Advertisement

Brain Imaging and Behavior

, Volume 8, Issue 2, pp 262–273 | Cite as

Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction

  • Leo Ungar
  • Andre Altmann
  • Michael D. Greicius
SI: Genetic Neuroimaging in Aging and Age-Related Diseases

Abstract

Alzheimer’s disease (AD) is an increasingly prevalent, fatal neurodegenerative disease that has proven resistant, thus far, to all attempts to prevent it, forestall it, or slow its progression. The ε4 allele of the Apolipoprotein E gene (APOE4) is a potent genetic risk factor for sporadic and late-onset familial AD. While the link between APOE4 and AD is strong, many expected effects, like increasing the risk of conversion from MCI to AD, have not been widely replicable. One critical, and commonly overlooked, feature of the APOE4 link to AD is that several lines of evidence suggest it is far more pronounced in women than in men. Here we review previous literature on the APOE4 by gender interaction with a particular focus on imaging-related studies.

Keywords

Alzheimer’s disease APOE: Gender Genetics Aging and aging-related diseases Neuroimaging 

References

  1. 2012 Alzheimer’s disease facts and figures. (2012). Alzheimers Dement, 8(2), 131–168. doi: 10.1016/j.jalz.2012.02.001
  2. Adamson, M. M., Hutchinson, J. B., Shelton, A. L., Wagner, A. D., & Taylor, J. L. (2011). Reduced hippocampal activity during encoding in cognitively normal adults carrying the APOE varepsilon4 allele. Neuropsychologia, 49(9), 2448–2455. doi: 10.1016/j.neuropsychologia.2011.04.022.PubMedCentralPubMedGoogle Scholar
  3. Aisen, P. S. (2011). Clinical trial methodologies for disease-modifying therapeutic approaches. Neurobiology of Aging, 32(Suppl 1), S64–S66. doi: 10.1016/j.neurobiolaging.2011.09.008.PubMedCentralPubMedGoogle Scholar
  4. Aizenstein, H. J., Nebes, R. D., Saxton, J. A., Price, J. C., Mathis, C. A., & Tsopelas, N. D. (2008). Frequent amyloid deposition without significant cognitive impairment among the elderly. Archives of Neurology, 65(11), 1509–1517. doi: 10.1001/archneur.65.11.1509.PubMedCentralPubMedGoogle Scholar
  5. Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., & Fox, N. C. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 7(3), 270–279. doi: 10.1016/j.jalz.2011.03.008.PubMedCentralPubMedGoogle Scholar
  6. Altmann, A. A., Tian, L., Henderson, V. W., & Greicius, M. D. (2013). APOE genotype by gender interaction revealed in CSF biomarkers and clinical conversion rates in the ADNI database. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 9(4), 245–246.Google Scholar
  7. Andrews-Zwilling, Y., Bien-Ly, N., Xu, Q., Li, G., Bernardo, A., & Yoon, S. Y. (2010). Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. Journal of Neuroscience, 30(41), 13707–13717. doi: 10.1523/JNEUROSCI.4040-10.2010.PubMedCentralPubMedGoogle Scholar
  8. Anstey, K., & Christensen, H. (2000). Education, activity, health, blood pressure and apolipoprotein E as predictors of cognitive change in old age: a review. Gerontology, 46(3), 163–177.PubMedGoogle Scholar
  9. Bai, F., Watson, D. R., Shi, Y., Wang, Y., Yue, C., & Teng, Y. (2011). Specifically progressive deficits of brain functional marker in amnestic type mild cognitive impairment. PLoS One, 6(9), e24271. doi: 10.1371/journal.pone.0024271.PubMedCentralPubMedGoogle Scholar
  10. Bales, K. R., Liu, F., Wu, S., Lin, S., Koger, D., & DeLong, C. (2009). Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. Journal of Neuroscience, 29(21), 6771–6779. doi: 10.1523/JNEUROSCI.0887-09.2009.PubMedGoogle Scholar
  11. Bateman, R. J., Xiong, C., Benzinger, T. L., Fagan, A. M., Goate, A., & Fox, N. C. (2012). Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. New England Journal of Medicine, 367(9), 795–804. doi: 10.1056/NEJMoa1202753.PubMedCentralPubMedGoogle Scholar
  12. Beaudreau, S. A., Kaci Fairchild, J., Spira, A. P., Lazzeroni, L. C., & O’Hara, R. (2012). Neuropsychiatric symptoms, apolipoprotein E gene, and risk of progression to cognitive impairment, no dementia and dementia: the Aging, Demographics, and Memory Study (ADAMS). International Journal of Geriatric Psychiatry. doi: 10.1002/gps.3868.PubMedGoogle Scholar
