Table of Contents Author Guidelines Submit a Manuscript
International Journal of Alzheimer’s Disease
Volume 2011 (2011), Article ID 721457, 14 pages
http://dx.doi.org/10.4061/2011/721457
Review Article

Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene

1Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, 71013 Foggia, Italy
2Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, 70121 Bari, Italy
3Institute of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, 06100 Perugia, Italy

Received 11 October 2010; Revised 11 February 2011; Accepted 11 February 2011

Academic Editor: Christiane Reitz

Copyright © 2011 Francesco Panza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. Qiu, D. De Ronchi, and L. Fratiglioni, “The epidemiology of the dementias: An update,” Current Opinion in Psychiatry, vol. 20, no. 4, pp. 380–385, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. Alzheimer's Association, “Alzheimer's disease facts and figures,” Alzheimers & Dementia, vol. 6, no. 2, pp. 158–194, 2010. View at Google Scholar
  3. R. Brookmeyer, E. Johnson, K. Ziegler-Graham, and H. M. Arrighi, “Forecasting the global burden of Alzheimer's disease,” Alzheimer's and Dementia, vol. 3, no. 3, pp. 186–191, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. M. S. Mega, J. L. Cummings, T. Fiorello, and J. Gornbein, “The spectrum of behavioral changes in Alzheimer's disease,” Neurology, vol. 46, no. 1, pp. 130–135, 1996. View at Google Scholar · View at Scopus
  5. P. Aalten, F. R. J. Verhey, M. Boziki et al., “Neuropsychiatric syndromes in dementia: results from the European Alzheimer disease Consortium: part I,” Dementia and Geriatric Cognitive Disorders, vol. 24, no. 6, pp. 457–463, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Steele, B. Rovner, G. A. Chase, and M. Folstein, “Psychiatric symptoms and nursing home placement of patients with Alzheimer's disease,” American Journal of Psychiatry, vol. 147, no. 8, pp. 1049–1051, 1990. View at Google Scholar · View at Scopus
  7. D. L. Murman, Q. Chen, M. C. Powell, S. B. Kuo, C. J. Bradley, and C. C. Colenda, “The incremental direct costs associated with behavioral symptoms in AD,” Neurology, vol. 59, no. 11, pp. 1721–1729, 2002. View at Google Scholar · View at Scopus
  8. N. Herrmann, K. L. Lanctôt, R. Sambrook et al., “The contribution of neuropsychiatric symptoms to the cost of dementia care,” International Journal of Geriatric Psychiatry, vol. 21, no. 10, pp. 972–976, 2006. View at Publisher · View at Google Scholar
  9. S. I. Finkel, J. Costa e Silva, G. Cohen, S. Miller, and N. Sartorius, “Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment,” International Psychogeriatrics, vol. 8, supplement 3, pp. 497–500, 1996. View at Publisher · View at Google Scholar
  10. C. G. Lyketsos, O. Lopez, B. Jones, A. L. Fitzpatrick, J. Breitner, and S. Dekosky, “Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study,” Journal of the American Medical Association, vol. 288, no. 12, pp. 1475–1483, 2002. View at Google Scholar · View at Scopus
  11. J. L. Cummings, M. Mega, K. Gray, S. Rosenberg-Thompson, D. A. Carusi, and J. Gornbein, “The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia,” Neurology, vol. 44, no. 12, pp. 2308–2314, 1994. View at Google Scholar · View at Scopus
  12. P. Aalten, F. R. J. Verhey, M. Boziki et al., “Consistency of neuropsychiatric syndromes across dementias: results from the European Alzheimer Disease Consortium: part II,” Dementia and Geriatric Cognitive Disorders, vol. 25, no. 1, pp. 1–8, 2007. View at Publisher · View at Google Scholar
  13. D. Seripa, F. Panza, M. Franceschi et al., “Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimer's disease,” Ageing Research Reviews, vol. 8, no. 3, pp. 214–236, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. J. C. Lambert and P. Amouyel, “Genetic heterogeneity of Alzheimer's disease: complexity and advances,” Psychoneuroendocrinology, vol. 32, no. 1, pp. S62–S70, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. D. Harold, R. Abraham, P. Hollingworth et al., “Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease,” Nature Genetics, vol. 41, no. 10, pp. 1088–1093, 2009. View at Publisher · View at Google Scholar
  16. J. C. Lambert, S. Heath, G. Even et al., “Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease,” Nature Genetics, vol. 41, no. 10, pp. 1094–1099, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Seshadri, A. L. Fitzpatrick, M. A. Ikram et al., “Genome-wide analysis of genetic loci associated with Alzheimer disease,” Journal of the American Medical Association, vol. 303, no. 18, pp. 1832–1840, 2010. View at Publisher · View at Google Scholar
