CoChat
Sign Up
Cited by 4Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

Whole Exome Sequencing Reveals a Novel APOE Mutation in a Patient With Sporadic Early-Onset Alzheimer's Disease

Open access
Bagaria, Jaya, Moon, Yeonsil, Bagyinszky, Eva, Shim, Kyu Hwan, An, Seong Soo A., Kim, SangYun, Han, Seol Heui·2022·Frontiers in Neurology
DOI 10.3389/fneur.2022.899644PMC PMC9226417
Open this paper in CoChat — free account

Abstract

Apolipoprotein (APOE) is implicated and verified as the main risk factor for early-onset Alzheimer's disease (AD). APOE is a protein that binds to lipids and is involved in cholesterol stability. Our paper reports a case of a sporadic early-onset AD (sEOAD) patient of a 54-year-old Korean man, where a novel APOE Leu159Pro heterozygous mutation was revealed upon Whole Exome Sequence analysis. The proband's CSF showed downregulated levels of Aβ42, with unchanged Tau levels. The mutation is in the Low-Density Lipoprotein Receptor (LDLR) region of the APOE gene, which mediates the clearance of APOE lipoproteins. LDLR works as a high-affinity point for APOE. Studies suggest that APOE-LDLR interplay could have varying effects. The LDLR receptor pathway has been previously suggested as a therapeutic target to treat tauopathy. However, the APOE-LDLR interaction has also shown a significant correlation with memory retention. Leu159Pro could be an interesting mutation that could be responsible for a less damaging pattern of AD by suppressing tau-association neurodegeneration while affecting the patient's memory retention and cognitive performance.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fneur.2022.899644