  13. Bertram, L., Lill, C. M., & Tanzi, R. E. (2010). The genetics of Alzheimer disease: back to the future. Neuron, 68(2), 270–281. doi: 10.1016/j.neuron.2010.10.013.PubMedGoogle Scholar
  14. Bertram, L., & Tanzi, R. E. (2012). The genetics of Alzheimer’s disease. Progress in Molecular Biology and Translational Science, 107, 79–100. doi: 10.1016/B978-0-12-385883-2.00008-4.PubMedGoogle Scholar
  15. Beydoun, M. A., Boueiz, A., Abougergi, M. S., Kitner-Triolo, M. H., Beydoun, H. A., & Resnick, S. M. (2012). Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia, cognitive impairment, and decline. Neurobiology of Aging, 33(4), 720–731. doi: 10.1016/j.neurobiolaging.2010.05.017. e724.PubMedCentralPubMedGoogle Scholar
  16. Blacker, D., Haines, J. L., Rodes, L., Terwedow, H., Go, R. C., & Harrell, L. E. (1997). ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology, 48(1), 139–147.PubMedGoogle Scholar
  17. 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. New England Journal of Medicine, 343(7), 450–456.PubMedCentralPubMedGoogle Scholar
  18. Bour, A., Grootendorst, J., Vogel, E., Kelche, C., Dodart, J. C., & Bales, K. (2008). Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks. Behavioural Brain Research, 193(2), 174–182. doi: 10.1016/j.bbr.2008.05.008.PubMedGoogle Scholar
  19. Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G. Q., & Xu, Q. (2004). Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. Journal of Neuroscience, 24(10), 2527–2534. doi: 10.1523/JNEUROSCI.4315-03.2004.PubMedGoogle Scholar
  20. Breitner, J. C., Wyse, B. W., Anthony, J. C., Welsh-Bohmer, K. A., Steffens, D. C., & Norton, M. C. (1999). APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology, 53(2), 321–331.PubMedGoogle Scholar
  21. Bretsky, P. M., Buckwalter, J. G., Seeman, T. E., Miller, C. A., Poirier, J., & Schellenberg, G. D. (1999). Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease. Alzheimer Disease and Associated Disorders, 13(4), 216–221.PubMedGoogle Scholar
  22. Caselli, R. J., Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., & Ahern, G. L. (2009). Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. New England Journal of Medicine, 361(3), 255–263. doi: 10.1056/NEJMoa0809437.PubMedCentralPubMedGoogle Scholar
  23. Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., & Patterson, B. W. (2011). Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Science Translational Medicine, 3(89), 89ra57. doi: 10.1126/scitranslmed.3002156.PubMedCentralPubMedGoogle Scholar
  24. Coker, L. H., Espeland, M. A., Rapp, S. R., Legault, C., Resnick, S. M., & Hogan, P. (2010). Postmenopausal hormone therapy and cognitive outcomes: the Women’s Health Initiative Memory Study (WHIMS). Journal of Steroid Biochemistry and Molecular Biology, 118(4–5), 304–310. doi: 10.1016/j.jsbmb.2009.11.007.PubMedGoogle Scholar
  25. Corder, E. H., Ghebremedhin, E., Taylor, M. G., Thal, D. R., Ohm, T. G., & Braak, H. (2004). The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Annals of the New York Academy of Sciences, 1019, 24–28. doi: 10.1196/annals.1297.005.PubMedGoogle Scholar
  26. Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., & Gaskell, P. C., Jr. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics, 7(2), 180–184.PubMedGoogle Scholar
  27. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Jr., & Rimmler, J. B. (1995). Apolipoprotein E, survival in Alzheimer’s disease patients, and the competing risks of death and Alzheimer’s disease. Neurology, 45(7), 1323–1328.PubMedGoogle Scholar
  28. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., & Small, G. W. (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.PubMedGoogle Scholar
  29. Craft, S., Teri, L., Edland, S. D., Kukull, W. A., Schellenberg, G., & McCormick, W. C. (1998). Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer’s disease. Neurology, 51(1), 149–153.PubMedGoogle Scholar
  30. Crivello, F., Lemaitre, H., Dufouil, C., Grassiot, B., Delcroix, N., & Tzourio-Mazoyer, N. (2010). Effects of ApoE-epsilon4 allele load and age on the rates of grey matter and hippocampal volumes loss in a longitudinal cohort of 1186 healthy elderly persons. NeuroImage, 53(3), 1064–1069. doi: 10.1016/j.neuroimage.2009.12.116.PubMedGoogle Scholar
