Advertisement

Molecular Neurobiology

, Volume 53, Issue 7, pp 4539–4547 | Cite as

Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer’s Disease Spectrum

  • Ying Liu
  • Lan TanEmail author
  • Hui-Fu Wang
  • Yong Liu
  • Xiao-Ke Hao
  • Chen-Chen Tan
  • Teng Jiang
  • Bing Liu
  • Dao-Qiang Zhang
  • Jin-Tai YuEmail author
  • Alzheimer’s Disease Neuroimaging Initiative
Article

Abstract

The apolipoprotein E ε4 (APOE ε4) allele is the most important genetic risk factor for Alzheimer’s disease (AD); however, the underlying mechanisms responsible for it remain controversial. We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the influence of APOE ε4 dose on clinical and neuroimaging biomarkers across the AD spectrum (from cognitive normal to AD patients with severe cognitive impairment). A total of 1718 participants from the ADNI cohort were selected, and we evaluated the impact of ε4 dose on cerebrospinal fluid (CSF) levels’ Abeta1-42 (Aβ1-42), tau, and phosphorylated-tau (p-tau); cortical amyloid deposition (Florbetapir-PET-AV45); brain atrophy (MRI); brain metabolism (FDG-PET); hippocampal metabolism; and cognitive declines, through different cognitive subgroups. We found that (1) ε4 was associated with decreased CSF beta-amyloid (Aβ1-42) and increased cerebral Aβ deposition across the AD spectrum; (2) increased CSF tau, P-tau and cerebral hypometabolism, hippocampal atrophy, and cognition decline were all associated with APOE ε4 in prodromal AD stage; (3) increased CSF tau, P-tau and cerebral hypometabolism appear to begin earlier than hippocampal atrophy and cognitive decline. We hypothesized that APOE ε4 increases cerebral amyloid-β (Aβ) deposition in all the stages of AD development, and also influences Aβ-initiated cascade of downstream neurodegenerative effects, thereby increasing the risk of AD.

Keywords

Alzheimer’s disease APOE Amyloid beta Biomarker ADNI 

Notes

Acknowledgments

Data collection and sharing was funded by ADNI (National Institutes of Health U01 AG024904). ADNI is funded by the National Institute on Aging; the National Institute of Biomedical Imaging and Bioengineering; the Alzheimer’s Association; the Alzheimer’s Drug Discovery Foundation; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Co, F. Hoffmann-LaRoche Ltd and Genetech, Inc; GE Healthcare; Innogenetics, NV; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development LLC; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals, Co, Pfizer, Inc; Piramal Imaging; Servier; Synarc Inc; and Takeda Pharmaceutical Co. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization was the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by grants from the National Natural Science Foundation of China (81471309, 81371406, 81171209), the Shandong Provincial Outstanding Medical Academic Professional Program, Qingdao Key Health Discipline Development Fund, and Qingdao Outstanding Health Professional Development Fund.

Conflict of Interest

The authors have no conflicts of interest to report.

Supplementary material

12035_2015_9388_MOESM1_ESM.docx (17 kb)
Supplementary Table S1 (DOCX 17 kb)
12035_2015_9388_MOESM2_ESM.docx (17 kb)
Supplementary Table S2 (DOCX 17 kb)
12035_2015_9388_MOESM3_ESM.docx (17 kb)
Supplementary Table S3 (DOCX 16 kb)
12035_2015_9388_MOESM4_ESM.docx (18 kb)
Supplementary Table S4 (DOCX 18 kb)
12035_2015_9388_Fig4_ESM.gif (91 kb)
Fig. s1

Cross-sectional analyses of six psychological scores across Alzheimer’s disease spectrum. Significant results were marked red star in below. MMSE = Mini-Mental State Exam, CDR-SB = Clinical Dementia Rating Scale Sum of Boxes score, ADAS = Alzheimer’s disease Assessment Scale, RAVLT = Rey Auditory Verbal Learning Test, FAQ = Functional Activities Questionnaire. (GIF 91 kb)

12035_2015_9388_MOESM5_ESM.tif (1003 kb)
High resolution image (TIFF 1003 kb)
12035_2015_9388_Fig5_ESM.gif (100 kb)
Fig. s2

Cross-sectional analyses of florbetapir cortical retention via PET AV45 across Alzheimer’s disease spectrum. Significant P values after Bonferroni-corrected were indicated using bold font. (GIF 99 kb)

12035_2015_9388_MOESM6_ESM.tif (806 kb)
High resolution image (TIFF 805 kb)