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 68 · Cited by 4

Research works printed but not linked: 58

  1. [1]Bature F Guinn BA Pang D Pappas Y. Signs and symptoms preceding the diagnosis of Alzheimer's disease: a systematic scoping review of literature from 1937 to 2016. BMJ Open. (2017) 7: e015746. 10.1136/bmjopen-2016-015746 28851777 PMC5724073 · DOI
  2. [2]Nardini E Hogan R Flamier A Bernier G. Alzheimer's disease: a tale of two diseases? Neural Regen Res. (2021) 16: 1958– 64. 10.4103/1673-5374.308070 33642366 PMC8343298 · DOI
  3. [3]Goate A Chartier-Harlin MC Mullan M Brown J Crawford F Fidani L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. (1991) 349: 704– 6. 10.1038/349704a0 1671712 · DOI · Paper page
  4. [4]Sherrington R Rogaev EI Liang Y Rogaeva EA Levesque G Ikeda M. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. (1995) 375: 754– 60. 10.1038/375754a0 7596406 · DOI · Paper page
  5. [5]Alzheimer's Disease Collaborative G. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. (1995) 11: 219– 22. 10.1038/ng1095-219 7550356 · DOI · Paper page
  6. [6]Cruts M Backhovens H Wang SY Van Gassen G Theuns J De Jonghe CD. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q243. Hum Mol Genet. (1995) 4: 2363– 71. 10.1093/hmg/4.12.2363 8634711 · DOI
  7. [7]Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. (1993) 261: 921– 3. 10.1126/science.8346443 8346443 · DOI · Paper page
  8. [8]Mahley RW Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. (2000) 1: 507– 37. 10.1146/annurev.genom.1.1.507 11701639 · DOI · Paper page
  9. [9]Bagyinszky E Youn YC An SS Kim S. The genetics of Alzheimer's disease. Clin Interv Aging. (2014) 9: 535– 51. 10.2147/CIA.S51571 24729694 PMC3979693 · DOI
  10. [10]Bagaria J Nho K An SSA. Importance of GWAS in finding un-targeted genetic association of sporadic Alzheimer's disease. Mol Cell Toxicol. (2021) 17: 233– 44. 10.1007/s13273-021-00130-z · DOI
  11. [11]van der Flier WM Pijnenburg YA Fox NCvScheltens P. Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ε4 allele. Lancet Neurol. (2011) 10: 280– 8. 10.1016/S1474-4422(10)70306-9 21185234 · DOI
  12. [12]Giau VV Bagyinszky E An SS Kim SY. Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat. (2015) 11: 1723– 37. 10.2147/NDT.S84266 26213471 PMC4509527 · DOI
  13. [14]Schoonenboom NS Reesink FE Verwey NA Kester MI Teunissen CE van de Ven PM. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology. (2012) 78: 47– 54. 10.1212/WNL.0b013e31823ed0f0 22170879 · DOI · Paper page
  14. [15]Dubois B Feldman HH Jacova C Dekosky ST Barberger-Gateau P Cummings J. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. (2007) 6: 734– 46. 10.1016/S1474-4422(07)70178-3 17616482 · DOI · Paper page
  15. [17]Hansson O Zetterberg H Buchhave P Londos E Blennow K Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. (2006) 5: 228– 34. 10.1016/S1474-4422(06)70355-6 16488378 · DOI · Paper page
  16. [18]Buchhave P Minthon L Zetterberg H Wallin AK Blennow K Hansson O. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. (2012) 69: 98– 106. 10.1001/archgenpsychiatry.2011.155 22213792 · DOI · Paper page
  17. [20]Izaks GJ Gansevoort RT van der Knaap AM Navis G Dullaart RP Slaets JP. The association of APOE genotype with cognitive function in persons aged 35 years or older. PLoS ONE. (2011) 6: e27415. 10.1371/journal.pone.0027415 22110642 PMC3215744 · DOI
  18. [21]Skoog I Davidsson P Aevarsson O Vanderstichele H Vanmechelen E Blennow K. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement Geriatr Cogn Disord. (2003) 15: 169– 76. 10.1159/000068478 12584433 · DOI · Paper page
  19. [22]Kinomura M Sugiyama H Saito T Matsunaga A Sada KE Kanzaki M. Novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy. Nephrol Dial Transplant. (2008) 23: 751– 6. 10.1093/ndt/gfm675 18045818 · DOI · Paper page
  20. [23]Bennet AM Di Angelantonio E Ye Z Wensley F Dahlin A Ahlbom A. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. (2007) 298: 1300– 11. 10.1001/jama.298.11.1300 17878422 · DOI · Paper page
  21. [24]Datta G Chaddha M Garber DW Chung BH Tytler EM Dashti N. The receptor binding domain of apolipoprotein E, linked to a model class A amphipathic helix, enhances internalization and degradation of LDL by fibroblasts. Biochemistry. (2000) 39: 213– 20. 10.1021/bi991209w 10625496 · DOI
  22. [25]Bradley WA Gianturco SH. ApoE is necessary and sufficient for the binding of large triglyceride-rich lipoproteins to the LDL receptor; apoB is unnecessary. J Lipid Res. (1986) 27: 40– 8. 10.1016/S0022-2275(20)38865-9 3958613 · DOI