  31. Cummings, J. L. (2010). Integrating ADNI results into Alzheimer’s disease drug development programs. Neurobiology of Aging, 31(8), 1481–1492. doi: 10.1016/j.neurobiolaging.2010.03.016.PubMedCentralPubMedGoogle Scholar
  32. Dal Forno, G., Carson, K. A., Brookmeyer, R., Troncoso, J., Kawas, C. H., & Brandt, J. (2002). APOE genotype and survival in men and women with Alzheimer’s disease. Neurology, 58(7), 1045–1050.PubMedGoogle Scholar
  33. Damoiseaux, J. S., Prater, K. E., Miller, B. L., & Greicius, M. D. (2012a). Functional connectivity tracks clinical deterioration in Alzheimer’s disease. Neurobiology of Aging, 33(4), 828 e819–830. doi: 10.1016/j.neurobiolaging.2011.06.024.Google Scholar
  34. Damoiseaux, J. S., Seeley, W. W., Zhou, J., Shirer, W. R., Coppola, G., & Karydas, A. (2012b). Gender modulates the APOE epsilon4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. Journal of Neuroscience, 32(24), 8254–8262. doi: 10.1523/JNEUROSCI.0305-12.2012.PubMedCentralPubMedGoogle Scholar
  35. den Heijer, T., Oudkerk, M., Launer, L. J., van Duijn, C. M., Hofman, A., & Breteler, M. M. (2002). Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology, 59(5), 746–748.Google Scholar
  36. 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. Alzheimers Dement, 6(4), 303–311. doi: 10.1016/j.jalz.2009.07.003.PubMedCentralPubMedGoogle Scholar
  37. Devanand, D. P., Pelton, G. H., Zamora, D., Liu, X., Tabert, M. H., & Goodkind, M. (2005). Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment. Archives of Neurology, 62(6), 975–980. doi: 10.1001/archneur.62.6.975.PubMedGoogle Scholar
  38. Dickson, M. R., Li, J., Wiener, H. W., Perry, R. T., Blacker, D., Bassett, S. S., et al. (2008). A genomic scan for age at onset of Alzheimer’s disease in 437 families from the NIMH Genetic Initiative. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B(6), 784–792. doi: 10.1002/ajmg.b.30689.PubMedCentralGoogle Scholar
  39. Drago, V., Babiloni, C., Bartres-Faz, D., Caroli, A., Bosch, B., & Hensch, T. (2011). Disease tracking markers for Alzheimer’s disease at the prodromal (MCI) stage. Journal of Alzheimer’s Disease, 26(Suppl 3), 159–199. doi: 10.3233/JAD-2011-0043.PubMedGoogle Scholar
  40. Drzezga, A., Grimmer, T., Henriksen, G., Muhlau, M., Perneczky, R., & Miederer, I. (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.PubMedGoogle Scholar
  41. Du, A. T., Schuff, N., Chao, L. L., Kornak, J., Jagust, W. J., & Kramer, J. H. (2006). Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiology of Aging, 27(5), 733–740. doi: 10.1016/j.neurobiolaging.2005.03.021.PubMedCentralPubMedGoogle Scholar
  42. Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., & Ladu, M. J. (2009). ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. Journal of Neuroscience, 29(48), 15317–15322. doi: 10.1523/JNEUROSCI.4026-09.2009.PubMedCentralPubMedGoogle Scholar
  43. Farlow, M. R. (2010). Should the ApoE genotype be a covariate for clinical trials in Alzheimer disease? Alzheimer’s Research & Therapy, 2(3), 15. doi: 10.1186/alzrt39.Google Scholar
  44. Farlow, M. R., Lahiri, D. K., Poirier, J., Davignon, J., Schneider, L., & Hui, S. L. (1998). Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer’s disease. Neurology, 50(3), 669–677.PubMedGoogle Scholar
  45. Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., & Mayeux, R. (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(16), 1349–1356.PubMedGoogle Scholar
  46. Filippini, N., Ebmeier, K. P., MacIntosh, B. J., Trachtenberg, A. J., Frisoni, G. B., & Wilcock, G. K. (2011). Differential effects of the APOE genotype on brain function across the lifespan. NeuroImage, 54(1), 602–610. doi: 10.1016/j.neuroimage.2010.08.009.PubMedGoogle Scholar
  47. Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., & Smith, S. M. (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.PubMedCentralPubMedGoogle Scholar
  48. Fleisher, A., Grundman, M., Jack, C. R., Jr., Petersen, R. C., Taylor, C., & Kim, H. T. (2005). Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment. Archives of Neurology, 62(6), 953–957. doi: 10.1001/archneur.62.6.953.PubMedGoogle Scholar
