis. Rejuvenation Res. 2015;18(1):3-13.
- Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R. The role of apoe and trem2 in alzheimer’s disease-current understanding and perspectives. Int J Mol Sci. 2018;20(1):81.
- Abdullah MMH, Vazquez-Vidal I, Baer DJ, House JD, Jones PJH, Desmarchelier C. Common genetic variations involved in the inter-individual variability of circulating cholesterol concentrations in response to diets: a narrative review of recent evidence. Nutrients. 2021;13(2):695.
- Bennet AM, Di Angelantonio E, Ye Z, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298(11):1300-1311.
- Sáiz-Vazquez O, Puente-Martínez A, Ubillos-Landa S, Pacheco-Bonrostro J, Santabárbara J. Cholesterol and alzheimer’s disease risk: a meta-meta-analysis. Brain Sci. 2020;10(6):386.
- Tikkanen MJ, Huttunen JK, Ehnholm C, Pietinen P. Apolipoprotein E4 homozygosity predisposes to serum cholesterol elevation during high fat diet. Arteriosclerosis. 1990;10(2):285-288.
- Miettinen TA, Gylling H, Vanhanen H, Ollus A. Cholesterol absorption, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes. Arterioscler Thromb. 1992;12(9):1044-1052.
- Osuntokun BO, Sahota A, Ogunniyi AO, et al. Lack of an association between apolipoprotein E epsilon 4 and Alzheimer’s disease in elderly Nigerians. Ann Neurol. 1995;38(3):463-465.
- Roses AD, Saunders AM. APOE is a major susceptibility gene for Alzheimer’s disease. Curr Opin Biotechnol. 1994;5(6):663-667.
- Sepehrnia B, Kamboh MI, Adams-Campbell LL, et al. Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks. Am J Hum Genet. 1989;45(4):586-591.
- Osuntokun BO, Hendrie HC, Ogunniyi AO, et al. Cross-cultural studies in Alzheimer’s disease. Ethn Dis. 1992;2(4):352-357.
- Hendrie HC, Murrell J, Gao S, Unverzagt FW, Ogunniyi A, Hall KS. International studies in dementia with particular emphasis on populations of African origin. Alzheimer Dis Assoc Disord. 2006;20(3 Suppl 2):S42-46.
- Laufs U, Dent R, Kostenuik PJ, Toth PP, Catapano AL, Chapman MJ. Why is hypercholesterolaemia so prevalent? A view from evolutionary medicine. Eur Heart J. 2019;40(33):2825-2830.
- The top 10 causes of death. WHO. Dec 2020.
- Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002;137(3):149-155.
Motion graphics by Avo Media
Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
Though the genetic contribution to lifespan may be relatively minor, are there specific genes that have been associated with longevity? The leading method for complex genetic mapping is called genome-wide association analysis, which is essentially a massive game of Go Fish, comparing a million or more letters of DNA between groups of similar people, looking for a match. So, for example, if you stretch out the DNA of hundreds of centenarians, and compare those sequences to that of noncentenarians, is there a DNA letter at a certain position that centenarians share disproportionately? The problem is that hundreds of centenarians are all researchers are typically able to find.
Extremely long-lived individuals, such as centenarians, comprise only a tiny fraction of the population, on the order of one in 10,000 or so. As you can imagine, the more people you have in a genome-wide association study, the more likely you’ll be able to find a needle in the DNA haystack. With so few people available to study for extreme longevity research, it becomes much more difficult to identify trends. Some researchers have tried solving this problem by lowering the age requirement to 85. Then you can enroll thousands into your study, but making it to 90 is not the same as making it to 100. In fact, statistically, it’s as hard to get from 90 to 100 as it is to get to 90 in the first place. So, by using younger age brackets, we may miss out on discovering some secret centenarian sauce.
