Skip to main content

Advertisement

SpringerLink
Log in

Imaging Brain Effects of APOE4 in Cognitively Normal Individuals Across the Lifespan

  • Review
  • Published:
Neuropsychology Review Aims and scope Submit manuscript

Abstract

The ε4 allele of the apolipoprotein E (APOE4) is associated with an increased risk of developing Alzheimer’s disease (AD). Hence, several studies have compared the brain characteristics of APOE4 carriers versus non-carriers in presymptomatic stages to determine early AD biomarkers. The present review provides an overview on APOE4-related brain changes in cognitively normal individuals, focusing on the main neuroimaging biomarkers for AD, i.e. cortical beta-amyloid (Aβ) deposition, hypometabolism and atrophy. The most consistent findings are observed with Aβ deposition as most studies report significantly higher cortical Aβ load in APOE4 carriers compared with non-carriers. Fluorodeoxyglucose-positron emission tomography studies are rare and tend to show hypometabolism in brain regions typically impaired in AD. Structural magnetic resonance imaging findings are the most numerous and also the most discrepant, showing atrophy in AD-sensitive regions in some studies but contradicting results as well. Altogether, this suggests a graded effect of APOE4, with a predominant effect on Aβ over brain structure and metabolism. Multimodal studies confirm this view and also suggest that APOE4 effects on brain structure and function are mediated by both Aβ-dependent and Aβ-independent pathological processes. Neuroimaging studies on asymptomatic APOE4 carriers offer relevant information to the understanding of early pathological mechanisms of the disease, although caution is needed as to whether APOE4 effects reflect AD pathological processes, and are representative of these effects in non-carriers.

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

Similar content being viewed by others

References

  • Alexopoulos, P., Richter-Schmidinger, T., Horn, M., Maus, S., Reichel, M., Sidiropoulos, C., et al. (2011). Hippocampal volume differences between healthy young apolipoprotein E ε2 and ε4 carriers. Journal of Alzheimer’s Disease, 26(2), 207–210.

    CAS  PubMed  Google Scholar 

  • Bacskai, B. J., Frosch, M. P., Freeman, S. H., Raymond, S. B., Augustinack, J. C., Johnson, K. A., et al. (2007). Molecular imaging with Pittsburgh compound B confirmed at autopsy: a case report. Archives of Neurology, 64(3), 431–434.

    PubMed  Google Scholar 

  • Barboriak, D. P., Doraiswamy, P. M., Krishnan, K. R., Vidyarthi, S., Sylvester, J., & Charles, H. C. (2000). Hippocampal sulcal cavities on MRI: relationship to age and apolipoprotein E genotype. Neurology, 54(11), 2150–2153.

    CAS  PubMed  Google Scholar 

  • Berlau, D. J., Corrada, M. M., Head, E., & Kawas, C. H. (2009). APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology, 72(9), 829–834.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bookheimer, S. Y., Strojwas, M. H., Cohen, M. S., Saunders, A. M., Pericak-Vance, M. A., Mazziotta, J. C., et al. (2000). Patterns of brain activation in people at risk for Alzheimer’s disease. The New England Journal of Medicine, 343(7), 450–456.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bu, G. (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nature Reviews Neuroscience, 10(5), 333–344.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bunce, D., Anstey, K. J., Cherbuin, N., Gautam, P., Sachdev, P., & Easteal, S. (2012). APOE genotype and entorhinal cortex volume in non-demented community-dwelling adults in midlife and early old age. Journal of Alzheimer’s Disease, 30(4), 935–942.

    PubMed  Google Scholar 

  • Burggren, A. C., Zeineh, M. M., Ekstrom, A. D., Braskie, M. N., Thompson, P. M., Small, G. W., et al. (2008). Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers. NeuroImage, 41(4), 1177–1183.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen, K., Reiman, E. M., Alexander, G. E., Caselli, R. J., Gerkin, R., Bandy, D., et al. (2007). Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates. The American Journal of Psychiatry, 164(6), 916–921.

    PubMed  Google Scholar 

  • Chen, K., Ayutyanont, N., Langbaum, J. B. S., Fleisher, A. S., Reschke, C., Lee, W., et al. (2012). Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: a cross-validation study using voxel-based multi-modal partial least squares. NeuroImage, 60(4), 2316–2322.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chételat, G., & Fouquet, M. (2013). Neuroimaging biomarkers for Alzheimer’s disease in asymptomatic APOE4 carriers. Revue Neurologique, 169(10), 729–736.

    PubMed  Google Scholar 

  • Chiang, G. C., Insel, P. S., Tosun, D., Schuff, N., Truran-Sacrey, D., Raptentsetsang, S. T., et al. (2010). Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects. Neurology, 75(22), 1976–1981.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chiang, G. C., Insel, P. S., Tosun, D., Schuff, N., Truran-Sacrey, D., Raptentsetsang, S. T., et al. (2011). Impact of apolipoprotein E4-cerebrospinal fluid β-amyloid interaction on hippocampal volume loss over 1 year in mild cognitive impairment. Alzheimer’s & Dementia, 7(5), 514–520.

    CAS  Google Scholar 

  • Clark, C. M., Schneider, J. A., Bedell, B. J., Beach, T. G., Bilker, W. B., Mintun, M. A., et al. (2011). Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA, the Journal of the American Medical Association, 305(3), 275–283.

    CAS  Google Scholar 

  • Clark, C. M., Pontecorvo, M. J., Beach, T. G., Bedell, B. J., Coleman, R. E., Doraiswamy, P. M., et al. (2012). Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurology, 11(8), 669–678.

    CAS  Google Scholar 

  • Cohen, R. M., Small, C., Lalonde, F., Friz, J., & Sunderland, T. (2001). Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology, 57(12), 2223–2228.

    CAS  PubMed  Google Scholar 

  • Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921–923.

    CAS  PubMed  Google Scholar 

  • Dean, D. C., 3rd, Jerskey, B. A., Chen, K., Protas, H., Thiyyagura, P., Roontiva, A., et al. (2014). Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurology, 71(1), 11–22.

    PubMed Central  PubMed  Google Scholar 

  • Den Heijer, T., Oudkerk, M., Launer, L. J., van Duijn, C. M., Hofman, A., & Breteler, M. M. B. (2002). Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology, 59(5), 746–748.

    Google Scholar 

  • Dennis, E. L., & Thompson, P. M. (2014). Functional brain connectivity using fMRI in aging and Alzheimer’s disease. Neuropsychology Review, 24(1), 49–62.

    PubMed  Google Scholar 

  • Dennis, N. A., Browndyke, J. N., Stokes, J., Need, A., Burke, J. R., Welsh-Bohmer, K. A., et al. (2010). Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimer’s & Dementia, 6(4), 303–311.

    Google Scholar 

  • Donix, M., Burggren, A. C., Suthana, N. A., Siddarth, P., Ekstrom, A. D., Krupa, A. K., et al. (2010a). Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism. NeuroImage, 53(1), 37–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Donix, M., Burggren, A. C., Suthana, N. A., Siddarth, P., Ekstrom, A. D., Krupa, A. K., et al. (2010b). Family history of Alzheimer’s disease and hippocampal structure in healthy people. The American Journal of Psychiatry, 167(11), 1399–1406.

    PubMed Central  PubMed  Google Scholar 

  • Donix, M., Small, G. W., & Bookheimer, S. Y. (2012). Family history and APOE-4 genetic risk in Alzheimer’s disease. Neuropsychology Review, 22(3), 298–309.

    PubMed Central  PubMed  Google Scholar 

  • Du, A.-T., Schuff, N., Chao, L. L., Kornak, J., Jagust, W. J., Kramer, J. H., et al. (2006). Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiology of Aging, 27(5), 733–740.

    PubMed Central  PubMed  Google Scholar 

  • Dubois, B., Feldman, H. H., Jacova, C., Cummings, J. L., Dekosky, S. T., Barberger-Gateau, P., et al. (2010). Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurology, 9(11), 1118–1127.

    Google Scholar 

  • Ellis, K. A., Lim, Y. Y., Harrington, K., Ames, D., Bush, A. I., Darby, D., et al. (2013). Decline in cognitive function over 18 months in healthy older adults with high amyloid-β. Journal of Alzheimer’s Disease, 34(4), 861–871.

