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  • Review Article
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Review Article

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

Abstract

Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40–60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses.

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References

  1. Tanzi RE, Bertram L . New frontiers in Alzheimer's disease genetics. Neuron 2001; 32: 181–184.

    Article  CAS  PubMed  Google Scholar 

  2. Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L et al. Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol 2000; 35: 1343–1352.

    Article  CAS  PubMed  Google Scholar 

  3. Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I et al. A full genome scan for late onset Alzheimer's disease. Hum Mol Genet 1999; 8: 237–245.

    Article  CAS  PubMed  Google Scholar 

  4. Jeste DV, Finkel SI . Psychosis of Alzheimer's disease and related dementias. Am J Geriatr Psychiatry 2000; 8: 29–34.

    Article  CAS  PubMed  Google Scholar 

  5. Sweet RA, Nimgaonkar VL, Kamboh MI, Lopez OL, Zhang F, DeKosky ST . Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer's disease. Arch Neurol 1998; 55: 1335–1340.

    Article  CAS  PubMed  Google Scholar 

  6. Sweet RA, Nimgaonkar VL, Devlin B, Lopez OL, DeKosky ST . Increased familial risk of the psychotic phenotype of Alzheimer disease. Neurology 2002; 58: 907–911.

    Article  CAS  PubMed  Google Scholar 

  7. Stedman's Medical Dictionary, 27th edn. Lippincott Williams & Wilkins: Baltimore, 2000.

  8. Tsuang MT, Faraone SV, Lyons MJ . Identification of the phenotype in psychiatric genetics. Eur Arch Psychiatry Clin Neurosci 1993; 243: 131–142.

    Article  CAS  PubMed  Google Scholar 

  9. Tariot PN, Mack JL, Patterson MB, Edland SD, Weiner MF, Fillenbaum G et al. The behavior rating scale for dementia of the Consortium to Establish a Registry for Alzheimer's Disease. Am J Psychiatry 1995; 152: 1349–1357.

    Article  CAS  PubMed  Google Scholar 

  10. Rubin EH, Drevets WC, Burke WJ . Nature of psychotic symptoms in senile dementia of the Alzheimer type. J Geriatr Psychiatry Neurol 1988; 1: 17–20.

    Google Scholar 

  11. Devanand DP, Miller L, Richards M, Marder K, Bell K, Mayeux R et al. The Columbia University Scale for Psychopathology in Alzheimer's disease. Arch Neurol 1992; 49: 371–376.

    Article  CAS  PubMed  Google Scholar 

  12. Burns A, Jacoby R, Levy R . Psychiatric phenomena in Alzheimer's disease. I: Disorders of thought content. Br J Psychiatry 1990; 157: 72–76.

    Article  CAS  PubMed  Google Scholar 

  13. Burns A, Jacoby R, Levy R . Psychiatric phenomena in Alzheimer's disease. II. Disorders of perception. Br J Psychiatry 1990; 157: 76–81.

    Article  CAS  PubMed  Google Scholar 

  14. Levin HS, High WM, Goethe KE, Sisson RA, Overall JE, Rhoades HM et al. The neurobehavioural rating scale: assessment of the behavioral sequelae of head injury by the clinician. J Neurol Neurosurg Psychiatry 1987; 50: 183–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotis A . Behavioral symptoms in Alzheimer's disease: phenomenology and treatment. J Clin Psychiatry 1987; 48: 9–15.

    PubMed  Google Scholar 

  16. Cummings JL . The neuropsychiatric inventory: assessing psychopathology in dementia patients. Neurology 1997; 48(Suppl 6):10S–16S.

    Article  Google Scholar 

  17. Mack JL, Patterson MB . The evaluation of behavioral disturbances in Alzheimer's disease: the utility of three rating scales. J Geriatr Psychiatry Neurol 1994; 7: 101–117.

    Article  Google Scholar 

  18. Wragg RE, Jeste DV . Overview of depression and psychosis in Alzheimer's disease. Am J Psychiatry 1989; 146: 577–587.