References

  1. 1.
    Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342(8873):697–699CrossRefPubMedGoogle Scholar
  2. 2.
    Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor Perspectives Med 2(3):a006312. doi: 10.1101/cshperspect.a006312 CrossRefGoogle Scholar
  3. 3.
    Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118. doi: 10.1038/nrneurol.2012.263 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yu JT, Tan L, Hardy J (2014) Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci. doi: 10.1146/annurev-neuro-071013-014300 PubMedGoogle Scholar
  5. 5.
    Drzezga A, Grimmer T, Henriksen G, Muhlau M, Perneczky R, Miederer I, Praus C, Sorg C et al (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72(17):1487–1494. doi: 10.1212/WNL.0b013e3181a2e8d0 CrossRefPubMedGoogle Scholar
  6. 6.
    Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67(1):122–131. doi: 10.1002/ana.21843 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fleisher AS, Chen K, Liu X, Roontiva A, Thiyyagura P, Ayutyanont N, Joshi AD, Clark CM et al (2011) Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol 68(11):1404–1411. doi: 10.1001/archneurol.2011.150 CrossRefPubMedGoogle Scholar
  8. 8.
    Caroli A, Frisoni GB, Alzheimer’s Disease Neuroimaging I (2010) The dynamics of Alzheimer’s disease biomarkers in the Alzheimer’s Disease Neuroimaging Initiative cohort. Neurobiol Aging 31(8):1263–1274. doi: 10.1016/j.neurobiolaging.2010.04.024 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, Small GW (2000) Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med 343(7):450–456. doi: 10.1056/NEJM200008173430701 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Moffat SD, Szekely CA, Zonderman AB, Kabani NJ, Resnick SM (2000) Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype. Neurology 55(1):134–136CrossRefPubMedGoogle Scholar
  11. 11.
    Bondi MW, Houston WS, Eyler LT, Brown GG (2005) fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology 64(3):501–508. doi: 10.1212/01.WNL.0000150885.00929.7E CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Langbaum JB, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL et al (2009) Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). NeuroImage 45(4):1107–1116. doi: 10.1016/j.neuroimage.2008.12.072 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Shaw LM, Trojanowski JQ, Aisen PS, Weiner M et al (2010) Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann Neurol 67(3):308–316. doi: 10.1002/ana.21953 PubMedPubMedCentralGoogle Scholar
  14. 14.
    Tosun D, Schuff N, Shaw LM, Trojanowski JQ, Weiner MW, Alzheimer’s Disease NeuroImaging I (2011) Relationship between CSF biomarkers of Alzheimer’s disease and rates of regional cortical thinning in ADNI data. J Alzheimer’s Dis JAD 26(Suppl 3):77–90. doi: 10.3233/JAD-2011-0006 PubMedGoogle Scholar
  15. 15.
    Mayeux R, Small SA, Tang M, Tycko B, Stern Y (2001) Memory performance in healthy elderly without Alzheimer’s disease: effects of time and apolipoprotein-E. Neurobiol Aging 22(4):683–689CrossRefPubMedGoogle Scholar
  16. 16.
    Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC (2004) Impact of APOE in mild cognitive impairment. Neurology 63(10):1898–1901CrossRefPubMedGoogle Scholar
  17. 17.
    Caselli RJ, Dueck AC, Locke DE, Hoffman-Snyder CR, Woodruff BK, Rapcsak SZ, Reiman EM (2011) Longitudinal modeling of frontal cognition in APOE epsilon4 homozygotes, heterozygotes, and noncarriers. Neurology 76(16):1383–1388. doi: 10.1212/WNL.0b013e3182167147 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Liu Y, Yu JT, Wang HF, Han PR, Tan CC, Wang C, Meng XF, Risacher SL et al (2014) APOE genotype and neuroimaging markers of Alzheimer’s disease: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. doi: 10.1136/jnnp-2014-307719 PubMedCentralGoogle Scholar
  19. 19.
    Motter R, Vigo-Pelfrey C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D, Chang L, Miller B et al (1995) Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 38(4):643–648. doi: 10.1002/ana.410380413 CrossRefPubMedGoogle Scholar
  20. 20.
    Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, Morris CM, O’Brien JT (1999) Apolipoprotein E epsilon4 allele, temporal lobe atrophy, and white matter lesions in late-life dementias. Arch Neurol 56(8):961–965CrossRefPubMedGoogle Scholar
  21. 21.
    Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack CR, Jagust W, Trojanowski JQ, Toga AW et al (2005) Ways toward an early diagnosis in Alzheimer’s disease: the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Alzheimer’s & Dementia J Alzheimer’s Assoc 1(1):55–66. doi: 10.1016/j.jalz.2005.06.003 CrossRefGoogle Scholar
  22. 22.
    Jack CR Jr, Bernstein MA, Borowski BJ, Gunter JL, Fox NC, Thompson PM, Schuff N, Krueger G et al (2010) Update on the magnetic resonance imaging core of the Alzheimer’s disease neuroimaging initiative. Alzheimer’s Dementia J Alzheimer’s Assoc 6(3):212–220. doi: 10.1016/j.jalz.2010.03.004 CrossRefGoogle Scholar
  23. 23.
    Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, Jack CR Jr, Jagust WJ et al (2010) Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology 74(3):201–209. doi: 10.1212/WNL.0b013e3181cb3e25 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, Lupo PJ, Reisch JS et al (2008) Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer’s research consortium study. Arch Neurol 65(8):1091–1095. doi: 10.1001/archneur.65.8.1091 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H et al (2009) Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 65(4):403–413. doi: 10.1002/ana.21610 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shen L, Kim S, Risacher SL, Nho K, Swaminathan S, West JD, Foroud T, Pankratz N et al (2010) Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: a study of the ADNI cohort. NeuroImage 53(3):1051–1063. doi: 10.1016/j.neuroimage.2010.01.042 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Risacher SL, Saykin AJ (2013) Neuroimaging and other biomarkers for Alzheimer’s disease: the changing landscape of early detection. Annu Rev Clin Psychol 9:621–648. doi: 10.1146/annurev-clinpsy-050212-185535 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhang D, Wang Y, Zhou L, Yuan H, Shen D (2011) Multimodal classification of Alzheimer’s disease and mild cognitive impairment. NeuroImage 55(3):856–867. doi: 10.1016/j.neuroimage.2011.01.008 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia J Alzheimer’s Assoc 7(3):263–269. doi: 10.1016/j.jalz.2011.03.005 CrossRefGoogle Scholar
  30. 30.
    Landau SM, Harvey D, Madison CM, Koeppe RA, Reiman EM, Foster NL, Weiner MW, Jagust WJ et al (2011) Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol Aging 32(7):1207–1218. doi: 10.1016/j.neurobiolaging.2009.07.002 CrossRefPubMedGoogle Scholar
  31. 31.
    Landau SM, Lal R, O’Neil JP, Baker S, Jagust WJ (2009) Striatal dopamine and working memory. Cereb Cortex 19(2):445–454. doi: 10.1093/cercor/bhn095 CrossRefPubMedGoogle Scholar
  32. 32.
    O’Bryant SE, Lacritz LH, Hall J, Waring SC, Chan W, Khodr ZG, Massman PJ, Hobson V et al (2010) Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer’s coordinating center database. Arch Neurol 67(6):746–749. doi: 10.1001/archneurol.2010.115 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, Karhunen PJ (2009) Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 65(6):650–657. doi: 10.1002/ana.21696 CrossRefPubMedGoogle Scholar
  34. 34.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55(3):306–319. doi: 10.1002/ana.20009 CrossRefPubMedGoogle Scholar
  35. 35.
    Tapiola T, Pirttila T, Mehta PD, Alafuzofff I, Lehtovirta M, Soininen H (2000) Relationship between apoE genotype and CSF beta-amyloid (1-42) and tau in patients with probable and definite Alzheimer’s disease. Neurobiol Aging 21(5):735–740CrossRefPubMedGoogle Scholar
  36. 36.
    Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J et al (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 106(16):6820–6825. doi: 10.1073/pnas.0900345106 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Villemagne VL, Pike KE, Chetelat G, Ellis KA, Mulligan RS, Bourgeat P, Ackermann U, Jones G et al (2011) Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 69(1):181–192. doi: 10.1002/ana.22248 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ossenkoppele R, van der Flier WM, Zwan MD, Adriaanse SF, Boellaard R, Windhorst AD, Barkhof F, Lammertsma AA et al (2013) Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology 80(4):359–365. doi: 10.1212/WNL.0b013e31827f0889 CrossRefPubMedGoogle Scholar
  39. 39.
    Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118(12):4002–4013. doi: 10.1172/JCI36663 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC et al (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3(89):89ra57. doi: 10.1126/scitranslmed.3002156 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, Mitani A, Joyner D et al (2012) Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. J Neurosci Off J Soc Neurosci 32(43):15181–15192. doi: 10.1523/JNEUROSCI.1542-12.2012 CrossRefGoogle Scholar
  42. 42.
    Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9(1):119–128. doi: 10.1016/S1474-4422(09)70299-6 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ying Liu
    • 1
  • Lan Tan
    • 1
    • 2
    Email author
  • Hui-Fu Wang
    • 2
  • Yong Liu
    • 4
  • Xiao-Ke Hao
    • 3
  • Chen-Chen Tan
    • 1
  • Teng Jiang
    • 2
  • Bing Liu
    • 4
  • Dao-Qiang Zhang
    • 3
  • Jin-Tai Yu
    • 1
    • 2
    • 5
    Email author
  • Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Department of Neurology, Qingdao Municipal Hospital, School of MedicineQingdao UniversityQingdaoChina
  2. 2.Department of Neurology, Qingdao Municipal HospitalNanjing Medical UniversityNanjingChina
  3. 3.Department of Computer Science and EngineeringNanjing University of Aeronautics and AstronauticsNanjingChina
  4. 4.Brainnetome Center, Institute of AutomationChinese Academy of SciencesBeijingChina
  5. 5.Memory and Aging Center, Department of NeurologyUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations