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


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.


Alzheimer’s disease APOE Amyloid beta Biomarker ADNI 



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 ( 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)
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Supplementary Table S2 (DOCX 17 kb)
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Supplementary Table S3 (DOCX 16 kb)
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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)


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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

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