  49. Ghebremedhin, E., Schultz, C., Thal, D. R., Rub, U., Ohm, T. G., Braak, E., et al. (2001). Gender and age modify the association between APOE and AD-related neuropathology. Neurology, 56(12), 1696–1701.PubMedGoogle Scholar
  50. Goldman, J. S., Hahn, S. E., Catania, J. W., LaRusse-Eckert, S., Butson, M. B., & Rumbaugh, M. (2011). Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genetics in Medicine, 13(6), 597–605. doi: 10.1097/GIM.0b013e31821d69b8.PubMedCentralPubMedGoogle Scholar
  51. Gomez-Tortosa, E., Barquero, M. S., Baron, M., Sainz, M. J., Manzano, S., & Payno, M. (2007). Variability of age at onset in siblings with familial Alzheimer disease. Archives of Neurology, 64(12), 1743–1748. doi: 10.1001/archneur.64.12.1743.PubMedGoogle Scholar
  52. Greicius, M. D., Srivastava, G., Reiss, A. L., & Menon, V. (2004). Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proceedings of the National Academy of Sciences of the United States of America, 101(13), 4637–4642.PubMedCentralPubMedGoogle Scholar
  53. Guerreiro, R. J., & Hardy, J. (2011). Alzheimer’s disease genetics: lessons to improve disease modelling. Biochemical Society Transactions, 39(4), 910–916. doi: 10.1042/BST0390910.PubMedGoogle Scholar
  54. Henderson, V. W. (2009). Aging, estrogens, and episodic memory in women. Cognitive and Behavioral Neurology, 22(4), 205–214. doi: 10.1097/WNN.0b013e3181a74ce7.PubMedCentralPubMedGoogle Scholar
  55. Hirono, N., Hashimoto, M., Yasuda, M., Kazui, H., & Mori, E. (2003). Accelerated memory decline in Alzheimer’s disease with apolipoprotein epsilon4 allele. Journal of Neuropsychiatry and Clinical Neurosciences, 15(3), 354–358.PubMedGoogle Scholar
  56. Huang, Y. (2010). Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends in Molecular Medicine, 16(6), 287–294. doi: 10.1016/j.molmed.2010.04.004.PubMedGoogle Scholar
  57. Jack, C. R., Jr. (2012). Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology, 263(2), 344–361. doi: 10.1148/radiol.12110433.PubMedCentralPubMedGoogle Scholar
  58. Jack, C. R., Jr., Bernstein, M. A., Borowski, B. J., Gunter, J. L., Fox, N. C., & Thompson, P. M. (2010). Update on the magnetic resonance imaging core of the Alzheimer’s disease neuroimaging initiative. Alzheimers Dement, 6(3), 212–220. doi: 10.1016/j.jalz.2010.03.004.PubMedCentralPubMedGoogle Scholar
  59. Jak, A. J., Houston, W. S., Nagel, B. J., Corey-Bloom, J., & Bondi, M. W. (2007). Differential cross-sectional and longitudinal impact of APOE genotype on hippocampal volumes in nondemented older adults. Dementia and Geriatric Cognitive Disorders, 23(6), 382–389. doi: 10.1159/000101340.PubMedCentralPubMedGoogle Scholar
  60. Jorm, A. F., Mather, K. A., Butterworth, P., Anstey, K. J., Christensen, H., & Easteal, S. (2007). APOE genotype and cognitive functioning in a large age-stratified population sample. Neuropsychology, 21(1), 1–8. doi: 10.1037/0894-4105.21.1.1.PubMedGoogle Scholar
  61. Kang, J. H., & Grodstein, F. (2012). Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging, 33(7), 1129–1137. doi: 10.1016/j.neurobiolaging.2010.10.007.PubMedCentralPubMedGoogle Scholar
  62. Khachaturian, A. S., Corcoran, C. D., Mayer, L. S., Zandi, P. P., & Breitner, J. C. (2004). Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Archives of General Psychiatry, 61(5), 518–524. doi: 10.1001/archpsyc.61.5.518.PubMedGoogle Scholar
  63. Kleiman, T., Zdanys, K., Black, B., Rightmer, T., Grey, M., & Garman, K. (2006). Apolipoprotein E epsilon4 allele is unrelated to cognitive or functional decline in Alzheimer’s disease: retrospective and prospective analysis. Dementia and Geriatric Cognitive Disorders, 22(1), 73–82. doi: 10.1159/000093316.PubMedGoogle Scholar
  64. 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. doi: 10.1016/j.neuroscience.2010.03.044.PubMedGoogle Scholar
  65. Landau, S. M., Harvey, D., Madison, C. M., Reiman, E. M., Foster, N. L., & Aisen, P. S. (2010). Comparing predictors of conversion and decline in mild cognitive impairment. Neurology, 75(3), 230–238. doi: 10.1212/WNL.0b013e3181e8e8b8.PubMedCentralPubMedGoogle Scholar