    Article  CAS  PubMed  Google Scholar 

  19. Paulsen JS, Salmon DP, Thal L, Romero R, Weisstein-Jenkins C, Galasko D et al. Incidence of and risk factors for hallucinations and delusions in patients with probable Alzheimer's disease. Neurology 2000; 54: 1965–1971.

    Article  CAS  PubMed  Google Scholar 

  20. Sweet RA, Hamilton RL, Lopez OL, Klunk WE, Wisniewski SR, Kaufer DI et al. Psychotic symptoms in Alzheimer's disease are not associated with more severe neuropathologic features. Int Psychogeriatr 2000; 12: 547–558.

    Article  CAS  PubMed  Google Scholar 

  21. Farber NB, Rubin EH, Newhouse PA, Kinscherf DA, Miller JP, Morris JC et al. Increased neocortical neurofibrillary tangle density in subjects with Alzheimer's disease. Arch Gen Psychiatry 2000; 57: 1165–1173.

    Article  CAS  PubMed  Google Scholar 

  22. Forstl H, Burns A, Levy R, Cairns N . Neuropathological correlates of psychotic phenomena in confirmed Alzheimer's disease. Br J Psychiatry 1994; 165: 53–59.

    Article  CAS  PubMed  Google Scholar 

  23. Kaufer DI, Cummings JL, Christine D, Bray T, Castellon S, Masterman D et al. Assessing the impact of neuropsy-chiatric symptoms in Alzheimer's disease: the Neuropsychiatric Inventory Caregiver Distress Scale. J Am Geriatr Soc 1998; 46: 210–215.

    Article  CAS  PubMed  Google Scholar 

  24. Deutsch LH, Bylsma FW, Rovner BW, Steele C, Folstein MF . Psychosis and physical aggression in probable Alzheimer's disease. Am J Psychiatry 1991; 148: 1159–1163.

    Article  CAS  PubMed  Google Scholar 

  25. Aarsland D, Cummings JL, Yenner G, Miller B . Relationship of aggressive behavior to other neuropsychiatric symptoms in patients with Alzheimer's disease. Am J Psychiatry 1996; 153: 243–247.

    Article  CAS  PubMed  Google Scholar 

  26. Sweet RA, Pollock BG, Sukonick DL, Mulsant BH, Rosen J, Klunk WE et al. The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer's disease. Int Psychogeriatr 2001; 13: 401–409.

    Article  CAS  PubMed  Google Scholar 

  27. Gilley DW, Wilson RS, Beckett LA, Evans DA . Psychotic symptoms and physically aggressive behavior in Alzheimer's disease. J Am Geriatr Soc 1997; 45: 1074–1079.

    Article  CAS  PubMed  Google Scholar 

  28. McShane R, Keene J, Fairburn C, Jacoby R, Hope T . Psychiatric symptoms in patients with dementia predict the later development of behavioural abnormalities. Psychol Med 1998; 28: 1119–1127.

    Article  CAS  PubMed  Google Scholar 

  29. Richards SS, Sweet RA . Treating psychosis in Alzheimer's disease. Alzheimer's Disease Manage Today 1999; 2: 3–9.

    Google Scholar 

  30. Stern Y, Mayeux R, Sano M, Hauser WA, Bush T . Predictors of disease course in patients with probable Alzheimer's disease. Neurology 1987; 37: 1649–1653.

    Article  CAS  PubMed  Google Scholar 

  31. Jeste DV, Wragg RE, Salmon DP, Harris MJ, Thal LJ . Cognitive deficits of patients with Alzheimer's disease with and without delusions. Am J Psychiatry 1992; 149: 184–189.

    Article  CAS  PubMed  Google Scholar 

  32. Rockwell E, Jackson E, Vilke G, Jeste DV . A study of delusions in a large cohort of Alzheimer's disease patients. Am J Geriatr Psychiatry 1994; 2: 157–164.

    PubMed  Google Scholar 

  33. Lopez OL, Kamboh MI, Becker JT, Kaufer DI, DeKosky ST . The apolipoprotein E e4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease. Neurology 1997; 49: 794–797.

    Article  CAS  PubMed  Google Scholar 

  34. Paulsen JS, Ready RE, Stout JC, Salmon DP, Thal LJ, Grant I et al. Neurobehaviors and psychotic symptoms in Alzheimer's disease. J Int Neuropsychol Soc 2000; 7: 815–820.