    CAS  PubMed  Google Scholar 

  • Espeseth, T., Westlye, L. T., Fjell, A. M., Walhovd, K. B., Rootwelt, H., & Reinvang, I. (2008). Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4. Neurobiology of Aging, 29(3), 329–340.

    CAS  PubMed  Google Scholar 

  • Fan, M., Liu, B., Zhou, Y., Zhen, X., Xu, C., Jiang, T., et al. (2010). Cortical thickness is associated with different apolipoprotein E genotypes in healthy elderly adults. Neuroscience Letters, 479(3), 332–336.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., 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, the Journal of the American Medical Association, 278(16), 1349–1356.

    CAS  Google Scholar 

  • Fennema-Notestine, C., Panizzon, M. S., Thompson, W. R., Chen, C.-H., Eyler, L. T., Fischl, B., et al. (2011). Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age. Journal of Alzheimer’s Disease, 26(Suppl 3), 49–60.

    PubMed Central  PubMed  Google Scholar 

  • Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., et al. (2009). Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proceedings of the National Academy of Sciences of the United States of America, 106(17), 7209–7214.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Filippini, N., Ebmeier, K. P., MacIntosh, B. J., Trachtenberg, A. J., Frisoni, G. B., Wilcock, G. K., et al. (2011). Differential effects of the APOE genotype on brain function across the lifespan. NeuroImage, 54(1), 602–610.

    CAS  PubMed  Google Scholar 

  • Fjell, A. M., Westlye, L. T., Grydeland, H., Amlien, I., Espeseth, T., Reinvang, I., et al. (2014a). Accelerating cortical thinning: unique to dementia or universal in aging? Cerebral Cortex, 24(4), 919–934.

    PubMed  Google Scholar 

  • Fjell, A. M., McEvoy, L., Holland, D., Dale, A. M., Walhovd, K. B., & Alzheimer’s Disease Neuroimaging Initiative. (2014b). What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Progress in Neurobiology [in press].

  • Fleisher, A. S., Chen, K., Liu, X., Ayutyanont, N., Roontiva, A., Thiyyagura, P., et al. (2013). Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiology of Aging, 34(1), 1–12.

    CAS  PubMed  Google Scholar 

  • Gallagher, M., & Koh, M. T. (2011). Episodic memory on the path to Alzheimer’s disease. Current Opinion in Neurobiology, 21(6), 929–934.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Genin, E., Hannequin, D., Wallon, D., Sleegers, K., Hiltunen, M., Combarros, O., et al. (2011). APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Molecular Psychiatry, 16(9), 903–907.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gold, B. T., Johnson, N. F., Powell, D. K., & Smith, C. D. (2012). White matter integrity and vulnerability to Alzheimer’s disease: preliminary findings and future directions. Biochimica et Biophysica Acta, 1822(3), 416–422.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Han, S. D., Houston, W. S., Jak, A. J., Eyler, L. T., Nagel, B. J., Fleisher, A. S., et al. (2007). Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response. Neurobiology of Aging, 28(2), 238–247.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hinrichs, A. L., Mintun, M. A., Head, D., Fagan, A. M., Holtzman, D. M., Morris, J. C., et al. (2010). Cortical binding of pittsburgh compound B, an endophenotype for genetic studies of Alzheimer’s disease. Biological Psychiatry, 67(6), 581–583.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Holtzman, D. M., 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(3), a006312.

    PubMed Central  PubMed  Google Scholar 

  • Honea, R. A., Vidoni, E., Harsha, A., & Burns, J. M. (2009). Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. Journal of Alzheimer’s Disease, 18(3), 553–564.

    PubMed Central  PubMed  Google Scholar 

  • Honea, R. A., Swerdlow, R. H., Vidoni, E. D., Goodwin, J., & Burns, J. M. (2010). Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease. Neurology, 74(2), 113–120.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Honea, R. A., Swerdlow, R. H., Vidoni, E. D., & Burns, J. M. (2011). Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease. Neurology, 76(9), 822–829.