  66. Lehmann, D. J., Refsum, H., Nurk, E., Warden, D. R., Tell, G. S., & Vollset, S. E. (2006). Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study. Journal of Neurology, Neurosurgery and Psychiatry, 77(8), 902–908. doi: 10.1136/jnnp.2005.077818.PubMedCentralPubMedGoogle Scholar
  67. Lemaitre, H., Crivello, F., Dufouil, C., Grassiot, B., Tzourio, C., Alperovitch, 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. doi: 10.1016/j.neuroimage.2004.10.016.PubMedGoogle Scholar
  68. Lu, P. H., Thompson, P. M., Leow, A., Lee, G. J., Lee, A., & Yanovsky, I. (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. doi: 10.3233/JAD-2010-101398.PubMedCentralPubMedGoogle Scholar
  69. MacGowan, S. H., Wilcock, G. K., & Scott, M. (1998). Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer’s disease. International Journal of Geriatric Psychiatry, 13(9), 625–630.PubMedGoogle Scholar
  70. Machulda, M. M., Jones, D. T., Vemuri, P., McDade, E., Avula, R., & Przybelski, S. (2011). Effect of APOE epsilon4 status on intrinsic network connectivity in cognitively normal elderly subjects. Archives of Neurology, 68(9), 1131–1136. doi: 10.1001/archneurol.2011.108.PubMedCentralPubMedGoogle Scholar
  71. Mayeux, R., Small, S. A., Tang, M., Tycko, B., & Stern, Y. (2001). Memory performance in healthy elderly without Alzheimer’s disease: effects of time and apolipoprotein-E. Neurobiology of Aging, 22(4), 683–689.PubMedGoogle Scholar
  72. McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Jr., & Kawas, C. H. (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. Alzheimers Dement, 7(3), 263–269. doi: 10.1016/j.jalz.2011.03.005.PubMedCentralPubMedGoogle Scholar
  73. Messner, D. A. (2011). Informed Choice in Direct-to-Consumer Genetic Testing for Alzheimer and Other Diseases: Lessons from Two Cases. New Genetics and Society, 30(1), 59–72. doi: 10.1080/14636778.2011.552300.PubMedCentralPubMedGoogle Scholar
  74. Meyer-Lindenberg, A., & Weinberger, D. R. (2006). Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nature Review Neuroscience, 7(10), 818–827.Google Scholar
  75. Moffat, S. D., Szekely, C. A., Zonderman, A. B., Kabani, N. J., & Resnick, S. M. (2000). Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype. Neurology, 55(1), 134–136.PubMedGoogle Scholar
  76. 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. doi: 10.1002/ana.21843.PubMedCentralPubMedGoogle Scholar
  77. Mortensen, E. L., & Hogh, P. (2001). A gender difference in the association between APOE genotype and age-related cognitive decline. Neurology, 57(1), 89–95.PubMedGoogle Scholar
  78. Nyholt, D. R., Yu, C.-E., & Visscher, P. M. (2008). On Jim Watson’s APOE status: genetic information is hard to hide. European Journal of Human Genetics, 17(2), 147–149.PubMedCentralPubMedGoogle Scholar
  79. Payami, H., Montee, K. R., Kaye, J. A., Bird, T. D., Yu, C. E., Wijsman, E. M., et al. (1994). Alzheimer’s disease, apolipoprotein E4, and gender. JAMA, 271(17), 1316–1317.PubMedGoogle Scholar
  80. Payami, H., Zareparsi, S., Montee, K. R., Sexton, G. J., Kaye, J. A., & Bird, T. D. (1996). Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. American Journal of Human Genetics, 58(4), 803–811.PubMedCentralPubMedGoogle Scholar
  81. Peskind, E. R., Li, G., Shofer, J., Quinn, J. F., Kaye, J. A., & Clark, C. M. (2006). Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Archives of Neurology, 63(7), 936–939. doi: 10.1001/archneur.63.7.936.PubMedGoogle Scholar
  82. Petersen, R. C., Smith, G. E., Ivnik, R. J., Tangalos, E. G., Schaid, D. J., & Thibodeau, S. N. (1995). Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA, 273(16), 1274–1278.PubMedGoogle Scholar
  83. Petersen, R. C., Thomas, R. G., Grundman, M., Bennett, D., Doody, R., & Ferris, S. (2005). Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine, 352(23), 2379–2388. doi: 10.1056/NEJMoa050151.PubMedGoogle Scholar
  84. Raber, J., Bongers, G., LeFevour, A., Buttini, M., & Mucke, L. (2002). Androgens protect against apolipoprotein E4-induced cognitive deficits. Journal of Neuroscience, 22(12), 5204–5209.PubMedGoogle Scholar