That brings us to the largest genome-wide association study of lifespan to date, based on data from a million people. How were researchers able to include so many subjects? By correlating the genetic fingerprints of half a million middle-aged individuals with the ages of both of their parents, they were able to find a dozen DNA regions linked to lifespan that appeared to account for up to five years difference between individuals. Twelve DNA markers is actually a surprisingly low number, compared to height, for example, which is determined by more than 400 different DNA spots. (Although, unlike lifespan, height is highly heritable.)
A review of all the genome-wide association studies for longevity put together only found one gene confirmed in multiple independent meta-analyses: the “Alzheimer’s gene” ApoE. Beyond just determining lower or higher dementia risk, ApoE is the single most important gene when it comes to longevity (though again, that’s not necessarily saying much). ApoE codes for a protein that is 299 amino acids long, called apolipoprotein E. Some people have ApoE genes that code for the protein with the amino acid cysteine at positions 112 and 158 (known as the ApoE2 variant), while others have an arginine in those spots (the ApoE4 variant of the protein). And ApoE3 is the third major type of variant, which has one of each. Having genes that code for the ApoE4 variant increases your risk of cognitive decline, full-blown Alzheimer’s disease, and premature death.
If you have one copy of the ApoE4 gene from your mother or father, your odds of becoming a centenarian are cut roughly in half, and if you have ApoE4 genes from both parents, your centenarian odds drop by more than 80 percent. What does this protein do to have such a powerful impact on our health and longevity?
ApoE is the primary cholesterol carrier in the brain, and plays a major role packaging and transporting LDL cholesterol throughout the body. The LDL cholesterol level in those with ApoE4 genes averages more than 40 points higher than those with ApoE2 genes, gunking up the arteries that feed both the heart and the brain. (LDL cholesterol is a risk factor not just for heart disease, but Alzheimer’s disease as well.) Switch people to a diet lower in animal fat and cholesterol, and those LDL differences can disappear—nearly a 60-point drop in LDL. The difference in cholesterol level caused by the different ApoE genes can simply disappear if you eat a diet low enough in saturated fat and cholesterol. So, diet can trump genetics.
This may explain the so-called Nigerian paradox. If you inherit one ApoE4 gene, your risk of getting Alzheimer’s may triple, and if you get ApoE4 genes from both parents—which occurs in about one in 50 people in the U.S.—you might end up with nine times the risk. The highest frequency of the ApoE4 variant occurs in Nigerians, but they also have some of the lowest rates of Alzheimer’s disease. How can that be? The population with the highest rate of the “Alzheimer’s gene” has one of the lowest rates of Alzheimer’s disease! This contradiction may be explained by Nigerians’ extremely low blood-cholesterol levels, thanks to a diet low in animal fat and consisting mainly of grains and vegetables.
Humans may have evolved to maintain an LDL level of about 25 mg/dL, but the average in the Western world is approximately 120 mg/dL. It’s no wonder that heart disease is the leading cause of death in high income countries, and Alzheimer’s disease, according to the World Health Organization, is killer #2.
Too often, doctors and patients have a fatalistic approach to chronic degenerative diseases, and Alzheimer’s is no exception. “It’s all in your genes,” they say, “and what will happen will happen.” But research shows that although you might have been dealt some poor genetic cards, you may be able to reshuffle the deck with diet.
Please consider volunteering to help out on the site.
- Milman S, Barzilai N. Dissecting the mechanisms underlying unusually successful human health span and life span. Cold Spring Harb Perspect Med. 2015;6(1):a025098.
- van den Berg N. Family matters in unraveling human longevity. Aging (Albany NY). 2020;12(22):22354-22355.
- Uffelmann E, Huang QQ, Munung NS, et al. Genome-wide association studies. Nat Rev Methods Primers. 2021;1(59):1-21.
- Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20(8):467-484.
- Broer L, van Duijn CM. Gwas and meta-analysis in aging/longevity. Adv Exp Med Biol. 2015;847:107-125.