  23. [27]Fan J Tao W Li X Li H Zhang J Wei D. The contribution of genetic factors to cognitive impairment and dementia: apolipoprotein E gene, gene interactions, and polygenic risk. Int J Mol Sci. (2019) 20: 8– 9. 10.3390/ijms20051177 30866553 PMC6429136 · DOI
  24. [28]Sando SB Melquist S Cannon A Hutton ML Sletvold O Saltvedt I. Epsilon 4 lowers age at onset and is a high risk factor for Alzheimer's disease; a case control study from central Norway. BMC Neurol. (2008) 8: 9. 10.1186/1471-2377-8-9 18416843 PMC2375917 · DOI · Paper page
  25. [29]Jia L Xu H Chen S Wang X Yang J Gong M. The APOE epsilon4 exerts differential effects on familial and other subtypes of Alzheimer's disease. Alzheimers Dement. (2020) 16: 1613– 23. 10.1002/alz.12153 32881347 PMC7984370 · DOI
  26. [32]Oikawa S Matsunaga A Saito T Sato H Seki T Hoshi K. Apolipoprotein E Sendai (arginine 145–>proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. (1997) 8: 820– 3. 10.1681/ASN.V85820 9176854 · DOI · Paper page
  27. [33]Sam R Wu H Yue L Mazzone T Schwartz MM Arruda JA. Lipoprotein glomerulopathy: a new apolipoprotein E mutation with enhanced glomerular binding. Am J Kidney Dis. (2006) 47: 539– 48. 10.1053/j.ajkd.2005.12.031 16490634 · DOI · Paper page
  28. [34]Cautero N Di Benedetto F De Ruvo N Montalti R Guerrini GP Ballarin R. Novel genetic mutation in apolipoprotein E2 homozygosis and its implication in organ donation: a case report. Transplant Proc. (2010) 42: 1349– 51. 10.1016/j.transproceed.2010.03.104 20534298 · DOI
  29. [35]Luo B Huang F Liu Q Li X Chen W Zhou SF Yu X. Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol. (2008) 28: 347– 53. 10.1159/000111828 18046082 PMC2785906 · DOI · Paper page
  30. [36]Bomback AS Song H D'Agati VD Cohen SD Neal A Appel GB. New apolipoprotein E mutation, apoE Las Vegas, in a European-American with lipoprotein glomerulopathy. Nephrol Dial Transplant. (2010) 25: 3442– 6. 10.1093/ndt/gfq389 20624773 · DOI · Paper page
  31. [38]Tokura T Itano S Kobayashi S Kuwabara A Fujimoto S Horike H. A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. J Atheroscler Thromb. (2011) 18: 536– 41. 10.5551/jat.8102 21467726 · DOI · Paper page
  32. [39]Ishibashi S Herz J Maeda N Goldstein JL Brown MS. The two-receptor model of lipoprotein clearance: tests of the hypothesis in “knockout” mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA. (1994) 91: 4431– 5. 10.1073/pnas.91.10.4431 8183926 PMC43799 · DOI · Paper page
  33. [40]Huang Y Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis. (2014) 72 (Pt A): 3– 12. 10.1016/j.nbd.2014.08.025 25173806 PMC4253862 · DOI · Paper page
  34. [41]Magistroni R Bertolotti M Furci L Fano RA Leonelli M Pisciotta L. Lipoprotein glomerulopathy associated with a mutation in apolipoprotein e. Clin Med Insights Case Rep. (2013) 6: 189– 96. 10.4137/CCRep.S12209 24348079 PMC3859823 · DOI · Paper page
  35. [42]Saito T Oikawa S Sato H Sasaki J. Lipoprotein glomerulopathy: renal lipidosis induced by novel apolipoprotein E variants. Nephron. (1999) 83: 193– 201. 10.1159/000045511 10529625 · DOI · Paper page
  36. [43]Toyota K Hashimoto T Ogino D Matsunaga A Ito M Masakane I. Founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet. (2013) 58: 254– 8. 10.1038/jhg.2013.8 23407349 · DOI · Paper page
  37. [44]Hu Z Huang S Wu Y Liu Y Liu X Su D. Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int. (2014) 85: 416– 24. 10.1038/ki.2013.335 24025644 · DOI · Paper page
  38. [45]Bagyinszky E Kang MJ Pyun J Giau VV An SSA Kim S. Early-onset Alzheimer's disease patient with prion (PRNP) pVal180Ile mutation. Neuropsychiatr Dis Treat. (2019) 15: 2003– 13. 10.2147/NDT.S215277 31410005 PMC6645694 · DOI
  39. [46]Rosenthal SL Wang X Demirci FY Barmada MM Ganguli M Lopez OL. Beta-amyloid toxicity modifier genes and the risk of Alzheimer's disease. Am J Neurodegener Dis. (2012) 1: 191– 8. Available online at: www.AJND.us/ISSN:2165-591X/AJND1207005 22984654 PMC3560458
  40. [47]Feher A Juhasz A Pakaski M Janka Z Kalman J. Association study of the ABCA7 rs3752246 polymorphism in Alzheimer's disease. Psychiatry Res. (2019) 279: 376– 7. 10.1016/j.psychres.2019.01.081 30717989 · DOI
  41. [48]Bamji-Mirza M Li Y Najem D Liu QY Walker D Lue LF. Genetic variations in ABCA7 can increase secreted levels of amyloid-beta40 and amyloid-beta42 peptides and ABCA7 transcription in cell culture models. J Alzheimers Dis. (2016) 53: 875– 92. 10.3233/JAD-150965 27314524 · DOI