  85. Raber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., & Pitas, R. E. (1998). Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proceedings of the National Academy of Sciences of the United States of America, 95(18), 10914–10919.PubMedCentralPubMedGoogle Scholar
  86. Raber, J., Wong, D., Yu, G. Q., Buttini, M., Mahley, R. W., Pitas, R. E., et al. (2000). Apolipoprotein E and cognitive performance. Nature, 404(6776), 352–354. doi: 10.1038/35006165.PubMedGoogle Scholar
  87. Raskind, M. A., Peskind, E. R., Wessel, T., & Yuan, W. (2000). Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology, 54(12), 2261–2268.PubMedGoogle Scholar
  88. Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J. (2001). Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3334–3339.PubMedCentralPubMedGoogle Scholar
  89. Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., & Minoshima, S. (1996). Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. New England Journal of Medicine, 334(12), 752–758.PubMedGoogle Scholar
  90. Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., & Osborne, D. (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. doi: 10.1073/pnas.2635903100.PubMedCentralPubMedGoogle Scholar
  91. Reiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., & Lee, W. (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. doi: 10.1073/pnas.0900345106.PubMedCentralPubMedGoogle Scholar
  92. Reiman, E. M., Langbaum, J. B., Fleisher, A. S., Caselli, R. J., Chen, K., & Ayutyanont, N. (2011). Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. Journal of Alzheimer’s Disease, 26(Suppl 3), 321–329. doi: 10.3233/JAD-2011-0059.PubMedCentralPubMedGoogle Scholar
  93. Reiman, E. M., Uecker, A., Caselli, R. J., Lewis, S., Bandy, D., & de Leon, M. J. (1998). Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer’s disease. Annals of Neurology, 44(2), 288–291. doi: 10.1002/ana.410440226.PubMedGoogle Scholar
  94. Reinvang, I., Winjevoll, I. L., Rootwelt, H., & Espeseth, T. (2010). Working memory deficits in healthy APOE epsilon 4 carriers. Neuropsychologia, 48(2), 566–573. doi: 10.1016/j.neuropsychologia.2009.10.018.PubMedGoogle Scholar
  95. Reverte, I., Klein, A. B., Ratner, C., Domingo, J. L., & Colomina, M. T. (2012). Behavioral phenotype and BDNF differences related to apoE isoforms and sex in young transgenic mice. Experimental Neurology, 237(1), 116–125. doi: 10.1016/j.expneurol.2012.06.015.PubMedGoogle Scholar
  96. Rigaud, A.-S., Traykov, L., Latour, F., Couderc, R., Moulin, F., & Forette, F. (2002). Presence or absence of at least one [small element of]4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer’s disease. Pharmacogenetics and Genomics, 12(5), 415–420.Google Scholar
  97. Rijpma, A., Jansen, D., Arnoldussen, I. A. C., Fang, X. T., Wiesmann, M., & Mutsaers, M. P. C. (2013). Sex Differences in Presynaptic Density and Neurogenesis in Middle-Aged ApoE4 and ApoE Knockout Mice. Journal of Neurodegenerative Diseases, 2013, 9. doi: 10.1155/2013/531326.Google Scholar
  98. Risner, M. E., Saunders, A. M., Altman, J. F., Ormandy, G. C., Craft, S., & Foley, I. M. (2006). Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics Journal, 6(4), 246–254. doi: 10.1038/sj.tpj.6500369.PubMedGoogle Scholar
  99. Rodrigue, K. M., Kennedy, K. M., Devous, M. D., Sr., Rieck, J. R., Hebrank, A. C., & Diaz-Arrastia, R. (2012). beta-Amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology, 78(6), 387–395. doi: 10.1212/WNL.0b013e318245d295.PubMedCentralPubMedGoogle Scholar
  100. Rogers, S. L., Farlow, M. R., Doody, R. S., Mohs, R., & Friedhoff, L. T. (1998). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology, 50(1), 136–145.PubMedGoogle Scholar
  101. Rosler, M., Anand, R., Cicin-Sain, A., Gauthier, S., Agid, Y., & Dal-Bianco, P. (1999). Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ, 318(7184), 633–638.PubMedCentralPubMedGoogle Scholar
  102. Salloway, S., Sperling, R., Gilman, S., Fox, N. C., Blennow, K., & Raskind, M. (2009). A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology, 73(24), 2061–2070. doi: 10.1212/WNL.0b013e3181c67808.PubMedCentralPubMedGoogle Scholar