  18. V. I. Zannis, P. W. Just, and J. L. Breslow, “Human apolipoprotein E isoprotein subclasses are genetically determined,” American Journal of Human Genetics, vol. 33, no. 1, pp. 11–24, 1981. View at Google Scholar · View at Scopus
  19. V. I. Zannis, J. L. Breslow, and G. Utermann, “Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes,” Journal of Lipid Research, vol. 23, no. 6, pp. 911–914, 1982. View at Google Scholar
  20. J. L. Breslow, J. McPherson, and A. L. Nussbaum, “Identification and DNA sequence of a human apolipoprotein E cDNA clone,” Journal of Biological Chemistry, vol. 257, no. 24, pp. 14639–14641, 1982. View at Google Scholar · View at Scopus
  21. H. K. Das, J. McPherson, and G. A. P. Bruns, “Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene,” Journal of Biological Chemistry, vol. 260, no. 10, pp. 6240–6247, 1985. View at Google Scholar
  22. Y.-K. Paik, D. J. Chang, and C. A. Reardon, “Nucleotide sequence and structure of the human apolipoprotein E gene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 10, pp. 3445–3449, 1985. View at Google Scholar
  23. M. Emi, L. L. Wu, M. A. Robertson et al., “Genotyping and sequence analysis of apolipoprotein E isoforms,” Genomics, vol. 3, no. 4, pp. 373–379, 1988. View at Google Scholar · View at Scopus
  24. V. Solfrizzi, C. Capurso, A. D'Introno et al., “Lifestyle-related factors in predementia and dementia syndromes,” Expert Review of Neurotherapeutics, vol. 8, no. 1, pp. 133–158, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. M. L. Levy, J. L. Cummings, L. A. Fairbanks, D. L. Sultzer, and G. W. Small, “Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease,” Biological Psychiatry, vol. 45, no. 4, pp. 422–425, 1999. View at Publisher · View at Google Scholar · View at Scopus
  26. D. Craig, D. J. Hart, K. McCool, S. P. McIlroy, and A. P. Passmore, “Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer's disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 9, pp. 1327–1330, 2004. View at Publisher · View at Google Scholar
  27. A. L. Pritchard, J. Harris, C. W. Pritchard et al., “The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 2, pp. 123–126, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. B. Borroni, M. Grassi, C. Agosti et al., “Genetic correlates of behavioral endophenotypes in Alzheimer disease: role of COMT, 5-HTTLPR and APOE polymorphisms,” Neurobiology of Aging, vol. 27, no. 11, pp. 1595–1603, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. P. Hollingworth, M. L. Hamshere, V. Moskvina et al., “Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer's disease,” Journal of the American Geriatrics Society, vol. 54, no. 9, pp. 1348–1354, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. G. D’Onofrio, F. Panza, D. Seripa et al., “The APOE polymorphism in Alzheimer’s disease patients with neuropsychiatric symptoms and syndromes,” International Journal of Geriatric Psychiatry. In press. View at Publisher · View at Google Scholar
  31. F. Panza, V. Frisardi, C. Capurso et al., “Late-Life depression, mild cognitive impairment, and dementia: possible continuum?” American Journal of Geriatric Psychiatry, vol. 18, no. 2, pp. 98–116, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. G. G. Potter and D. C. Steffens, “Contribution of depression to cognitive impairment and dementia in older adults,” Neurologist, vol. 13, no. 3, pp. 105–117, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. G. S. Alexopoulos, “Depression in the elderly,” Lancet, vol. 365, no. 9475, pp. 1961–1970, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. R. E. Wragg and D. V. Jeste, “Overview of depression and psychosis in Alzheimer's disease,” American Journal of Psychiatry, vol. 146, no. 5, pp. 577–587, 1989. View at Google Scholar · View at Scopus
  35. S. A. Beaudreau and R. O'Hara, “Late-life anxiety and cognitive impairment: a review,” American Journal of Geriatric Psychiatry, vol. 16, no. 10, pp. 790–803, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. K. B. Wolitzky-Taylor, N. Castriotta, E. J. Lenze, M. A. Stanley, and M. G. Craske, “Anxiety disorders in older adults: a comprehensive review,” Depression and Anxiety, vol. 27, no. 2, pp. 190–211, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. R. C. Kessler, P. Berglund, O. Demler, R. Jin, K. R. Merikangas, and E. E. Walters, “Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication,” Archives of General Psychiatry, vol. 62, no. 6, pp. 593–602, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. D. A. Regier, J. H. Boyd, J. D. Burke Jr. et al., “One-month prevalence of mental disorders in the United States, Based on five epidemiologic catchment area sites,” Archives of General Psychiatry, vol. 45, no. 11, pp. 977–986, 1988. View at Google Scholar · View at Scopus
