Apolipoprotein e and central nervous system disorders: Reviews of clinical findings

Psychiatry and Clinical Neurosciences

Volumn 64, Issue 6, 2010, Pages 592-607

  Takeda, Masatoshi ^a   Martínez, Rocío ^b   Kudo, Takashi ^a   Tanaka, Toshihisa ^a   Okochi, Masayasu ^a   Tagami, Shinji ^a   Morihara, Takashi ^a   Hashimoto, Ryota ^a   Cacabelos, Ramón ^b  

^a OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b CAMILO JOSÉ CELA UNIVERSITY   (Spain)

Author keywords

Alzheimer's disease; apolipoprotein E; dementia; genetic risk; neurodegeneration

Indexed keywords

AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN E; APOLIPOPROTEIN E4; PRESENILIN 1; PRESENILIN 2;

ALZHEIMER DISEASE; CEREBROVASCULAR DISEASE; DEMENTIA; DOWN SYNDROME; ENVIRONMENTAL FACTOR; EXERCISE; GENE; GENOTYPE PHENOTYPE CORRELATION; HEAD INJURY; HEREDITY; HUMAN; MULTIINFARCT DEMENTIA; MULTIPLE SCLEROSIS; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PLEIOTROPY; PRION DISEASE; PROTEIN FUNCTION; REVIEW; RISK FACTOR; SCHIZOPHRENIA;

EID: 78649664226     PISSN: 13231316     EISSN: 14401819     Source Type: Journal    
DOI: 10.1111/j.1440-1819.2010.02148.x     Document Type: Review

References (176)