    PubMed Central  PubMed  Google Scholar 

  • Hostage, C. A., Roy Choudhury, K., Doraiswamy, P. M., Petrella, J. R., & Alzheimer’s Disease Neuroimaging Initiative. (2013). Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer’s disease. PLoS One, 8(2), e54483.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hua, X., Hibar, D. P., Lee, S., Toga, A. W., Jack, C. R., Jr., Weiner, M. W., et al. (2010). Sex and age differences in atrophic rates: an ADNI study with n = 1368 MRI scans. Neurobiology of Aging, 31(8), 1463–1480.

    PubMed Central  PubMed  Google Scholar 

  • Huang, Y. (2010). Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends in Molecular Medicine, 16(6), 287–294.

    CAS  PubMed  Google Scholar 

  • Huang, Y., & Mucke, L. (2012). Alzheimer mechanisms and therapeutic strategies. Cell, 148(6), 1204–1222.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ikonomovic, M. D., Klunk, W. E., Abrahamson, E. E., Mathis, C. A., Price, J. C., Tsopelas, N. D., et al. (2008). Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain, 131(Pt 6), 1630–1645.

    PubMed Central  PubMed  Google Scholar 

  • Jack, C. R., Jr., Petersen, R. C., Xu, Y. C., O’Brien, P. C., Waring, S. C., Tangalos, E. G., et al. (1998). Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Annals of Neurology, 43(3), 303–310.

    PubMed Central  PubMed  Google Scholar 

  • Jagust, W. J., Landau, S. M., & Alzheimer’s Disease Neuroimaging Initiative. (2012). Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. The Journal of Neuroscience, 32(50), 18227–18233.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kantarci, K., Lowe, V., Przybelski, S. A., Weigand, S. D., Senjem, M. L., Ivnik, R. J., et al. (2012). APOE modifies the association between Aβ load and cognition in cognitively normal older adults. Neurology, 78(4), 232–240.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kerchner, G. A., Berdnik, D., Shen, J. C., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., et al. (2014). APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology, 82(8), 691–697.

    CAS  PubMed  Google Scholar 

  • Khan, W., Giampietro, V., Ginestet, C., Dell’Acqua, F., Bouls, D., Newhouse, S., Dobson, R., et al. (2014). No differences in hippocampal volume between carriers and non-carriers of the ApoE ε4 and ε2 alleles in young healthy adolescents. Journal of Alzheimer’s Disease, 40(1), 37–43.

    CAS  PubMed  Google Scholar 

  • Kim, J., Basak, J. M., & Holtzman, D. M. (2009). The role of apolipoprotein E in Alzheimer’s disease. Neuron, 63(3), 287–303.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Knickmeyer, R. C., Wang, J., Zhu, H., Geng, X., Woolson, S., Hamer, R. M., et al. (2014). Common variants in psychiatric risk genes predict brain structure at birth. Cerebral Cortex, 24(5), 1230–1246.

    PubMed  Google Scholar 

  • Knopman, D. S., Jack, C. R., Jr, Wiste, H. J., Lundt, E. S., Weigand, S. D., Vemuri, P., et al. (2014). (18) F-fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons. Neurobiology of Aging [in press].

  • Kok, E., Haikonen, S., Luoto, T., Huhtala, H., Goebeler, S., Haapasalo, H., & Karhunen, P. J. (2009). Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Annals of Neurology, 65(6), 650–657.

    CAS  PubMed  Google Scholar 

  • Kukolja, J., Thiel, C. M., Eggermann, T., Zerres, K., & Fink, G. R. (2010). Medial temporal lobe dysfunction during encoding and retrieval of episodic memory in non-demented APOE epsilon4 carriers. Neuroscience, 168(2), 487–497.

    CAS  PubMed  Google Scholar 

  • Langbaum, J. B. S., Chen, K., Caselli, R. J., Lee, W., Reschke, C., Bandy, D., et al. (2010). Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele. Archives of Neurology, 67(4), 462–468.

    PubMed Central  PubMed  Google Scholar 

  • Leinonen, V., Alafuzoff, I., Aalto, S., Suotunen, T., Savolainen, S., Någren, K., et al. (2008). Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh compound B. Archives of Neurology, 65(10), 1304–1309.