  39. G. Ramachandran, K. Marder, M. Tang et al., “A preliminary study of apolipoprotein E genotype and psychiatric manifestations of Alzheimer's disease,” Neurology, vol. 47, no. 1, pp. 256–259, 1996. View at Google Scholar · View at Scopus
  40. R. Cacabelos, B. Rodríguez, C. Carrera, K. Beyer, J. I. Lao, and M. A. Sellers, “Behavioral changes associated with different apolipoprotein E genotypes in dementia,” Alzheimer Disease and Associated Disorders, vol. 11, no. 4, pp. S27–S34, 1997. View at Google Scholar · View at Scopus
  41. G. M. Murphy, J. Taylor, J. R. Tinklenberg, and J. A. Yesavage, “The apolipoprotein E ε4 allele is associated with increased behavioral disturbance in Alzheimer's disease,” American Journal of Geriatric Psychiatry, vol. 5, no. 1, pp. 88–89, 1997. View at Google Scholar · View at Scopus
  42. K. R. R. Krishnan, L. A. Tupler, J. C. Ritchie et al., “Apolipoprotein E-4 frequency in geriatric depression,” Biological Psychiatry, vol. 40, no. 1, pp. 69–71, 1996. View at Publisher · View at Google Scholar · View at Scopus
  43. D. C. Steffens, B. L. Plassman, M. J. Helms, K. A. Welsh-Bohmer, A. M. Saunders, and J. C. S. Breitner, “A twin study of late-onset depression and apolipoprotein E ε4 as risk factors for Alzheimer's disease,” Biological Psychiatry, vol. 41, no. 8, pp. 851–856, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. A. S. Rigaud, L. Traykov, L. Caputo et al., “Association of the apolipoprotein E ε4 allele with late-onset depression,” Neuroepidemiology, vol. 20, no. 4, pp. 268–272, 2001. View at Publisher · View at Google Scholar · View at Scopus
  45. R. S. Wilson, L. L. Barnes, C. F. Mendes De Leon et al., “Depressive symptoms, cognitive decline, and risk of AD in older persons,” Neurology, vol. 59, no. 3, pp. 364–370, 2002. View at Google Scholar · View at Scopus
  46. F. Irie, K. H. Masaki, H. Petrovitch et al., “Apolipoprotein E ε4 allele genotype and the effect of depressive symptoms on the risk of dementia in men: the Honolulu-Asia aging study,” Archives of General Psychiatry, vol. 65, no. 8, pp. 906–912, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. J. M. Kim, S. Y. Kim, K. Y. Bae et al., “Apolipoprotein E4 genotype and depressive symptoms as risk factors for dementia in an older Korean population,” Psychiatry Investigation, vol. 7, no. 2, pp. 135–140, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. T. Müller-Thomsen, S. Arlt, S. Ganzer et al., “Depression in Alzheimer's disease might be associated with apolipoprotein E ε4 allele frequency in women but not in men,” Dementia and Geriatric Cognitive Disorders, vol. 14, no. 2, pp. 59–63, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. L. Delano-Wood, W. S. Houston, J. A. Emond et al., “APOE genotype predicts depression in women with Alzheimer's disease: a retrospective study,” International Journal of Geriatric Psychiatry, vol. 23, no. 6, pp. 632–636, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. B. Reisberg, S. R. Auer, and I. M. Monteiro, “Behavioral pathology in Alzheimer's disease (BEHAVE-AD) rating scale,” International Psychogeriatrics, vol. 8, no. 3, pp. 301–308, 1996. View at Publisher · View at Google Scholar · View at Scopus
  51. J. L. Cummings, “Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis,” Neurobiology of Aging, vol. 21, no. 6, pp. 845–861, 2000. View at Publisher · View at Google Scholar · View at Scopus
  52. K. Shinosaki, T. Nishikawa, and M. Takeda, “Neurobiological basis of behavioral and psychological symptoms in dementia of the Alzheimer type,” Psychiatry and Clinical Neurosciences, vol. 54, no. 6, pp. 611–620, 2000. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Holmes, R. Levy, D. M. McLoughlin, J. F. Powell, and S. Lovestone, “Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 61, no. 6, pp. 580–583, 1996. View at Google Scholar · View at Scopus
  54. C. Holmes, D. M. McLoughlin, J. Powell, and S. Lovestone, “Reply,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 63, no. 2, pp. 273–274, 1997. View at Google Scholar
  55. C. Holmes, C. Russ, G. Kirov et al., “Apolipoprotein E: Depressive illness, depressive symptoms, and Alzheimer's disease,” Biological Psychiatry, vol. 43, no. 3, pp. 159–164, 1998. View at Publisher · View at Google Scholar · View at Scopus
  56. R. Cacabelos, B. Rodríguez, C. Carrera et al., “APOE-related frequency of cognitive and noncognitive symptoms in dementia,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 18, no. 10, pp. 693–706, 1996. View at Google Scholar · View at Scopus
  57. M. Lehtovirta, H. Soininen, S. Helisalmi et al., “Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism,” Neurology, vol. 46, no. 2, pp. 413–419, 1996. View at Google Scholar · View at Scopus
  58. M. Cantillon, D. Harwood, W. Barker et al., “No association between apolipoprotein E genotype and late-onset depression in Alzheimer's disease,” Biological Psychiatry, vol. 41, no. 2, pp. 246–248, 1997. View at Publisher · View at Google Scholar · View at Scopus
  59. G. Spalletta, S. Bernardini, L. Bellincampi, G. Federici, A. Trequattrini, and C. Caltagirone, “Delusion symptoms are associated with ApoE ε4 allelic variant at the early stage of Alzheimer's disease with late onset,” European Journal of Neurology, vol. 13, no. 2, pp. 176–182, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. Y. Forsell, E. H. Corder, H. Basun, L. Lannfelt, M. Viitanen, and B. Winblad, “Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age +75,” Biological Psychiatry, vol. 42, no. 10, pp. 898–903, 1997. View at Publisher · View at Google Scholar · View at Scopus
  61. Y. Forsell, H. Basun, E. H. Corder, L. Lannfelt, and B. Winblad, “Psychotic symptoms and apolipoprotein E genotypes in an elderly population,” Biological Psychiatry, vol. 44, no. 2, pp. 139–140, 1998. View at Publisher · View at Google Scholar · View at Scopus
  62. O. L. Lopez, M. I. Kamboh, J. T. Becker, D. I. Kaufer, and S. T. DeKosky, “The apolipoprotein E ε4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease,” Neurology, vol. 49, no. 3, pp. 794–797, 1997. View at Google Scholar · View at Scopus
  63. C. G. Lyketsos, L. Baker, A. Warren et al., “Depression, delusions, and hallucinations in Alzheimer's disease: no relationship to apolipoprotein E genotype,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 9, no. 1, pp. 64–67, 1997. View at Google Scholar · View at Scopus
  64. N. Hirono, E. Mori, M. Yasuda et al., “Factors associated with psychotic symptoms in Alzheimer's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 64, no. 5, pp. 648–652, 1998. View at Google Scholar · View at Scopus
  65. N. Hirono, E. Mori, M. Yasuda et al., “Lack of effect of apolipoprotein E E4 allele on neuropsychiatric manifestations in Alzheimer's disease,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 11, no. 1, pp. 66–70, 1999. View at Google Scholar · View at Scopus
  66. D. G. Harwood, W. W. Barker, R. L. Ownby, -. P. ST. George, and R. Duara, “Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer's disease,” American Journal of Geriatric Psychiatry, vol. 7, no. 2, pp. 119–123, 1999. View at Google Scholar · View at Scopus
  67. C. Y. Liu, C. J. Hong, T. Y. Liu et al., “Lack of association between the apolipoprotein E genotype and depression in Alzheimer's disease,” Journal of Geriatric Psychiatry and Neurology, vol. 15, no. 1, pp. 20–23, 2002. View at Google Scholar · View at Scopus
  68. N. Scarmeas, J. Brandt, M. Albert et al., “Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease,” Neurology, vol. 58, no. 8, pp. 1182–1188, 2002. View at Google Scholar · View at Scopus
  69. T. Gabryelewicz, D. Religa, M. Styczynska et al., “Behavioural pathology in Alzheimer's disease with special reference to apolipoprotein E genotype,” Dementia and Geriatric Cognitive Disorders, vol. 14, no. 3-4, pp. 208–212, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. R. A. Sweet, V. L. Nimgaonkar, B. Devlin, O. L. Lopez, and S. T. DeKosky, “Increased familial risk of the psychotic phenotype of Alzheimer disease,” Neurology, vol. 58, no. 6, pp. 907–911, 2002. View at Google Scholar · View at Scopus
  71. D. Craig, D. J. Hart, S. P. McIlroy, and A. P. Passmore, “Association analysis of apolipoprotein E genotype and risk of depressive symptoms in Alzheimer's disease,” Dementia and Geriatric Cognitive Disorders, vol. 19, no. 2-3, pp. 154–157, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. J. B. Chang, P. N. Wang, W. T. Chen et al., “ApoE ε4 allele is associated with incidental hallucinations and delusions in patients with AD,” Neurology, vol. 63, no. 6, pp. 1105–1107, 2004. View at Google Scholar · View at Scopus
  73. J. Robertson, J. Curley, J. Kaye, J. Quinn, T. Pfankuch, and J. Raber, “apoE isoforms and measures of anxiety in probable AD patients and Apoe-/- mice,” Neurobiology of Aging, vol. 26, no. 5, pp. 637–643, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. R. Monastero, E. Mariani, C. Camarda et al., “Association between apolipoprotein E ε4 allele and apathy in probable Alzheimer's disease,” Acta Psychiatrica Scandinavica, vol. 113, no. 1, pp. 59–63, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. W. M. Van Der Flier, S. Staekenborg, Y. A. L. Pijnenburg et al., “Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease,” Dementia and Geriatric Cognitive Disorders, vol. 23, no. 1, pp. 42–46, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. K. F. Zdanys, T. G. Kleiman, M. G. MacAvoy et al., “Apolipoprotein E ε4 allele increases risk for psychotic symptoms in Alzheimer's disease,” Neuropsychopharmacology, vol. 32, no. 1, pp. 171–179, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. M. P. Chopra, R. D. Landes, R. A. Jones, Z. L. Feldman, C. Beck, and S. T. Griffin, “Does the apolipoproten E ε4 genotype influence the expression of depression with cognitive impairment?” International Journal of Geriatric Psychiatry, vol. 24, no. 6, pp. 650–652, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. M. Del Prete, S. Spaccavento, A. Craca, P. Fiore, and P. Angelelli, “Neuropsychiatric symptoms and the APOE genotype in Alzheimer's disease,” Neurological Sciences, vol. 30, no. 5, pp. 367–373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. D. L. Woods, B. Bushnell, H. Kim, D. Geschwind, and J. Cummings, “Apolipoprotein epsilon4 status is associated with behavioral symptoms in nursing home residents with dementia,” International Psychogeriatrics, vol. 21, supplement 4, pp. 722–728, 2009. View at Google Scholar
  80. C. Ballard, H. Massey, H. Lamb, and C. Morris, “Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 63, no. 2, pp. 273–274, 1997. View at Google Scholar · View at Scopus
  81. L. G. Apostolova and J. L. Cummings, “Neuropsychiatric manifestations in mild cognitive impairment: A systematic review of the literature,” Dementia and Geriatric Cognitive Disorders, vol. 25, no. 2, pp. 115–126, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. V. R. Porter, W. G. Buxton, L. A. Fairbanks et al., “Frequency and characteristics of anxiety among patients with Alzheimer's disease and related dementias,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 15, no. 2, pp. 180–186, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. L. A. Farrer, L. A. Cupples, J. L. Haines et al., “Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis,” Journal of the American Medical Association, vol. 278, no. 16, pp. 1349–1356, 1997. View at Google Scholar · View at Scopus
  84. J. Raber, “Role of apolipoprotein E in anxiety,” Neural Plasticity, vol. 2007, Article ID 91236, 7 pages, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. J. A. Siegel, G. E. Haley, and J. Raber, “Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice,” Neurobiology of Aging. In press. View at Publisher · View at Google Scholar · View at Scopus
  86. R. S. Marin, “Apathy: a neuropsychiatric syndrome,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 3, no. 3, pp. 243–254, 1991. View at Google Scholar · View at Scopus
  87. S. Ishii, N. Weintraub, and J. R. Mervis, “Apathy: a common psychiatric syndrome in the elderly,” Journal of the American Medical Directors Association, vol. 10, no. 6, pp. 381–393, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publishing, Arlington, Va, USA, 4th edition, 2004.
  89. A. M. Landes, S. D. Sperry, M. E. Strauss, and D. S. Geldmacher, “Apathy in Alzheimer's disease,” Journal of the American Geriatrics Society, vol. 49, no. 12, pp. 1700–1707, 2001. View at Publisher · View at Google Scholar · View at Scopus
  90. M. L. Levy, J. L. Cummings, L. A. Fairbanks et al., “Apathy is not depression,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 10, no. 3, pp. 314–319, 1998. View at Google Scholar · View at Scopus
  91. S. E. Starkstein, L. Sabe, S. Vázquez et al., “Neuropsychological, psychiatric, and cerebral blood flow findings in vascular dementia and Alzheimer's disease,” Stroke, vol. 27, no. 3, pp. 408–414, 1996. View at Google Scholar · View at Scopus
  92. G. D’Onofrio, D. Sancarlo, F. Panza et al., “Neuropsychiatric symptoms in patients with Alzheimer’s disease and vascular dementia,” Current Alzheimer Research. In press.
  93. R. A. Sweet, V. L. Nimgaonkar, B. Devlin, and D. V. Jeste, “Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype,” Molecular Psychiatry, vol. 8, no. 4, pp. 383–392, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. D. V. Jeste, T. W. Meeks, D. S. Kim, and G. S. Zubenko, “Research agenda for DSM-V: diagnostic categories and criteria for neuropsychiatric syndromes in dementia,” Journal of Geriatric Psychiatry and Neurology, vol. 19, no. 3, pp. 160–171, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. S. A. Ropacki and D. V. Jeste, “Epidemiology of and risk factors for psychosis of Alzheimer's disease: a review of 55 studies published from 1990 to 2003,” American Journal of Psychiatry, vol. 162, no. 11, pp. 2022–2030, 2005. View at Publisher · View at Google Scholar · View at Scopus
  96. C. G. Lyketsos, J. M. E. Sheppard, M. Steinberg et al., “Neuropsychiatric disturbance in Alzheimer's disease clusters into three groups: the Cache County Study,” International Journal of Geriatric Psychiatry, vol. 16, no. 11, pp. 1043–1053, 2001. View at Publisher · View at Google Scholar · View at Scopus
  97. D. V. Jeste and S. I. Finkel, “Psychosis of Alzheimer's disease and related dementias: diagnostic criteria for a distinct syndrome,” American Journal of Geriatric Psychiatry, vol. 8, no. 1, pp. 29–34, 2000. View at Google Scholar · View at Scopus
  98. S. A. Bacanu, B. Devlin, K. V. Chowdari, S. T. DeKosky, V. L. Nimgaonkar, and R. A. Sweet, “Heritability of psychosis in Alzheimer disease,” American Journal of Geriatric Psychiatry, vol. 13, no. 7, pp. 624–627, 2005. View at Publisher · View at Google Scholar · View at Scopus
  99. R. A. Sweet, M. I. Kamboh, S. R. Wisniewski et al., “Apolipoprotein E and alpha-1-antichymotrypsin genotypes do not predict time to psychosis in Alzheimer's disease,” Journal of Geriatric Psychiatry and Neurology, vol. 15, no. 1, pp. 24–30, 2002. View at Google Scholar · View at Scopus
  100. B. Nacmias, A. Tedde, P. Forleo et al., “Association between 5-HT receptor polymorphism and psychotic symptoms in Alzheimer's disease,” Biological Psychiatry, vol. 50, no. 6, pp. 472–475, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. M. F. Weiner, G. Vega, R. C. Risser et al., “Apolipoprotein Eε4, other risk factors, and course of Alzheimer's disease,” Biological Psychiatry, vol. 45, no. 5, pp. 633–638, 1999. View at Publisher · View at Google Scholar · View at Scopus
  102. P. Aalten, M. E. De Vugt, R. Lousberg et al., “Behavioral problems indementia: a factor analysis of the neuropsychiatric inventory,” Dementia and Geriatric Cognitive Disorders, vol. 15, no. 2, pp. 99–105, 2003. View at Publisher · View at Google Scholar · View at Scopus
  103. J. Cohen-Mansfield, “Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique,” American Journal of Geriatric Psychiatry, vol. 9, no. 4, pp. 361–381, 2001. View at Publisher · View at Google Scholar · View at Scopus
  104. J. Cohen-Mansfield and P. Werner, “Longitudinal predictors of non-aggressive agitated behaviors in the elderly,” International Journal of Geriatric Psychiatry, vol. 14, no. 10, pp. 831–844, 1999. View at Publisher · View at Google Scholar · View at Scopus
  105. L. H. Deutsch, F. W. Bylsma, B. W. Rovner, C. Steele, and M. F. Folstein, “Psychosis and physical aggression in probable Alzheimer's disease,” American Journal of Psychiatry, vol. 148, no. 9, pp. 1159–1163, 1991. View at Google Scholar · View at Scopus
  106. M. A. DeMichele-Sweet and R. A. Sweet, “Genetics of psychosis in Alzheimer's disease: a review,” Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 761–780, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. B. Borroni, C. Costanzi, and A. Padovani, “Genetic susceptibility to behavioural and psychological symptoms in alzheimer disease,” Current Alzheimer Research, vol. 7, no. 2, pp. 158–164, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. S. López-León, A. C. J. W. Janssens, A. M. González-Zuloeta Ladd et al., “Meta-analyses of genetic studies on major depressive disorder,” Molecular Psychiatry, vol. 13, no. 8, pp. 772–785, 2008. View at Publisher · View at Google Scholar · View at Scopus
  109. M. O. McCarron, D. Delong, and M. J. Alberts, “APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis,” Neurology, vol. 53, no. 6, pp. 1308–1311, 1999. View at Google Scholar · View at Scopus
  110. H. Sawada, F. Udaka, Y. Izumi et al., “Cerebral white matter lesions are not associated with apoE genotype but with age and female sex in Alzheimer's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 68, no. 5, pp. 653–656, 2000. View at Publisher · View at Google Scholar · View at Scopus