  103. Samuraki, M., Matsunari, I., Chen, W. P., Shima, K., Yanase, D., & Takeda, N. (2012). Glucose metabolism and gray-matter concentration in apolipoprotein E epsilon4 positive normal subjects. Neurobiology of Aging, 33(10), 2321–2323. doi: 10.1016/j.neurobiolaging.2011.11.020.PubMedGoogle Scholar
  104. Saunders, A. M., Strittmatter, W. J., Schmechel, D., George-Hyslop, P. H., Pericak-Vance, M. A., & Joo, S. H. (1993). Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology, 43(8), 1467–1472.PubMedGoogle Scholar
  105. Shaw, L. M., Vanderstichele, H., Knapik-Czajka, M., Clark, C. M., Aisen, P. S., & Petersen, R. C. (2009). Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Annals of Neurology, 65(4), 403–413. doi: 10.1002/ana.21610.PubMedCentralPubMedGoogle Scholar
  106. Sheline, Y. I., Morris, J. C., Snyder, A. Z., Price, J. L., Yan, Z., & D’Angelo, G. (2010). APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Abeta42. Journal of Neuroscience, 30(50), 17035–17040. doi: 10.1523/JNEUROSCI.3987-10.2010.PubMedCentralPubMedGoogle Scholar
  107. Sloane, P. D., Zimmerman, S., Suchindran, C., Reed, P., Wang, L., Boustani, M., et al. (2002). The public health impact of Alzheimer’s disease, 2000–2050: potential implication of treatment advances. Annual Review of Public Health, 23, 213–231.PubMedGoogle Scholar
  108. Slooter, A. J., Houwing-Duistermaat, J. J., van Harskamp, F., Cruts, M., Van Broeckhoven, C., & Breteler, M. M. (1999). Apolipoprotein E genotype and progression of Alzheimer’s disease: the Rotterdam Study. Journal of Neurology, 246(4), 304–308.PubMedGoogle Scholar
  109. Small, G. W., Ercoli, L. M., Silverman, D. H., Huang, S. C., Komo, S., & Bookheimer, S. Y. (2000). Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 97(11), 6037–6042.PubMedCentralPubMedGoogle Scholar
  110. Small, G. W., Mazziotta, J. C., Collins, M. T., Baxter, L. R., Phelps, M. E., & Mandelkern, M. A. (1995). Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA, 273(12), 942–947.PubMedGoogle Scholar
  111. Sorg, C., Riedl, V., Muhlau, M., Calhoun, V. D., Eichele, T., & Laer, L. (2007). Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 104(47), 18760–18765.PubMedCentralPubMedGoogle Scholar
  112. Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., & Fagan, A. M. (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. Alzheimers Dement, 7(3), 280–292. doi: 10.1016/j.jalz.2011.03.003.PubMedCentralPubMedGoogle Scholar
  113. Stern, Y., Brandt, J., Albert, M., Jacobs, D. M., Liu, X., & Bell, K. (1997). The absence of an apolipoprotein epsilon4 allele is associated with a more aggressive form of Alzheimer’s disease. Annals of Neurology, 41(5), 615–620. doi: 10.1002/ana.410410510.PubMedGoogle Scholar
  114. Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., et al. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 90(5), 1977–1981.PubMedCentralPubMedGoogle Scholar
  115. Sunderland, T., Mirza, N., Putnam, K. T., Linker, G., Bhupali, D., & Durham, R. (2004). Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer’s disease: the effect of APOE epsilon4 allele. Biological Psychiatry, 56(9), 670–676. doi: 10.1016/j.biopsych.2004.07.021.PubMedGoogle Scholar
  116. Swan, G. E., Lessov-Schlaggar, C. N., Carmelli, D., Schellenberg, G. D., & La Rue, A. (2005). Apolipoprotein E epsilon4 and change in cognitive functioning in community-dwelling older adults. Journal of Geriatric Psychiatry and Neurology, 18(4), 196–201. doi: 10.1177/0891988705281864.PubMedGoogle Scholar
  117. Talbot, C., Lendon, C., Craddock, N., Shears, S., Morris, J. C., & Goate, A. (1994). Protection against Alzheimer’s disease with apoE epsilon 2. Lancet, 343(8910), 1432–1433.PubMedGoogle Scholar
  118. Tierney, M. C., Szalai, J. P., Snow, W. G., Fisher, R. H., Tsuda, T., & Chi, H. (1996). A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment. Neurology, 46(1), 149–154.PubMedGoogle Scholar
  119. Tilvis, R. S., Strandberg, T. E., & Juva, K. (1998). Apolipoprotein E phenotypes, dementia and mortality in a prospective population sample. Journal of American Geriatrics Society, 46(6), 712–715.Google Scholar