  42. [49]Berg CN Sinha N Gluck MA. The effects of APOE and ABCA7 on cognitive function and Alzheimer's disease risk in African Americans: a focused mini review. Front Hum Neurosci. (2019) 13: 387. 10.3389/fnhum.2019.00387 31749691 PMC6848225 · DOI
  43. [50]Chang YT Hsu SW Huang SH Huang CW Chang WN Lien CY. ABCA7 polymorphisms correlate with memory impairment and default mode network in patients with APOEepsilon4-associated Alzheimer's disease. Alzheimers Res Ther. (2019) 11: 103. 10.1186/s13195-019-0563-3 31831047 PMC6909474 · DOI
  44. [51]Lamartiniere Y Boucau MC Dehouck L Krohn M Pahnke J Candela P. ABCA7 downregulation modifies cellular cholesterol homeostasis and decreases amyloid-beta peptide efflux in an in vitro model of the blood-brain barrier. J Alzheimers Dis. (2018) 64: 1195– 211. 10.3233/JAD-170883 30010117 · DOI · Paper page
  45. [52]Dib S Pahnke J Gosselet F. Role of ABCA7 in human health and in Alzheimer's Disease. Int J Mol Sci. (2021) 22: 4– 9. 10.3390/ijms22094603 33925691 PMC8124837 · DOI
  46. [53]Vardarajan BN Zhang Y Lee JH Cheng R Bohm C Ghani M. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. (2015) 77: 215– 27. 10.1002/ana.24305 25382023 PMC4367199 · DOI · Paper page
  47. [54]Barthelson K Newman M Lardelli M. Sorting out the role of the sortilin-related receptor 1 in Alzheimer's Disease. J Alzheimers Dis Rep. (2020) 4: 123– 40. 10.3233/ADR-200177 32587946 PMC7306921 · DOI
  48. [55]Reitz C. Dyslipidemia and the risk of Alzheimer's disease. Curr Atheroscler Rep. (2013) 15: 307. 10.1007/s11883-012-0307-3 23328907 PMC3564220 · DOI · Paper page
  49. [56]Gaidukov L Viji RI Yacobson S Rosenblat M Aviram M Tawfik DS. ApoE induces serum paraoxonase PON1 activity and stability similar to ApoA-I. Biochemistry. (2010) 49: 532– 8. 10.1021/bi9013227 20025294 · DOI
  50. [57]Allan CM I Walker D Segrest JP Taylor JM. Identification and characterization of a new human gene (APOC4) in the apolipoprotein E, C-I, and C-II gene locus. Genomics. (1995) 28: 291– 300. 10.1006/geno.1995.1144 8530039 · DOI
  51. [58]Jong MC Hofker MH Havekes LM. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol. (1999) 19: 472– 84. 10.1161/01.ATV.19.3.472 10073946 · DOI · Paper page
  52. [60]Kockx M Jessup W Kritharides L. Regulation of endogenous apolipoprotein E secretion by macrophages. Arterioscler Thromb Vasc Biol. (2008) 28: 1060– 7. 10.1161/ATVBAHA.108.164350 18388328 · DOI
  53. [61]Rocchi A Pellegrini S Siciliano G Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. (2003) 61: 1– 24. 10.1016/S0361-9230(03)00067-4 12788204 · DOI
  54. [63]Fagan AM Mintun MA Mach RH Lee SY Dence CS Shah AR. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. (2006) 59: 512– 9. 10.1002/ana.20730 16372280 · DOI · Paper page
  55. [64]Yamamoto T Choi HW Ryan RO. Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor. Anal Biochem. (2008) 372: 222– 6. 10.1016/j.ab.2007.09.005 17923100 PMC2174959 · DOI · Paper page
  56. [66]Johnson LA Olsen RHJ Merkens LS DeBarber A Steiner RD Sullivan PM. Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner. Neurobiol Dis. (2014) 64: 150– 62. 10.1016/j.nbd.2013.12.016 24412220 PMC3936477 · DOI
  57. [67]Arboleda-xVelasquez JF Lopera F O'Hare M Delgado-Tirado S Marino C Chmielewska N. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. (2019) 25: 1680– 3. 10.1038/s41591-019-0611-3 31686034 PMC6898984 · DOI · Paper page
  58. [68]Hernandez I Gelpi E Molina-Porcel L Bernal S Rodríguez-Santiago B Dols-Icardo O. Heterozygous APOE Christchurch in familial Alzheimer's disease without mutations in other Mendelian genes. Neuropathol. Appl. Neurobiol. (2021) 47: 579– 82. 10.1111/nan.12670 33095930 · DOI · Paper page

Authors
Bagaria, J., Moon, Y., Bagyinszky, E., Shim, K. H., An, S. S. A., Kim, S., & Han, S. H.
Affiliations
  • Gachon University (KR)
  • Konkuk University (KR)
  • Seoul National University (KR)
Corresponding author
  • An, Seong Soo A.
  • Han, Seol Heui
ORCID
Venue
Frontiers in Neurology
Publisher
Frontiers Media SA
Published
2022-06-10
Volume
13
Pages
899644-899644
ISSN
1664-2295 (ISSN-L)
DOI
10.3389/fneur.2022.899644
PMC
PMC9226417
OpenAlex
W4281717111
Cited by
4
References
68
Citations by year
2025: 1 · 2024: 1 · 2023: 2
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation of Korea (2020R1A2B5B01002463, 2021R1A6A1A03038996)
  • Gachon University (GCU-202008480012)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
apolipoprotein E, LDL receptor, amyloid-beta 42, tau protein, cerebrospinal fluid biomarkers, memory retention, cognitive performance, tauopathy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review