    PubMed  Google Scholar 

  • Lemaître, H., Crivello, F., Dufouil, C., Grassiot, B., Tzourio, C., Alpérovitch, A., et al. (2005). No epsilon4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects. NeuroImage, 24(4), 1205–1213.

    PubMed  Google Scholar 

  • Lim, Y. Y., Ellis, K. A., Pietrzak, R. H., Ames, D., Darby, D., Harrington, K., et al. (2012). Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. Neurology, 79(16), 1645–1652.

    CAS  PubMed  Google Scholar 

  • Lim, Y. Y., Ellis, K. A., Ames, D., Darby, D., Harrington, K., Martins, R. N., et al. (2013). Aβ amyloid, cognition, and APOE genotype in healthy older adults. Alzheimer’s & Dementia.

  • Lim, Y. Y., Maruff, P., Pietrzak, R. H., Ames, D., Ellis, K. A., Harrington, K., et al. (2014). Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer’s disease. Brain, 137(Pt 1), 221–231.

    PubMed  Google Scholar 

  • Lind, J., Larsson, A., Persson, J., Ingvar, M., Nilsson, L.-G., Bäckman, L., et al. (2006). Reduced hippocampal volume in non-demented carriers of the apolipoprotein E epsilon4: relation to chronological age and recognition memory. Neuroscience Letters, 396(1), 23–27.

    CAS  PubMed  Google Scholar 

  • Liu, Y., Paajanen, T., Westman, E., Wahlund, L.-O., Simmons, A., Tunnard, C., et al. (2010a). Effect of APOE ε4 allele on cortical thicknesses and volumes: the addneuromed study. Journal of Alzheimer’s Disease, 21(3), 947–966.

    CAS  PubMed  Google Scholar 

  • Liu, Y., Paajanen, T., Westman, E., Zhang, Y., Wahlund, L.-O., Simmons, A., et al. (2010b). APOE ε2 allele is associated with larger regional cortical thicknesses and volumes. Dementia and Geriatric Cognitive Disorders, 30(3), 229–237.

    PubMed  Google Scholar 

  • Liu, C.-C., Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology, 9(2), 106–118.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lowe, V. J., Weigand, S. D., Senjem, M. L., Vemuri, P., Jordan, L., Kantarci, K., et al. (2014). Association of hypometabolism and amyloid levels in aging, normal subjects. Neurology [in press].

  • Lu, P. H., Thompson, P. M., Leow, A., Lee, G. J., Lee, A., Yanovsky, I., et al. (2011). Apolipoprotein E genotype is associated with temporal and hippocampal atrophy rates in healthy elderly adults: a tensor-based morphometry study. Journal of Alzheimer’s Disease, 23(3), 433–442.

    PubMed Central  PubMed  Google Scholar 

  • Mathis, C. A., Kuller, L. H., Klunk, W. E., Snitz, B. E., Price, J. C., Weissfeld, L. A., et al. (2013). In vivo assessment of amyloid-β deposition in nondemented very elderly subjects. Annals of Neurology, 73(6), 751–761.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Matura, S., Prvulovic, D., Jurcoane, A., Hartmann, D., Miller, J., Scheibe, M., et al. (2014). Differential effects of the ApoE4 genotype on brain structure and function. NeuroImage, 89, 81–91.

    CAS  PubMed  Google Scholar 

  • Mielke, M. M., Wiste, H. J., Weigand, S. D., Knopman, D. S., Lowe, V. J., Roberts, R. O., et al. (2012). Indicators of amyloid burden in a population-based study of cognitively normal elderly. Neurology, 79(15), 1570–1577.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mormino, E. C., Betensky, R. A., Hedden, T., Schultz, A. P., Ward, A., Huijbers, W., et al. (2014). Amyloid and APOE {varepsilon} 4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology [in press].

  • Morra, J. H., Tu, Z., Apostolova, L. G., Green, A. E., Avedissian, C., Madsen, S. K., et al. (2009). Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer’s disease, mild cognitive impairment, and elderly controls. NeuroImage, 45(1 Suppl), S3–15.