- Zhang ZD, Milman S, Lin JR, et al. Genetics of extreme human longevity to guide drug discovery for healthy ageing. Nat Metab. 2020;2(8):663-672.
- Timmers PR, Mounier N, Lall K, et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. Elife. 2019;8:e39856.
- Wood AR, Esko T, Yang J, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014;46(11):1173-1186.
- Deelen J, Evans DS, Arking DE, et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat Commun. 2019;10(1):3669.
- Rea IM, Dellet M, Mills KI, ACUME2 Project. Living long and ageing well: is epigenomics the missing link between nature and nurture? Biogerontology. 2016;17(1):33-54.
- Hauser PS, Narayanaswami V, Ryan RO. Apolipoprotein E: from lipid transport to neurobiology. Prog Lipid Res. 2011;50(1):62-74.
- Sebastiani P, Gurinovich A, Nygaard M, et al. Apoe alleles and extreme human longevity. J Gerontol A Biol Sci Med Sci. 2019;74(1):44-51.
- Garatachea N, Marín PJ, Santos-Lozano A, Sanchis-Gomar F, Emanuele E, Lucia A. The ApoE gene is related with exceptional longevity: a systematic review and meta-analysis. Rejuvenation Res. 2015;18(1):3-13.
- Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R. The role of apoe and trem2 in alzheimer’s disease-current understanding and perspectives. Int J Mol Sci. 2018;20(1):81.
- Abdullah MMH, Vazquez-Vidal I, Baer DJ, House JD, Jones PJH, Desmarchelier C. Common genetic variations involved in the inter-individual variability of circulating cholesterol concentrations in response to diets: a narrative review of recent evidence. Nutrients. 2021;13(2):695.
- Bennet AM, Di Angelantonio E, Ye Z, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298(11):1300-1311.
- Sáiz-Vazquez O, Puente-Martínez A, Ubillos-Landa S, Pacheco-Bonrostro J, Santabárbara J. Cholesterol and alzheimer’s disease risk: a meta-meta-analysis. Brain Sci. 2020;10(6):386.
- Tikkanen MJ, Huttunen JK, Ehnholm C, Pietinen P. Apolipoprotein E4 homozygosity predisposes to serum cholesterol elevation during high fat diet. Arteriosclerosis. 1990;10(2):285-288.
- Miettinen TA, Gylling H, Vanhanen H, Ollus A. Cholesterol absorption, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes. Arterioscler Thromb. 1992;12(9):1044-1052.
- Osuntokun BO, Sahota A, Ogunniyi AO, et al. Lack of an association between apolipoprotein E epsilon 4 and Alzheimer’s disease in elderly Nigerians. Ann Neurol. 1995;38(3):463-465.
- Roses AD, Saunders AM. APOE is a major susceptibility gene for Alzheimer’s disease. Curr Opin Biotechnol. 1994;5(6):663-667.
- Sepehrnia B, Kamboh MI, Adams-Campbell LL, et al. Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks. Am J Hum Genet. 1989;45(4):586-591.
- Osuntokun BO, Hendrie HC, Ogunniyi AO, et al. Cross-cultural studies in Alzheimer’s disease. Ethn Dis. 1992;2(4):352-357.
- Hendrie HC, Murrell J, Gao S, Unverzagt FW, Ogunniyi A, Hall KS. International studies in dementia with particular emphasis on populations of African origin. Alzheimer Dis Assoc Disord. 2006;20(3 Suppl 2):S42-46.
- Laufs U, Dent R, Kostenuik PJ, Toth PP, Catapano AL, Chapman MJ. Why is hypercholesterolaemia so prevalent? A view from evolutionary medicine. Eur Heart J. 2019;40(33):2825-2830.
- The top 10 causes of death. WHO. Dec 2020.
- Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002;137(3):149-155.
Motion graphics by Avo Media
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APOE—The Single Most Important Gene for Longevity
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