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apo e4

Allelic form of apo E Structure: - Arg :site R112 - Met :site M125 - Arg :site R158 Pathology: - associated with 50% of familial late-onset Alzheimer's disease (AD) - each apo-E4 allele confers a 3-4-fold increased risk of AD [7,13,14,15] - 2-fold risk of AD among women [6] - only slight increase in risk of AD among men [6] - most patients with AD do not carry the apo E4 allele [7] - 48% overall, 61% in Northern Europe [10] - cortical thickness of the left entorhinal cortex is lowest in children with the apoE4 allele < apoE3 < apoE2 [11] - apo E4 may also be a risk factor for amyloid angiopathy, independent of AD [3] - the apo E4 allele is associated with a significantly higher amyloid plaque burden than observed with the apo E3 & apo E2 alleles - the higher amyloid plaque burden & risk of AD may related to differential binding of apo E4 to the A4 amyloid peptide or differential processing of A4-bound apo E4 - thus apo E4 appears to enhance A4 deposition in the brain, especially A4/40 by diminishing A4 clearance [4]. - the burden of neurofibrillary tangles is allegedly not as sensitive to the apo E4 allele as the burden of amyloid plaques - apo E4 may also carry a 4-fold higher risk of cardiovascular disease [5] - cognitive impairment in patients with early Parkinson's disease & the apoE4 allele may be mitigated by exercise [12] Laboratory: - apolipoprotein E4 in blood

Properties

GENERAL: apolipoprotein E RELATED: apolipoprotein E genotype apolipoprotein-E gene cerebral amyloid angiopathy Alzheimer's disease SIZE: entity length = 317 aa MW = 36 kD COMPARTMENT: extracellular compartment FORM: apo e4 MOTIF: signal sequence {1-18} consensus repeat {80-101} consensus repeat {102-123} consensus repeat {124-145} consensus repeat {146-167} Ser phosphorylation site {S147} LDL receptor binding {158-168} MOTIF: binding site SITE: 162-165 FOR-BINDING-OF: heparin consensus repeat {168-189} consensus repeat {190-211} consensus repeat {212-233} Thr glycosylation site {T212} binding site SITE: 229-236 FOR-BINDING-OF: heparin consensus repeat {234-255} Thr glycosylation site {T307} Ser glycosylation site {S308} SECRETED-BY: hepatocyte astrocyte WITHIN: central nervous system COMPONENT-OF: chylomicron MISC-INFO: CONCENTRATION 2-6 MG/DL

References

  1. Mendelian Inheritance in Man (1990) MIM#107741
  2. Strittmatter WJ et al Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81 PMID: 8446617
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 2352
  4. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  5. Rutlege JC, UC Davis Dept of Medicine Grand Rounds, Aug 2, 2007
  6. Altmann A et al Sex modifies the APOE-related risk of developing Alzheimer disease. Annals of Neurology. April 14, 2014 http://onlinelibrary.wiley.com/doi/10.1002/ana.24135/abstract
  7. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  8. Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009 May;10(5):333-44. Review. PMID: 19339974 Free PMC Article
  9. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013 Feb;9(2):106-18. PMID: 23296339 Free PMC Article
  10. Ward A, Crean S, Mercaldi CJ et al Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):1-17. Review. PMID: 22179327 Free Article
  11. Shaw P, Lerch JP, Pruessner JC et al Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PMID: 17509484
  12. Kim R, Park S, Yoo D et al. on Association of physical activity and APOE genotype with longitudinal cognitive change in early PD. Neurology 2021 Mar 31; [e-pub] PMID: 33790041 https://n.neurology.org/content/early/2021/03/31/WNL.0000000000011852
  13. Lane-Donovan C, Herz J. ApoE, ApoE Receptors, and the synapse in Alzheimer's disease. Trends Endocrinol Metab. 2017;28(4):273-284 PMID: 28057414 PMCID: PMC5366078Free PMC article https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(16)30170-9
  14. Uddin MS, Kabir MT, Al Mamun A et al. APOE and Alzheimer's disease: evidence mounts that targeting APOE4 may combat Alzheimer's pathogenesis. Mol Neurobiol. 2019;56(4):2450-2465 PMID: 30032423 https://link.springer.com/article/10.1007/s12035-018-1237-z
  15. Zhao N, Liu CC, Qiao W, et al. Apolipoprotein E, receptors, and modulation of Alzheimer's disease. Biol Psychiatry. 2018;83(4):347-357 PMID: 28434655 PMCID: PMC5599322Free PMC article https://www.biologicalpsychiatryjournal.com/article/S0006-3223(17)31358-6/fulltext

Databases & Figures

OMIM correlations MORBIDMAP 107741 UniProt P02649 Pfam PF01442 Entrez Gene 348 Kegg hsa:348 ApoE allele frequencies