    PubMed Central  PubMed  Google Scholar 

  • Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., et al. (2010). APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Annals of Neurology, 67(1), 122–131.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mosconi, L., Brys, M., Switalski, R., Mistur, R., Glodzik, L., Pirraglia, E., et al. (2007). Maternal family history of Alzheimer’s disease predisposes to reduced brain glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America, 104(48), 19067–19072.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mosconi, L., Mistur, R., Switalski, R., Brys, M., Glodzik, L., Rich, K., et al. (2009). Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology, 72(6), 513–520.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mueller, S. G., & Weiner, M. W. (2009). Selective effect of age, Apo e4, and Alzheimer’s disease on hippocampal subfields. Hippocampus, 19(6), 558–564.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mueller, S. G., Schuff, N., Raptentsetsang, S., Elman, J., & Weiner, M. W. (2008). Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer’s disease using high resolution MRI at 4 T. NeuroImage, 42(1), 42–48.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murphy, K. R., Landau, S. M., Choudhury, K. R., Hostage, C. A., Shpanskaya, K. S., Sair, H. I., et al. (2013). Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. NeuroImage, 78, 474–480.

    CAS  PubMed Central  PubMed  Google Scholar 

  • O’Dwyer, L., Lamberton, F., Matura, S., Tanner, C., Scheibe, M., Miller, J., et al. (2012). Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study. PLoS One, 7(11), e48895.

    PubMed Central  PubMed  Google Scholar 

  • Plassman, B. L., Welsh-Bohmer, K. A., Bigler, E. D., Johnson, S. C., Anderson, C. V., Helms, M. J., et al. (1997). Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition. Neurology, 48(4), 985–989.

    CAS  PubMed  Google Scholar 

  • Protas, H. D., Chen, K., Langbaum, J. B. S., Fleisher, A. S., Alexander, G. E., Lee, W., et al. (2013). Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurology, 70(3), 320–325.

    PubMed Central  PubMed  Google Scholar 

  • Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., et al. (1996). Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. The New England Journal of Medicine, 334(12), 752–758.

    CAS  PubMed  Google Scholar 

  • Reiman, E. M., Uecker, A., Caselli, R. J., Lewis, S., Bandy, D., de Leon, M. J., et al. (1998). Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer’s disease. Annals of Neurology, 44(2), 288–291.

    CAS  PubMed  Google Scholar 

  • Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., et al. (2004). Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proceedings of the National Academy of Sciences of the United States of America, 101(1), 284–289.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., et al. (2005). Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proceedings of the National Academy of Sciences of the United States of America, 102(23), 8299–8302.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Reiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., et al. (2009). Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 106(16), 6820–6825.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rimajova, M., Lenzo, N. P., Wu, J.-S., Bates, K. A., Campbell, A., Dhaliwal, S. S., et al. (2008). Fluoro-2-deoxy-D-glucose (FDG)-PET in APOEepsilon4 carriers in the Australian population. Journal of Alzheimer’s Disease, 13(2), 137–146.

    CAS  PubMed  Google Scholar 

  • Risacher, S. L., Shen, L., West, J. D., Kim, S., McDonald, B. C., Beckett, L. A., et al. (2010). Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort. Neurobiology of Aging, 31(8), 1401–1418.

    PubMed Central  PubMed  Google Scholar 

  • Rodrigue, K. M., Kennedy, K. M., Devous, M. D., Sr., Rieck, J. R., Hebrank, A. C., Diaz-Arrastia, R., et al. (2012). β-Amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology, 78(6), 387–395.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Roe, C. M., Fagan, A. M., Grant, E. A., Hassenstab, J., Moulder, K. L., Maue Dreyfus, D., et al. (2013). Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology, 80(19), 1784–1791.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Roussotte, F. F., Gutman, B. A., Madsen, S. K., Colby, J. B., Narr, K. L., Thompson, P. M., et al. (2014). The apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging. Neurobiology of Aging, 35(6), 1309–1317.

