Skip to main content

Advertisement

SpringerLink
Log in

The Neurobiology and Age-Related Prevalence of the ε4 Allele of Apolipoprotein E in Alzheimer’s Disease Cohorts

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterised by amyloid beta (Aβ) plaques and tau neurofibrillary tangles in the brain. Human apolipoprotein E (ApoE) is a lipid transport protein coded by the polymorphic APOE gene, with three major alleles: ε2, ε3 and ε4. After age, the ε4 allele is the greatest risk factor for developing sporadic AD, conferring an increased risk of 3–4 and 8–12 times for one or two copies of the allele, respectively. This risk is reported to vary by demographic factors including sex, ethnicity and geography. In order to understand the risk of ApoE ε4 in relation to age, the primary risk factor for developing AD, we need to understand how the prevalence of APOE genotypes changes with age. Here, we present the first data on age-related prevalence of APOE ε4 in AD in three AD cohorts in Australia and the USA. There is a significant association between age and ε4 prevalence, particularly for ε4 homozygotes, such that as age increases the prevalence of ε4 decreases. Further studies on a random, population-based sample of the population are needed to provide more generalizable data, particularly in the >90-year-old age group.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • ABS (2014). Australian Bureau of Statistics. Causes of Death, Australia 2012. ABS cat. no. 3303.0. Canberra:ABS.

  • ALZGENE (2010). Meta-analysis of all published AD association studies (case-control only) APOE_E2/3/4. Available from http://www.alzgene.org/meta.asp?geneID=83. Date accessed: 9 March 2016.

  • Bang OY, Kwak YT, Joo IS, Huh K (2003) Important link between dementia subtype and apolipoprotein E: a meta-analysis. Yonsei Med J 44:401–413

    Article  CAS  PubMed  Google Scholar 

  • Castellano JM, Kim J, Stewart FR, et al. (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3:89ra57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Li Q, Wang J (2011) Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A 108:14813–14818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corder EH, Saunders AM, Risch NJ, et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7:180–184

    Article  CAS  PubMed  Google Scholar 

  • Corder EH, Saunders AM, Strittmatter WJ, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  CAS  PubMed  Google Scholar 

  • Cramer PE, Cirrito JR, Wesson DW, et al. (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335:1503–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Das HK, McPherson J, Bruns GA, Karathanasis SK, Breslow JL (1985) Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. J Biol Chem 260:6240–6247

    CAS  PubMed  Google Scholar 

  • Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8:1–21

    Article  CAS  PubMed  Google Scholar 

  • Deloukas P, Kanoni S, Willenborg C, et al. (2013) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45:25–33

    Article  CAS  PubMed  Google Scholar 

  • Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155:487–495

    Article  PubMed  Google Scholar 

  • Eisenberg DT, Kuzawa CW, Hayes MG (2010) Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol 143:100–111

    Article  PubMed  Google Scholar 

  • El-Lebedy D, Raslan HM, Mohammed AM (2016) Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol 15:12

    Article  PubMed  PubMed Central  Google Scholar 

  • Ellis KA, Bush AI, Darby D, et al. (2009) The Australian imaging, biomarkers and lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. Int Psychogeriatr 21:672–687

    Article  PubMed  Google Scholar 

  • Elosua R, Ordovas JM, Cupples LA, et al. (2004) Association of APOE genotype with carotid atherosclerosis in men and women: the Framingham Heart Study. J Lipid Res 45:1868–1875

    Article  CAS  PubMed  Google Scholar 

  • Farrer LA, Cupples LA, Haines JL, et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis APOE and Alzheimer Disease Meta Analysis Consortium JAMA 278:1349–1356

    CAS  PubMed  Google Scholar 

  • Farrer LA, Cupples LA, van Duijn CM, et al. (1995) Apolipoprotein E genotype in patients with Alzheimer’s disease: implications for the risk of dementia among relatives. Ann Neurol 38:797–808