  111. J. Davignon, J. S. Cohn, L. Mabile, and L. Bernier, “Apolipoprotein E and atherosclerosis: insight from animal and human studies,” Clinica Chimica Acta, vol. 286, no. 1-2, pp. 115–143, 1999. View at Publisher · View at Google Scholar · View at Scopus
  112. E. Brscic, S. Bergerone, A. Gagnor et al., “Acute myocardial infarction in young adults: prognostic role of angiatensin-converting enzyme, angiotensin II type I receptor, apolipoprotein E, endothelial constitutive nitric oxide synthase, and glycoprotein IIIa genetic polymorphisms at medium-term follow-up,” American Heart Journal, vol. 139, no. 6, pp. 979–984, 2000. View at Publisher · View at Google Scholar · View at Scopus
  113. F. E. De Leeuw, F. Richard, J. C. De Groot et al., “Interaction between hypertension, apoE, and cerebral white matter lesions,” Stroke, vol. 35, no. 5, pp. 1057–1060, 2004. View at Publisher · View at Google Scholar · View at Scopus
  114. G. S. Alexopoulos, B. S. Meyers, R. C. Young, T. Kakuma, D. Silbersweig, and M. Charlson, “Clinically defined vascular depression,” American Journal of Psychiatry, vol. 154, no. 4, pp. 562–565, 1997. View at Google Scholar · View at Scopus
  115. G. S. Alexopoulos, S. K. Schultz, and B. D. Lebowitz, “Late-life depression: a model for medical classification,” Biological Psychiatry, vol. 58, no. 4, pp. 283–289, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. K. A. Treiber, C. G. Lyketsos, C. Corcoran et al., “Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study,” International Psychogeriatrics, vol. 20, no. 3, pp. 538–553, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. J. O'Brien, R. Perry, R. Barber, A. Gholkar, and A. Thomas, “The association between white matter lesions on magnetic resonance imaging and noncognitive symptoms,” Annals of the New York Academy of Sciences, vol. 903, pp. 482–489, 2000. View at Google Scholar
  118. Y. E. Geda, D. S. Knopman, D. A. Mrazek et al., “Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study,” Archives of Neurology, vol. 63, no. 3, pp. 435–440, 2006. View at Publisher · View at Google Scholar · View at Scopus
  119. M. Michikawa, QI. W. Fan, I. Isobe, and K. Yanagisawa, “Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture,” Journal of Neurochemistry, vol. 74, no. 3, pp. 1008–1016, 2000. View at Publisher · View at Google Scholar · View at Scopus
  120. T. Arendt, C. Schindler, M. K. Brückner et al., “Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein ε4 allele,” Journal of Neuroscience, vol. 17, no. 2, pp. 516–529, 1997. View at Google Scholar
  121. F. C. Crawford, R. D. Vanderploeg, M. J. Freeman et al., “APOE genotype influences acquisition and recall following traumatic brain injury,” Neurology, vol. 58, no. 7, pp. 1115–1118, 2002. View at Google Scholar · View at Scopus
  122. A. H. Craig, J. L. Cummings, L. Fairbanks et al., “Cerebral blood flow correlates of apathy in Alzheimer disease,” Archives of Neurology, vol. 53, no. 11, pp. 1116–1120, 1996. View at Google Scholar · View at Scopus
  123. O. Migneco, M. Benoit, P. M. Koulibaly et al., “Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer's disease and nondemented patients,” NeuroImage, vol. 13, no. 5, pp. 896–902, 2001. View at Publisher · View at Google Scholar · View at Scopus
  124. S. Tekin, M. S. Mega, D. M. Masterman et al., “Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease,” Annals of Neurology, vol. 49, no. 3, pp. 355–361, 2001. View at Publisher · View at Google Scholar · View at Scopus
  125. S. Mcpherson, L. Fairbanks, S. Tiken, J. L. Cummings, and C. Back-Madruga, “Apathy and executive function in Alzheimer's disease,” Journal of the International Neuropsychological Society, vol. 8, no. 3, pp. 373–381, 2002. View at Publisher · View at Google Scholar · View at Scopus
  126. P. A. Boyle and P. F. Malloy, “Treating apathy in Alzheimer's disease,” Dementia and Geriatric Cognitive Disorders, vol. 17, no. 1-2, pp. 91–99, 2004. View at Publisher · View at Google Scholar · View at Scopus
  127. H. Soininen, O. Kosunen, S. Helisalmi et al., “A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein ε4 allele,” Neuroscience Letters, vol. 187, no. 2, pp. 79–82, 1995. View at Publisher · View at Google Scholar · View at Scopus
  128. H. Yamaguchi, S. Sugihara, A. Ogawa, N. Oshima, and Y. Ihara, “Alzheimer β amyloid deposition enhanced by ApoE ε4 gene precedes neurofibrillary pathology in the frontal association cortex of nondemented senior subjects,” Journal of Neuropathology and Experimental Neurology, vol. 60, no. 7, pp. 731–739, 2001. View at Google Scholar