    CAS  PubMed  Google Scholar 

  • Rowe, C. C., Ellis, K. A., Rimajova, M., Bourgeat, P., Pike, K. E., Jones, G., et al. (2010). Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiology of Aging, 31(8), 1275–1283.

    PubMed  Google Scholar 

  • Samuraki, M., Matsunari, I., Chen, W.-P., Shima, K., Yanase, D., Takeda, N., et al. (2012). Glucose metabolism and gray-matter concentration in apolipoprotein E ε4 positive normal subjects. Neurobiology of Aging, 33(10), 2321–2323.

    CAS  PubMed  Google Scholar 

  • Saunders, A. M., Schmader, K., Breitner, J. C., Benson, M. D., Brown, W. T., Goldfarb, L., et al. (1993). Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer’s disease and in other amyloid-forming diseases. Lancet, 342(8873), 710–711.

    CAS  PubMed  Google Scholar 

  • Scheinin, N. M., Wikman, K., Jula, A., Perola, M., Vahlberg, T., Rokka, J., et al. (2014). Cortical 11C-PIB Uptake is Associated with Age, APOE Genotype, and Gender in « Healthy Aging ». Journal of Alzheimer’s Disease [in press].

  • Schmidt, H., Schmidt, R., Fazekas, F., Semmler, J., Kapeller, P., Reinhart, B., et al. (1996). Apolipoprotein E e4 allele in the normal elderly: neuropsychologic and brain MRI correlates. Clinical Genetics, 50(5), 293–299.

    CAS  PubMed  Google Scholar 

  • Schuff, N., Woerner, N., Boreta, L., Kornfield, T., Shaw, L. M., Trojanowski, J. Q., et al. (2009). MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain, 132(Pt 4), 1067–1077.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shaw, P., Lerch, J. P., Pruessner, J. C., Taylor, K. N., Rose, A. B., Greenstein, D., et al. (2007). Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurology, 6(6), 494–500.

    CAS  Google Scholar 

  • Small, G. W., Mazziotta, J. C., Collins, M. T., Baxter, L. R., Phelps, M. E., Mandelkern, M. A., et al. (1995). Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA, the Journal of the American Medical Association, 273(12), 942–947.

    CAS  Google Scholar 

  • Soininen, H., Partanen, K., Pitkänen, A., Hallikainen, M., Hänninen, T., Helisalmi, S., et al. (1995). Decreased hippocampal volume asymmetry on MRIs in nondemented elderly subjects carrying the apolipoprotein E epsilon 4 allele. Neurology, 45(2), 391–392.

    CAS  PubMed  Google Scholar 

  • Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., et al. (2011). Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the national institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia, 7(3), 280–292.

    Google Scholar 

  • Striepens, N., Scheef, L., Wind, A., Meiberth, D., Popp, J., Spottke, A., et al. (2011). Interaction effects of subjective memory impairment and ApoE4 genotype on episodic memory and hippocampal volume. Psychological Medicine, 41(9), 1997–2006.

    CAS  PubMed  Google Scholar 

  • Suthana, N. A., Krupa, A., Donix, M., Burggren, A., Ekstrom, A. D., Jones, M., et al. (2010). Reduced hippocampal CA2, CA3, and dentate gyrus activity in asymptomatic people at genetic risk for Alzheimer’s disease. NeuroImage, 53(3), 1077–1084.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Taylor, J. L., Scanlon, B. K., Farrell, M., Hernandez, B., Adamson, M. M., Ashford, J. W., Noda, A., et al. (2014). APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years. Neurobiology of Aging [in press].

  • Thompson, W. K., Hallmayer, J., & O’Hara, R. (2011). Design considerations for characterizing psychiatric trajectories across the lifespan: application to effects of APOE-ε4 on cerebral cortical thickness in Alzheimer’s disease. The American Journal of Psychiatry, 168(9), 894–903.

    PubMed  Google Scholar 

  • Tohgi, H., Takahashi, S., Kato, E., Homma, A., Niina, R., Sasaki, K., et al. (1997). Reduced size of right hippocampus in 39- to 80-year-old normal subjects carrying the apolipoprotein E epsilon4 allele. Neuroscience Letters, 236(1), 21–24.