    Article  CAS  PubMed  Google Scholar 

  • Frieden C, Garai K (2013) Concerning the structure of apoE. Protein Sci 22:1820–1825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garai K, Verghese PB, Baban B, Holtzman DM, Frieden C (2014) The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry 53:6323–6331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giau VV, Bagyinszky E, An SSA, Kim SY (2015) Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat 11:1723–1737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Golabek AA, Soto C, Vogel T, Wisniewski T (1996) The interaction between apolipoprotein E and Alzheimer's amyloid beta-peptide is dependent on beta-peptide conformation. J Biol Chem 271:10602–10606

    Article  CAS  PubMed  Google Scholar 

  • Havel RJ, Kane JP (1973) Primary dysbetalipoproteinemia: predominance of a specific apoprotein species in triglyceride-rich lipoproteins. Proc Natl Acad Sci U S A 70:2015–2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holtzman DM, Bales KR, Tenkova T, et al. (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 97:2892–2897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine 2:a006312

    PubMed  PubMed Central  Google Scholar 

  • Huang Y (2010) Mechanisms linking apolipoprotein E isoforms with cardiovascular and neurological diseases. Curr Opin Lipidol 21:337–345

    Article  CAS  PubMed  Google Scholar 

  • Innerarity TL, Friedlander EJ, Rall SC, Weisgraber KH, Mahley RW (1983) The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments Journal of Biological Chemistry 258:12341–12347

    CAS  PubMed  Google Scholar 

  • Jiang Q, Lee CYD, Mandrekar S, et al. (2008) ApoE promotes the proteolytic degradation of Aβ. Neuron 58:681–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keene CD, Cudaback E, Li X, Montine KS, Montine TJ (2011) Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease. Curr Opin Neurobiol 21:920–928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim J, Jiang H, Park S, et al. (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci 31:18007–18012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim J, Yoon H, Basak J, Kim J (2014) Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Mol Cells 37:767–776

    Article  PubMed  PubMed Central  Google Scholar 

  • LaDu MJ, Falduto MT, Manelli AM, Reardon CA, Getz GS, Frail DE (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269:23403–23406

    CAS  PubMed  Google Scholar 

  • Lim, Y. Y., Laws, S. M., Villemagne, V. L., et al. (2016). A beta-related memory decline in APOE epsilon4 noncarriers: implications for Alzheimer disease. Neurology.

  • Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Louhija J, Miettinen HE, Kontula K, Tikkanen MJ, Miettinen TA, Tilvis RS (1994) Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians. Arterioscler Thromb 14:1084–1089

    Article  CAS  PubMed  Google Scholar 

  • Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537

    Article  CAS  PubMed  Google Scholar 

  • Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A 103:5644–5651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50:S183–S188

    Article  PubMed  PubMed Central  Google Scholar 

  • Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82:4245–4249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayila W, Fang MW, Cheng ZH, Qiu CC (2005) Polymorphism of apolipoprotein E gene and natural longevity in the Xinjiang Uighur people: an association study. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22:462–463

    CAS  PubMed  Google Scholar 

  • Mohamad, E. H., Antoine, P., Amouyel, P., Lambert, J. C., Pasquier, F. and Kapogiannis, D. (2016). Apolipoprotein E (APOE) epsilon4 and episodic memory decline in Alzheimer’s disease: A review. Ageing Res Rev.

  • Mozaffarian D, Benjamin EJ, Go AS, et al. (2016) Executive Summary: Heart Disease and Stroke Statistics—2016 update: a report from the American Heart Association. Circulation 133:447–454

    Article  PubMed  Google Scholar 

  • Nolte RT, Atkinson D (1992) Conformational analysis of apolipoprotein A-I and E-3 based on primary sequence and circular dichroism. Biophys J 63:1221–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • OMIM (2016). Online ‘Mendelian Inheritance in Man’ (OMIM) Apolipoprotein E; APOE -107741. Available from https://omim.org/entry/107741. Date accessed: 9 March 2016.

  • Pietrzak RH, Lim YY, Ames D, et al. (2015) Trajectories of memory decline in preclinical Alzheimer's disease: results from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of ageing. Neurobiol Aging 36:1231–1238

    Article  CAS  PubMed  Google Scholar 

  • Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9:63–75.e62

    Article  PubMed  Google Scholar 

  • R Core Team (2015) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/.

