Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk for cerebral amyloid angiopathy and age-related cognitive decline during normal ageing.
APOE gene is on chromosome 19. The APOE gene consists of four exons and three introns, totaling 3597 base pairs.
Three alleles - E2, E3, and E4.
E4 is an ancient allele.
E3 increased in frequency in the last 200,000 years.
Estimated Percentages of the U.S. Population with the Six Possible e2, e3 and e4 Pairs of the Apolipoprotein E (APOE) Gene
The human APOE gene exists as three polymorphic alleles—ε2, ε3 and ε4—which have a worldwide frequency of 8.4%, 77.9% and 13.7%, respectively. However, the frequency of the ε4 allele is dramatically increased to ~40% in patients with AD.
E4 allele seems to be good for young people and can mount better inflammatory response to pathogens and other stresses.
E3 seems to be good for older people because it protects against the chronic diseases of ageing.
In environments of high levels of infection, people with with E4 are advantaged.
In environments of low levels of infection, people with with E3 are healthiest and longest lived.
People with E3/E4 genotype are particularly susceptible to diseases caused by a small bacterium chlamydia pnumoniae.
Long ago humans primarily consumed plant foods and E4 allele was better suited. Humans started consuming more animal-based diets and were better served by E3 allele.
Meat eaters who have E4 allele are highly susceptible to cholesterolemia and cardiovascular diseases.
Good Ref. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726719/
ApoE is composed of 299 amino acids and has a molecular mass of ~34 kDa. Differences between the three ApoE isoforms are limited to amino acids 112 and 158, where either cysteine or arginine is present:
ApoE2 (Cys112, Cys158),
ApoE3 (Cys112, Arg158), and
ApoE4 (Arg112, Arg158).
The single amino acid differences at these two positions affect the structure of ApoE isoforms and influence their ability to bind lipids, receptors and Aβ (Amyloyd-β). Human and animal studies clearly indicate that ApoE isoforms differentially affect Aβ aggregation and clearance.
Early-onset familial AD, which typically develops before the age of 65 years and accounts for only a small portion (<1%) of AD cases, is primarily caused by overproduction of Aβ owing to mutations in either the APP gene or genes encoding presenilin 1 (PSEN1) or presenilin 2 (PSEN2).
The majority of AD cases occur late in life (>65 years) and are commonly referred to as late-onset AD (LOAD). Although multiple genetic and environmental risk factors are involved in LOAD pathogenesis, overall impairment in Aβ clearance is probably a major contributor to disease development. Genetically, the ε4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for LOAD.
APOE gene is on chromosome 19. The APOE gene consists of four exons and three introns, totaling 3597 base pairs.
Three alleles - E2, E3, and E4.
E4 is an ancient allele.
E3 increased in frequency in the last 200,000 years.
Estimated Percentages of the U.S. Population with the Six Possible e2, e3 and e4 Pairs of the Apolipoprotein E (APOE) Gene
The human APOE gene exists as three polymorphic alleles—ε2, ε3 and ε4—which have a worldwide frequency of 8.4%, 77.9% and 13.7%, respectively. However, the frequency of the ε4 allele is dramatically increased to ~40% in patients with AD.
| APOE Pair | % | |||
| e2/e2 | 0.5 | |||
| e2/e3 | 11 | |||
| e2/e4 | 2 | |||
| e3/e3 | 61 | |||
| e3/e4 | 23 | |||
| e4/e4 | 2 |
E4 allele seems to be good for young people and can mount better inflammatory response to pathogens and other stresses.
E3 seems to be good for older people because it protects against the chronic diseases of ageing.
In environments of high levels of infection, people with with E4 are advantaged.
In environments of low levels of infection, people with with E3 are healthiest and longest lived.
People with E3/E4 genotype are particularly susceptible to diseases caused by a small bacterium chlamydia pnumoniae.
Long ago humans primarily consumed plant foods and E4 allele was better suited. Humans started consuming more animal-based diets and were better served by E3 allele.
Meat eaters who have E4 allele are highly susceptible to cholesterolemia and cardiovascular diseases.
Good Ref. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726719/
ApoE is composed of 299 amino acids and has a molecular mass of ~34 kDa. Differences between the three ApoE isoforms are limited to amino acids 112 and 158, where either cysteine or arginine is present:
ApoE2 (Cys112, Cys158),
ApoE3 (Cys112, Arg158), and
ApoE4 (Arg112, Arg158).
The single amino acid differences at these two positions affect the structure of ApoE isoforms and influence their ability to bind lipids, receptors and Aβ (Amyloyd-β). Human and animal studies clearly indicate that ApoE isoforms differentially affect Aβ aggregation and clearance.
Early-onset familial AD, which typically develops before the age of 65 years and accounts for only a small portion (<1%) of AD cases, is primarily caused by overproduction of Aβ owing to mutations in either the APP gene or genes encoding presenilin 1 (PSEN1) or presenilin 2 (PSEN2).
The majority of AD cases occur late in life (>65 years) and are commonly referred to as late-onset AD (LOAD). Although multiple genetic and environmental risk factors are involved in LOAD pathogenesis, overall impairment in Aβ clearance is probably a major contributor to disease development. Genetically, the ε4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for LOAD.
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