    Article  Google Scholar 

  35. Drevets WC, Rubin EH . Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type. Biol Psychiatry 1989; 25: 39–48.

    Article  CAS  PubMed  Google Scholar 

  36. Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST . Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol 1999; 56: 1266–1272.

    Article  CAS  PubMed  Google Scholar 

  37. Levy ML, Cummings J, Fairbanks LA, Bravi D, Calvani M, Carta A . Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer's disease. Am J Psychiatry 1996; 153: 1438–1443.

    Article  CAS  PubMed  Google Scholar 

  38. Ballard CG, O'Brien JT, Coope B, Wilcock G . Psychotic symptoms in dementia and the rate of cognitive decline.J Am Geriatr Soc 1997; 45: 1031–1032.

    Article  CAS  PubMed  Google Scholar 

  39. McShane R, Keene J, Gedling J, Fairburn C, Jacoby R, Hope T . Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up. BMJ 1997; 314: 266–270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mortimer JA, Ebbitt B, Jun SP, Finch MD . Predictors of cognitive and functional progression in patients with probable Alzheimer's disease. Neurology 1992; 42: 1689–1696.

    Article  CAS  PubMed  Google Scholar 

  41. Magni E, Binetti G, Bianchetti A, Trabucchi M . Risk of mortality and institutionalization in demented patients with delusions. J Geriatr Psychiatry Neurol 1996; 9: 123–126.

    Article  CAS  PubMed  Google Scholar 

  42. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47: 1113–1124.

    Article  CAS  PubMed  Google Scholar 

  43. Lopez OL, Hamilton RL, Becker JT, Wisniewski S, Kaufer DI, DeKosky ST . Severity of cognitive impairment and the clinical diagnosis of AD with Lewy bodies. Neurology 2000; 54: 1780–1787.

    Article  CAS  PubMed  Google Scholar 

  44. Galasko DR, Gould RL, Abramson IS, Salmon DP . Measuring cognitive change in a cohort of patients with Alzheimer's disease. Stat Med 2000; 19: 1421–1432.

    Article  CAS  PubMed  Google Scholar 

  45. Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R et al. Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology 1998; 51: 351–357.

    Article  CAS  PubMed  Google Scholar 

  46. Lopez OL, Wisniewski S, Hamilton RL, Becker JT, Kaufer DI, DeKosky ST . Predictors of progression in patients with AD and Lewy bodies. Neurology 2000; 54(9):1774–1779.

    Article  CAS  PubMed  Google Scholar 

  47. Hamilton RL . Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using a-synuclein immunohistochemistry. Brain Pathol 2000; 10:378–384.

    Article  CAS  PubMed  Google Scholar 

  48. Devanand DP, Jacobs DM, Tang MX, Castillo-Castaneda CD, Sano M, Marder K et al. The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry 1997; 54: 257–263.

    Article  CAS  PubMed  Google Scholar 

  49. Ballard CG, O'Brien JT, Swann AG, Thompson P, Neill D, McKeith IG . Natural history of psychosis and depression in dementia with Lewy bodies and Alzheimer's disease: persistance and new cases over 1 year of follow up. J Clin Psychiatry 2001; 62: 46–49.

    Article  CAS  PubMed  Google Scholar 

  50. Cohen-Mansfield J, Taylor L, Werner P . Delusions and hallucinations in an adult day care population. Am J Geriatr Psychiatry 1998; 6: 104–121.

    CAS  PubMed  Google Scholar 

  51. Marin DB, Green CR, Schmeidler J, Harvey PD, Lawlor BA, Ryan TM et al. Noncognitive disturbances in Alzheimer's disease: frequency, longitudinal course, and relationship to cognitive symptoms. J Am Geriatr Soc 1997; 45: 1331–1338.

    Article  CAS  PubMed  Google Scholar 

  52. Rubin EH, Kinscherf BA . Psychopathology of very mild dementia of the Alzheimer type. Am J Psychiatry 1989; 146: 1017–1021.

    Article  CAS  PubMed  Google Scholar 

  53. Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JCS . Mental and behavioral disturbances in dementia: findings from the Cache County study on memory in aging. Am J Psychiatry 2000; 157: 708–714.

    Article  CAS  PubMed  Google Scholar 

  54. Sweet RA, Pollock BG . Late life psychosis: advances in understanding and treatment. In: Katz I Oslin D (eds). Annual Review of Gerontology and Geriatrics Vol 19: Focus on Psychopharmacologic Interventions in Late Life. Springer Publishing Company: New York, 1999.

    Google Scholar 

  55. Jeste DV, Heaton SC, Paulsen JS, Ercoli L, Harris MJ, Heaton RK . Clinical and neuropsychological comparison of psychotic depression with nonpsychotic depression and schizophrenia. Am J Psychiatry 1996; 153: 490–496.

    Article  CAS  PubMed  Google Scholar 

  56. Zubenko GS, Moossy J, Martinez AJ, Rao G, Claassen D, Rosen J et al. Neuropathologic and neurochemical correlates of psychosis in primary dementia. Arch Neurol 1991; 48: 619–624.

    Article  CAS  PubMed  Google Scholar 

  57. Mukaetova-Ladinska EB, Harrington CR, Xuereb J, Roth M, Wischik CM . Biochemical, neuropathological, and clinical correlations of neurofibrillary degeneration in Alzheimer's disease. In: SI Finkel, M Bergener, (eds). Treating Alzheimer's and other Dementias. Springer: New York, 1995: 57–80.

    Google Scholar 

  58. Weiner MF, Risser RC, Cullum CM, Honig L, White C III, Speciale S et al. Alzheimer's disease and its Lewy body variant: a clinical analysis of postmortem verified cases. Am J Psychiatry 1996; 153: 1269–1273.

    Article  CAS  PubMed  Google Scholar 

  59. Starkstein SE, Vazquez S, Petracca G, Sabe L, Migliorelli R, Tesón A et al. A SPECT study of delusions in Alzheimer's disease. Neurology 1994; 44: 2055–2059.

    Article  CAS  PubMed  Google Scholar 

  60. Sultzer DL, Mahler ME, Mandelkern MA, Cummings JL, Van Gorp WG, Hinkin CH et al. The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 1995; 7: 476–484.

    Article  CAS  PubMed  Google Scholar 

  61. Sweet RA, Panchalingam K, Pettegrew JW, McClure RJ, Hamilton RL, Lopez OL et al. Psychosis in Alzheimer disease: postmortem magnetic resonance spectroscopy evidence of excess neuronal and membrane phospholipid pathology. Neurobiol Aging 2002; 23:547–553.

    Article  CAS  PubMed  Google Scholar 

  62. Keshavan MS, Stanley JA, Pettegrew JW . Magnetic resonance spectroscopy in schizophrenia: methological issues and findings-part II. Biol Psychiatry 2000; 48: 369–380.

    Article  CAS  PubMed  Google Scholar 

  63. Rajkowska G, Selemon LD, Goldman-Rakic PS . Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 1998; 55: 215–224.

    Article  CAS  PubMed  Google Scholar 

  64. Pierri JN, Edgar CL, Auh S, Sampson A, Lewis DA . Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex in schizophrenia. Arch Gen Psychiatry 2001; 58: 466–473.

    Article  CAS  PubMed  Google Scholar 

  65. Sweet RA, Pierri JN, Lewis DA . Deep layer 3 pyramidal cell somal volume is reduced in auditory association cortex of subjects with schizophrenia. Society for Neuroscience Abstracts 27, 446.16. 2001.

  66. Glantz LA, Lewis DA . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.

    Article  CAS  PubMed  Google Scholar 

  67. Glantz LA, Lewis DA . Reduction of synaptophysin immunoreactivity in the prefrontal cortex of sujects with schizophrenia: regional and diagnostic specificity. Arch Gen Psychiatry 1997; 54: 943–952.

    Article  CAS  PubMed  Google Scholar 

  68. Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N et al. Structural abnormalities of subicular dentrites in subjects with schizophrenia and mood disorders. Arch Gen Psychiatry 2000; 57: 349–356.

    Article  CAS  PubMed  Google Scholar 

  69. Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 1998; 65:446–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bird TD, Wijsman EM, NOchlin D, Leehey M, Sumi SM, Payami H et al. Chromosome 17 and hereditary dementia: linkage studies in three non-Alzheimer families and kindreds with late-onset FAD. Neurology 1997; 48: 950–955.

    Article  Google Scholar 

  71. Tunstall N, Fraser L, Lovestone S, Owen MJ, Williams J, Rice F et al. Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease. Br J Psychiatry 2000; 176: 156–159.

    Article  CAS  PubMed  Google Scholar 

  72. Gilley DW, Whalen ME, Wilson RS, Bennett DA . Hallucinations and associated factors in Alzheimer's disease. J Neuropsychiatry 1991; 3:371–376.

    Article  CAS  Google Scholar 

  73. Kotrla KJ, Chacko RC, Harper RG, Doody R . Clinical variables associated with psychosis in Alzheimer's disease. Am J Psychiatry 1995; 152:1377–1379.

    Article  CAS  PubMed  Google Scholar 

  74. Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han L, Choi C . Absence of Neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55: 225–232.

    Article  CAS  PubMed  Google Scholar 

  75. Holmes C, Smith H, Ganderton R, Arranz M, Collier D, Powell J et al. Psychosis and aggression in Alzheimer's disease: the effect of dopamine receptor gene variation. J Neurol Neurosurg Psychiatry 2001; 71(6): 777–779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Holmes C, Arranz MJ, Powell JF, Collier D, Lovestone S . 5–HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum Mol Genet 1998; 7: 1507–1509.

    Article  CAS  PubMed  Google Scholar 

  77. Williams J, Spurlock G, Holmans P, Mant R, Murphy K, Jones L et al. A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia. Mol Psychiatry 1998; 3: 141–149.

    Article  CAS  PubMed  Google Scholar 

  78. Blacker D, Haines JL, Rodes L, Terwedow H, Go RCP, Harrell LE et al. ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology 1997; 48: 139–147.

    Article  CAS  PubMed  Google Scholar 

  79. Bacanu SA, Devlin B, Chowdari KV, DeKosky ST, Nimgaonkar VL, Sweet RA . Linkage analysis of Alzheimer disease with psychosis. Neurology 2002; 59: 118–120.

    Article  CAS  PubMed  Google Scholar 

  80. Pericak-Vance MA, Gaskell PC, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA et al. Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 1997; 278: 1237–1241.

    Article  CAS  PubMed  Google Scholar 

  81. Coon H, Myles-Worsley M, Tiobech J, Hoff M, Rosenthal J, Bennett P et al. Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol Psychiatry 1998; 3: 521–527.

    Article  CAS  PubMed  Google Scholar 

  82. Camp NJ, Neuhausen SL, Tiobech J, Polloi A, Coon H, Myles-Worsley M . Genomewide multipoint linkage analysis of seven extended Palauan pedigrees with schizophrenia, by a Markov-chain Monte Carlo method. Am J Hum Genet 2001; 69: 1278–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. DeLisi LE, Shaw SH, Crow TJ, Shields G, Smith AB, Larach VW et al. A genome-wide scan for linkage to schimosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry, 2002; 159: 803–812.

    Article  PubMed  Google Scholar 

  84. Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV et al. Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. Am J Hum Genet 2000; 67: 652–663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Harwood DG, Barker WW, Ownby RL, St. George-Hyslop PH, Duara R . Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer's disease. Am J Geriatr Psychiatry 1999; 7:119–123.

    CAS  PubMed  Google Scholar 

  86. Ramachandran G, Marder K, Tang M, Schofield PW, Chun MR, Devanand DP et al. A preliminary study of apolipoprotein E genotype and psychiatric manifestations of Alzheimer's disease. Neurology 1996; 47: 256–259.

    Article  CAS  PubMed  Google Scholar 

  87. Ballard C, Massey H, Lamb H, Morris C . Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 1997; 63: 273–273.

    Article  CAS  PubMed  Google Scholar 

  88. Hirono N, Mori E, Yasuda M, Ikejiri Y, Imamura T, Shimomura T et al. Factors associated with psychotic symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry 1998; 64: 648–652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cacabelos R, Rodriquez B, Carrera C, Beyer K, Lao JI, Sellers MA . Behavioral changes associated with different apolipoprotein E genotypes in dementia. Alzheimer Dis Assoc Disord 1997; 11: S27–S34.

    PubMed  Google Scholar 

  90. Forsell Y, Basun H, Corder EH, Lannfelt L, Winblad B . Psychotic symptoms and apolipoprotein E genotypes in an elderly population. Biol Psychiatry 1998; 44: 139–140.

    Article  CAS  PubMed  Google Scholar 

  91. Levy ML, Cummings J, Fairbanks LA, Sultzer DL, Small GW . Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease. Biol Psychiatry 1999; 45: 422–425.

    Article  CAS  PubMed  Google Scholar 

  92. Lehtovirta M, Soininen H, Helisalmi S, Mannerman A, Helkala EL, Hartikainen P et al. Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: Relation to apolipoprotein E polymorphism. Neurology 1996; 46: 413–419.

    Article  CAS  PubMed  Google Scholar 

  93. Lyketsos CG, Baker L, Warren A, Steele C, Brandt J, Steinberg M et al. Depression, delusions, and hallucinations in Alzheimer's disease: no relationship to apolipoprotein E genotype. J Neuropsychiatry Clin Neurosci 1997; 9: 64–67.

    Article  CAS  PubMed  Google Scholar 

  94. Corder EH, Saunders AM, Strittmatter WJSDE, Gaskell PC, Small GW, Roses AD et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261:921–923.

    Article  CAS  PubMed  Google Scholar 

  95. Sweet RA, Kamboh MI, Wisniewski SR, Lopez OL, Klunk WE, Kaufer DI et al. APOE and ACT genotypes do not predict time to psychosis in Alzheimer's disease. J Geriatr Psychiatry Neurol 2002; 15: 24–30.

    Article  PubMed  Google Scholar 

  96. Li T, Holmes C, Sham PC, Vallada H, Birkett J, Kirov G et al. Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer's diseases. Neuroreport 1997; 8: 683–686.

    Article  CAS  PubMed  Google Scholar 

  97. Oliveira JRM,, Gallindo RM, Maia LGS, Brito-Marques PR, Otto PA, Passos-Bueno MR et al. The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease. Mol Psychiatry 1998; 3: 438–441.

    Article  CAS  PubMed  Google Scholar 

  98. Zill P, Padberg F, de Jonge S, Hampel H, Burger K, Stubner S et al. Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients. Neurosci Lett 2000; 284: 113–115.

    Article  CAS  PubMed  Google Scholar 

  99. Olson JM . A general conditional-logistic model for affected-relative-pair linkage studies. Am J Hum Genet 1999; 65: 1760–1769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Devlin B, Jones BL, Bacanu SA, Roeder K . Mixture models for linkage analysis of affected sibling pairs and covariates. Genet Epidemiol 2002; 22: 52–65.

    Article  PubMed  Google Scholar 

  101. Goddard KA, Witte JS, Suarez BK, Catalona WJ, Olson JM . Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am J Hum Genet 2001; 68: 1197–1206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Almasy L, Blangero J . Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet 2001; 105: 42–44.

    Article  CAS  PubMed  Google Scholar 

  103. Blangero J, Williams JT, Almasy L . Variance component methods for detecting complex trait loci. Adv Genet 2001; 42:151–181.

    Article  CAS  PubMed  Google Scholar 

  104. Devlin B, Roeder K, Bacanu SA . Unbiased methods for population-based association studies. Genet Epidemiol 2001; 21: 273–284.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by Research Grant AG05133 from the National Institute of Aging, by NIMH grants MH-43693, MH-49671, MH-59101, and by the Department of Veterans Affairs. The authors gratefully acknowledge the assistance of Traci Thrower in the preparation of the manuscript.

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Sweet, R., Nimgaonkar, V., Devlin, B. et al. Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype. Mol Psychiatry 8, 383–392 (2003). https://doi.org/10.1038/sj.mp.4001262

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