  • Ryu S, Atzmon G, Barzilai N, Raghavachari N, Suh Y (2016) Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mech Ageing Dev 155:7–9

    Article  CAS  PubMed  Google Scholar 

  • Schachter F, Faure-Delanef L, Guenot F, et al. (1994) Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6:29–32

    Article  CAS  PubMed  Google Scholar 

  • Shore VG, Shore B (1973) Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components Biochemistry 12:502–507

    CAS  PubMed  Google Scholar 

  • Singh PP, Singh M, Mastana SS (2006) APOE distribution in world populations with new data from India and the UK. Ann Hum Biol 33:279–308

    Article  CAS  PubMed  Google Scholar 

  • Sparrow JT, Sparrow DA, Fernando G, Culwell AR, Kovar M, Gotto AM (1992) Apolipoprotein E: phospholipid binding studies with synthetic peptides from the carboxyl terminus. Biochemistry 31:1065–1068

    Article  CAS  PubMed  Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Huang DY, et al. (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90:8098–8102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sweet RA, Seltman H, Emanuel JE, et al. (2012) Effect of Alzheimer’s disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study. Am J Psychiatry 169:954–962

    Article  PubMed  PubMed Central  Google Scholar 

  • Tai LM, Ghura S, Koster KP, et al. (2015) APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 133:465–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Todd S, Barr S, Roberts M, Passmore AP (2013) Survival in dementia and predictors of mortality: a review. Int J Geriatr Psychiatry 28:1109–1124

    PubMed  Google Scholar 

  • Tombaugh TN, McIntyre NJ (1992) The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 40:922–935

  • Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Visvikis-Siest S, Marteau JB (2006) Genetic variants predisposing to cardiovascular disease. Curr Opin Lipidol 17:139–151

    Article  CAS  PubMed  Google Scholar 

  • Weisgraber KH, Innerarity TL, Mahley RW (1982) Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem 257:2518–2521

    CAS  PubMed  Google Scholar 

  • Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO (2015) White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol 25:63–78

    Article  PubMed  Google Scholar 

  • WHO (2011). Global Atlas on cardiovascular disease prevention and control. Edited by Mendis S, Puska P and Norrving B. World Health Organisation, Geneva. Available from: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/.

  • Wilson C, Wardell M, Weisgraber K, Mahley R, Agard D (1991) Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science 252:1817–1822

    Article  CAS  PubMed  Google Scholar 

  • Zannis VI, Kardassis D, Zanni EE (1993) Genetic mutations affecting human lipoproteins, their receptors, and their enzymes. Adv Hum Genet 21:145–319

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Simone Wilk, Chris Fowler and James Doecke for assistance with data retrieval; Oliver Thomas for advice on statistical analysis and Laura Cortes Castrillon for assistance with PyMol. ALH is funded by a Dementia Research Development Fellowship (APP1106911); PP is funded by an Australian Postgraduate Award and an International Postgraduate Research Scholarship. We wish to thank ADNI, AIBL and the National Alzheimer’s Coordinating Centre including all investigators, participants and their families. A complete list of principle investigators and funding sources can be found in the Supplementary Material. The Florey Institute acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. University of Melbourne, The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Amy L. Heffernan, Colin L. Masters & Blaine R. Roberts

  2. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia

    Cameron Chidgey

  3. School of Biosciences, University of Melbourne, Parkville, VIC, Australia

    Po Peng

  4. Cooperative Research Centre for Mental Health, Parkville, VIC, Australia

    Blaine R. Roberts

Authors
  1. Amy L. Heffernan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cameron Chidgey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Po Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Colin L. Masters
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Blaine R. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Blaine R. Roberts.

Electronic supplementary material

ESM 1

(DOCX 29 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heffernan, A.L., Chidgey, C., Peng, P. et al. The Neurobiology and Age-Related Prevalence of the ε4 Allele of Apolipoprotein E in Alzheimer’s Disease Cohorts. J Mol Neurosci 60, 316–324 (2016). https://doi.org/10.1007/s12031-016-0804-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-016-0804-x

Keywords

Search

Navigation