  129. D. E. Schmechel, A. M. Saunders, W. J. Strittmatter et al., “Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 20, pp. 9649–9653, 1993. View at Publisher · View at Google Scholar · View at Scopus
  130. T. Gomez-Isla, H. L. West, G. W. Rebeck et al., “Clinical and pathological correlates of apolipoprotein ε4 in Alzheimer's disease,” Annals of Neurology, vol. 39, no. 1, pp. 62–70, 1996. View at Google Scholar · View at Scopus
  131. G. S. Zubenko, J. Moossy, A. J. Martinez et al., “Neuropathologic and neurochemical correlates of psychosis in primary dementia,” Archives of Neurology, vol. 48, no. 6, pp. 619–624, 1991. View at Google Scholar · View at Scopus
  132. R. A. Sweet, R. L. Hamilton, O. L. Lopez et al., “Psychotic symptoms in Alzheimer's disease are not associated with more severe neuropathologic features,” International Psychogeriatrics, vol. 12, no. 4, pp. 547–558, 2000. View at Publisher · View at Google Scholar · View at Scopus
  133. J. Poirier, M. C. Delisle, R. Quirion et al., “Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 26, pp. 12260–12264, 1995. View at Publisher · View at Google Scholar · View at Scopus
  134. J. L. Cummings and D. Kaufer, “Neuropsychiatric aspects of Alzheimer's disease: the cholinergic hypothesis revisited,” Neurology, vol. 47, no. 4, pp. 876–883, 1996. View at Google Scholar · View at Scopus
  135. H. Forstl, A. Burns, R. Levy, and N. Cairns, “Neuropathological correlates of psychotic phenomena in confirmed Alzheimer's disease,” British Journal of Psychiatry, vol. 164, pp. 53–59, 1994. View at Google Scholar · View at Scopus
  136. S. E. Starkstein, S. Vazquez, G. Petracca et al., “A SPECT study of delusions in Alzheimer's disease,” Neurology, vol. 44, no. 11, pp. 2055–2059, 1994. View at Google Scholar · View at Scopus
  137. K. U. Lee, J. S. Lee, KI. W. Kim et al., “Influence of the apolipoprotein E type 4 allele on cerebral glucose metabolism in Alzheimer's disease patients,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 15, no. 1, pp. 78–83, 2003. View at Publisher · View at Google Scholar · View at Scopus
  138. C. H. Van Dyck, J. Gelernter, M. G. MacAvoy et al., “Absence of an apolipoprotein E ε4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease,” Archives of Neurology, vol. 55, no. 11, pp. 1460–1466, 1998. View at Google Scholar · View at Scopus
  139. M. Lehtovirta, H. Soininen, M. P. Laakso et al., “SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E ε4 allele,” Journal of Neurology Neurosurgery and Psychiatry, vol. 60, no. 6, pp. 644–649, 1996. View at Google Scholar · View at Scopus
  140. M. Hashimoto, M. Yasuda, S. Tanimukai et al., “Apolipoprotein E ε4 and the pattern of regional brain atrophy in Alzheimer's disease,” Neurology, vol. 57, no. 8, pp. 1461–1466, 2001. View at Google Scholar · View at Scopus
  141. M. Basso, J. Gelernter, J. Yang et al., “Apolipoprotein E epsilon4 is associated with atrophy of the amygdala in Alzheimer's disease,” Neurobiology of Aging, vol. 27, no. 10, pp. 1416–1424, 2006. View at Publisher · View at Google Scholar · View at Scopus
  142. M. Kanai, M. Shizuka, K. Urakami et al., “Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease,” Neuroscience Letters, vol. 267, no. 1, pp. 65–68, 1999. View at Publisher · View at Google Scholar · View at Scopus
  143. M. J. McNamara, T. Gomez-Isla, and B. T. Hyman, “Apolipoprotein E genotype and deposits of Aβ40 and Aβ42 in Alzheimer disease,” Archives of Neurology, vol. 55, no. 7, pp. 1001–1004, 1998. View at Publisher · View at Google Scholar · View at Scopus
  144. S. Tekin, M. S. Mega, D. M. Masterman et al., “Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease,” Annals of Neurology, vol. 49, no. 3, pp. 355–361, 2001. View at Publisher · View at Google Scholar · View at Scopus
  145. N. Hirono, M. S. Mega, I. D. Dinov, F. Mishkin, and J. L. Cummings, “Left frontotemporal hypoperfusion is associated with aggression in patients with dementia,” Archives of Neurology, vol. 57, no. 6, pp. 861–866, 2000. View at Google Scholar · View at Scopus
  146. B. Lawlor, “Serotonin and Alzheimer’s disease,” Psychiatric Annals, vol. 20, pp. 567–570, 1990. View at Google Scholar
  147. K. J. Reinikainen, H. Soininen, and P. J. Reikkinen, “Neurotransmitter changes in Alzheimer’s dementia and agitation,” Journal of Neuroscience Research, vol. 27, no. 4, pp. 576–586, 1990. View at Google Scholar
  148. C. Reitz and R. Mayeux, “Endophenotypes in normal brain morphology and Alzheimer's disease: a review,” Neuroscience, vol. 164, no. 1, pp. 174–190, 2009. View at Google Scholar · View at Scopus