  120. Tohgi, H., Takahashi, S., Kato, E., Homma, A., Niina, R., & Sasaki, K. (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.PubMedGoogle Scholar
  121. Trachtenberg, A. J., Filippini, N., Ebmeier, K. P., Smith, S. M., Karpe, F., & Mackay, C. E. (2012). The effects of APOE on the functional architecture of the resting brain. NeuroImage, 59(1), 565–572. doi: 10.1016/j.neuroimage.2011.07.059.PubMedGoogle Scholar
  122. Trojanowski, J. Q., Vandeerstichele, H., Korecka, M., Clark, C. M., Aisen, P. S., & Petersen, R. C. (2010). Update on the biomarker core of the Alzheimer’s Disease Neuroimaging Initiative subjects. Alzheimers Dement, 6(3), 230–238. doi: 10.1016/j.jalz.2010.03.008.PubMedCentralPubMedGoogle Scholar
  123. Tupler, L. A., Krishnan, K. R., Greenberg, D. L., Marcovina, S. M., Payne, M. E., & MacFall, J. R. (2007). Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve. Neurobiology of Aging, 28(11), 1644–1656. doi: 10.1016/j.neurobiolaging.2006.07.001.PubMedGoogle Scholar
  124. van Duijn, C. M., de Knijff, P., Wehnert, A., De Voecht, J., Bronzova, J. B., & Havekes, L. M. (1995). The apolipoprotein E epsilon 2 allele is associated with an increased risk of early-onset Alzheimer’s disease and a reduced survival. Annals of Neurology, 37(5), 605–610. doi: 10.1002/ana.410370510.PubMedGoogle Scholar
  125. Van Gerven, P. W., Van Boxtel, M. P., Ausems, E. E., Bekers, O., & Jolles, J. (2012). Do apolipoprotein E genotype and educational attainment predict the rate of cognitive decline in normal aging? A 12-year follow-up of the Maastricht Aging Study. Neuropsychology, 26(4), 459–472. doi: 10.1037/a0028685.PubMedGoogle Scholar
  126. van Meer, P., Acevedo, S., & Raber, J. (2007). Impairments in spatial memory retention of GFAP-apoE4 female mice. Behavioural Brain Research, 176(2), 372–375. doi: 10.1016/j.bbr.2006.10.024.PubMedCentralPubMedGoogle Scholar
  127. Vemuri, P., Wiste, H. J., Weigand, S. D., Knopman, D. S., Trojanowski, J. Q., & Shaw, L. M. (2010). Serial MRI and CSF biomarkers in normal aging, MCI, and AD. Neurology, 75(2), 143–151. doi: 10.1212/WNL.0b013e3181e7ca82.PubMedCentralPubMedGoogle Scholar
  128. Wang, K., Liang, M., Wang, L., Tian, L., Zhang, X., Li, K., et al. (2007). Altered functional connectivity in early Alzheimer’s disease: a resting-state fMRI study. Human Brain Mapping, 28(10), 967–978. doi: 10.1002/hbm.20324.PubMedGoogle Scholar
  129. Wang, P. N., Hong, C. J., Lin, K. N., Liu, H. C., & Chen, W. T. (2011). APOE epsilon4 increases the risk of progression from amnestic mild cognitive impairment to Alzheimer’s disease among ethnic Chinese in Taiwan. Journal of Neurology, Neurosurgery and Psychiatry, 82(2), 165–169. doi: 10.1136/jnnp.2010.209122.PubMedGoogle Scholar
  130. Ward, A., Crean, S., Mercaldi, C. J., Collins, J. M., Boyd, D., Cook, M. N., et al. (2012). Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology, 38(1), 1–17. doi: 10.1159/000334607.PubMedGoogle Scholar
  131. 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 epsilon4 carriers: relationships with memory performance. Journal of Neuroscience, 31(21), 7775–7783. doi: 10.1523/JNEUROSCI.1230-11.2011.PubMedGoogle Scholar
  132. Wilcock, G. K., Lilienfeld, S., & Gaens, E. (2000). Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ, 321(7274), 1445–1449.PubMedCentralPubMedGoogle Scholar
  133. Yaffe, K., Haan, M., Byers, A., Tangen, C., & Kuller, L. (2000). Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology, 54(10), 1949–1954.PubMedGoogle Scholar
  134. Zhang, H. Y., Wang, S. J., Xing, J., Liu, B., Ma, Z. L., & Yang, M. (2009). Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer’s disease. Behavioural Brain Research, 197(1), 103–108.PubMedGoogle Scholar
  135. Zhong, N., & Weisgraber, K. H. (2009). Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. Journal of Biological Chemistry, 284(10), 6027–6031. doi: 10.1074/jbc.R800009200.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Leo Ungar
    • 1
  • Andre Altmann
    • 1
  • Michael D. Greicius
    • 1
  1. 1.Functional Imaging in Neuropsychiatric Disorders (FIND) Lab, Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA

Personalised recommendations