    CAS  PubMed  Google Scholar 

  • Trachtenberg, A. J., Filippini, N., & Mackay, C. E. (2012). The effects of APOE-ε4 on the BOLD response. Neurobiology of Aging, 33(2), 323–334.

    CAS  PubMed  Google Scholar 

  • Tuminello, E. R., & Han, S. D. (2011). The apolipoprotein e antagonistic pleiotropy hypothesis: review and recommendations. International Journal of Alzheimer’s Disease, 2011, 726197.

    PubMed Central  PubMed  Google Scholar 

  • Villemagne, V. L., & Rowe, C. C. (2013). Long night’s journey into the day: amyloid-β imaging in Alzheimer’s disease. Journal of Alzheimer’s Disease, 33(Suppl 1), S349–359.

    PubMed  Google Scholar 

  • Villemagne, V. L., Pike, K. E., Chetelat, G., Ellis, K. A., Mulligan, R. S., Bourgeat, P., et al. (2011). Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Annals of Neurology, 69(1), 181–192.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Villemagne, V. L., Burnham, S., Bourgeat, P., Brown, B., Ellis, K. A., Salvado, O., et al. (2013). Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurology, 12(4), 357–367.

    CAS  Google Scholar 

  • Vlassenko, A. G., Mintun, M. A., Xiong, C., Sheline, Y. I., Goate, A. M., Benzinger, T. L. S., et al. (2011). Amyloid-beta plaque growth in cognitively normal adults: longitudinal [11C] Pittsburgh compound B data. Annals of Neurology, 70(5), 857–861.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Westlye, E. T., Lundervold, A., Rootwelt, H., Lundervold, A. J., & Westlye, L. T. (2011). Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE ε4 carriers: relationships with memory performance. The Journal of Neuroscience, 31(21), 7775–7783.

    CAS  PubMed  Google Scholar 

  • Wierenga, C. E., & Bondi, M. W. (2007). Use of functional magnetic resonance imaging in the early identification of Alzheimer’s disease. Neuropsychology Review, 17(2), 127–143.

    PubMed Central  PubMed  Google Scholar 

  • Wishart, H. A., Saykin, A. J., McAllister, T. W., Rabin, L. A., McDonald, B. C., Flashman, L. A., et al. (2006). Regional brain atrophy in cognitively intact adults with a single APOE epsilon4 allele. Neurology, 67(7), 1221–1224.

    CAS  PubMed  Google Scholar 

  • Yi, D., Lee, D. Y., Sohn, B. K., Choe, Y. M., Seo, E. H., Byun, M. S., et al. (2014). Beta-Amyloid Associated Differential Effects of APOE ε4 on Brain Metabolism in Cognitively Normal Elderly. The American Journal of Geriatric Psychiatry: official journal of the American Association for Geriatric Psychiatry [in press].

Download references

Conflicts of Interest

None to disclose.

Author information

Authors and Affiliations

  1. INSERM, U1077, Caen, France

    Marine Fouquet, Florent L. Besson, Julie Gonneaud, Renaud La Joie & Gaël Chételat

  2. Université de Caen Basse-Normandie, UMR-S1077, Caen, France

    Marine Fouquet, Florent L. Besson, Julie Gonneaud, Renaud La Joie & Gaël Chételat

  3. Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    Marine Fouquet, Florent L. Besson, Julie Gonneaud, Renaud La Joie & Gaël Chételat

  4. CHU de Caen, U1077, Caen, France

    Marine Fouquet, Florent L. Besson, Julie Gonneaud, Renaud La Joie & Gaël Chételat

  5. Department of Nuclear Medicine, CHU de Caen, Caen, France

    Florent L. Besson

Authors
  1. Marine Fouquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florent L. Besson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie Gonneaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renaud La Joie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gaël Chételat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gaël Chételat.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fouquet, M., Besson, F.L., Gonneaud, J. et al. Imaging Brain Effects of APOE4 in Cognitively Normal Individuals Across the Lifespan. Neuropsychol Rev 24, 290–299 (2014). https://doi.org/10.1007/s11065-014-9263-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11065-014-9263-8

Keywords

Search

Navigation