1. Takeda M, Morihara T, Okochi M, Sadik G, Tanaka T,. Mild cognitive impairment and subjective cognitive impairment. Psychogeriatrics 2008; 8: 155-160.
2. Finkel SI, Costae Silva J, Cihen G, Miller S, Sartorius N,. Behavioural and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int. Psychogeriatr. 1996; 8 (Suppl. 3): S497-S500.
3. Amano N, Inuzuka S, Ogihara T,. Behavioral and psychological symptoms of dementia and medical treatment. Psychogeriatrics 2009; 9: 45-49.
4. Oshima N,. Beneficial and adverse effects of pharmacotherapy with risperidone on behavioral and psychological symptoms of dementia (BPSD). Psychogeriatrics 2008; 8: 175-177.
5. Shigenobu K, Ikeda M, Fukuhara R, et al. Reducing the burden of caring for Alzheimer's disease through the amelioration of 'delusions of theft' by drug therapy. Int. J. Geriatr. Psychiatry 2002; 17: 211-217.
6. Takita M,. How to treat behavioral and psychological symptoms of dementia (BPSD): do not treat patients exhibiting symptoms like BPSD with neuroleptics from the beginning. Psychogeriatrics 2008; 8: 148-150.
7. Iwasaki K, Satoh-Nakagawa T, Maruyama M, et al. A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients. J. Clin. Psychiatry 2005; 66: 248-252.
8. Kimura T, Hayashida H, Furukawa H, Miyauchi D, Takamatsu J,. Five cases of frontotemporal dementia with behavioral symptoms improved by Yokukansan. Psychogeriatrics 2009; 9: 38-43.
9. Mizukami K,. Kampo therapy as an alternative to pharmacotherapy using antipsychotic medicines for behavioral and psychological symptoms of dementia (BPSD). Psychogeriatrics 2008; 8: 137-141.
10. Narumoto J, Miya H, Shibata K, et al. Challenging behavior of patients with frontal dysfunction managed successfully with behavioral intervention. Psychogeriatrics 2009; 9: 147-150.
11. Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K,. Effect of aromatherapy on patients with Alzheimer's disease. Psychogeriatrics 2009; 9: 173-179.
12. Le Roux MC, Kemp R,. Effect of a companion dog on depression and anxiety levels of elderly residents in a long-term care facility. Psychogeriatrics 2009; 9: 23-26.
13. Kinoshita T,. Role of the home visit medical service for patients with behavioral and psychological symptoms of dementia (BPSD) living in the community. Psychogeriatrics 2008; 8: 142-147.
14. Tanaka T, Kazui H, Tanimukai H, et al. Prevention of psychiatric illness in the elderly, I: path to prevention of dementia. Psychogeriatrics 2009; 9: 111-115.
15. Kutsumi M, Ito M, Sugiura K, Terabe M, Mikami H,. Management of behavioral and psychological symptoms of dementia in long-term care facilities in Japan. Psychogeriatrics 2009; 9: 186-195.
16. Ikeda M,. Fronto-temporal dementia. In:, Ritchie CW, et al. (eds). Therapeutic Strategies in Dementia. Clinical Publishing, Oxford, 2007; 287-299.
17. Kosaka K,. Behavioral and psychological symptoms of dementia (BPSD) in dementia with Lewy bodies. Psychogeriatrics 2008; 8: 134-136.
18. Chen SJ, Shen YC, Chen ST, Lin CCH,. Aripiprazole-associated dystonia in a patient with vascular dementia. Psychogeriatrics 2008; 8: 199-200.
19. Tanimukai H, Kudo T, Tanaka T, Grundke-Iqbal I, Iqbal K, Takeda M,. Novel therapeutic strategies for neurodegenerative disease. Psychogeriatrics 2009; 9: 103-109.
20. Yanagi K, Tanaka T, Kato K, Morihara T, Kudo T, Takeda M,. Involvement of puromycin-sensitive aminopeptidase in proteolysis of tau protein in cultured cells, and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) mutant tau. Psychogeriatrics 2009; 9: 157-166.
21. Jiang J, Okochi M, Tagami S, et al. Macrophage colony stimulating factor is associated with excretion of amyloid-beta peptides from cerebrospinal fluid to peripheral blood. Psychogeriatrics 2008; 8: 188-195.
22. th Congress of the International Psychogeriatric Association and recent expansion of research into psychogeriatrics. Psychogeriatrics 2008; 8: 1-3.
23. Konishi K, Hori K, Oda T, et al. Effects of aging on behavioral symptoms in Alzheimer's disease. Psychogeriatrics 2009; 9: 11-16.
24. Weisgraber KH, Rall SC, Mahley RW,. Human E apoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J. Biol. Chem. 1981; 256: 9077-9083.
25. Rall SC, Weisgraber KH, Innerarity TL, Mahley RW,. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc. Natl. Acad. Sci. USA 1982; 79: 4696-4700.
26. Smit M, De Knijff P, Van Der Kooij-Meijs E, et al. Genetic heterogeneity in familial dysbetalipoproteinemia: the E2(Lys146-to-Gln) variant results in a dominant mode of inheritance. J. Lipid Res. 1990; 31: 45-53.
27. Lusis AJ, Zollman S, Sparkes RS, et al. Assignment of the human gene for cholesteryl ester transfer protein to chromosome 16q12-16q21. Genomics 1987; 1: 232-242.
28. Fullerton SM, Clark AG, Weiss KM, et al. Sequence polymorphism at the human apolipoprotein AII gene (APOA2): unexpected deficit of variation in an African-American sample. Hum. Genet. 2002; 111: 75-87.
29. Cacabelos R,. Molecular genetics of Alzheimer's disease and aging. Methods Find. Exp. Clin. Pharmacol. 2005; 27 (Suppl. A): 1-573.
30. Corbo RM, Scacchi R,. Apolipoprotein E (APOE) allele distribution in the world: is APOE*4 a 'thrifty' allele? Ann. Hum. Genet. 1999; 63: 301-310.
31. Siest G, Pillot T, Regis-Bailly A, Leininger-Muller B, et al. Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin. Chem. 1995; 41: 1060-1086.
32. Seet WT, Mary Anne TJ, Yen TS,. Apolipoprotein E genotyping in the Malay, Chinese and Indian ethnic groups in Malaysia: A study on the distribution of the different apoE alleles and genotypes. Clin. Chim. Acta 2004; 340: 201-205.
33. Brown MS, Goldstein JL,. A receptor-mediated pathway for cholesterol homeostasis. Science 1986; 232: 34-47.
34. Davignon J,. Apolipoprotein E polymorphism and atherosclerosis. Curr. Sci. 1993; 5: 1-5.
35. Boerwinkle E, Visvikis S, Welsh D, Steinmetz J, Hanash SM, Sing CF,. The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, beta-lipoprotein and triglycerides in a sample of unrelated individuals. Am. J. Hum. Genet. 1987; 27: 567-582. (Pubitemid 17103694)
36. Fan D, Li Q, Korando L, Jerome WG, Wang J,. A monomeric human apolipoprotein E carboxyl-terminal domain. Biochemistry 2004; 43: 5055-5064.
37. Cacabelos R, Fernández-Novoa L, Lombardi V, Corzo L, Pichel V, Kubota Y,. Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications. Neurol. Res. 2003; 25: 567-580.
38. Cacabelos R,. Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia. Pharmacogenomics 2004; 5: 1049-1105.
39. Cacabelos R, Fernández-Novoa L, Corzo L,. Phenotypic profiles and functional genomics in Alzheimer's disease and in dementia with a vascular component. Neurol. Res. 2004; 26: 459-480.
40. Uusitupa M, Sarkkinen E, Kervinen K, Kesaniemi YA,. Apolipoprotein E phenotype and blood pressure. Lancet 1994; 343: 57.
41. Menzel HJ, Kladetsky RG, Assmann G,. Apolipoprotein E polymorphism and coronary artery disease. Atherosclerosis 1983; 3: 310-315.
42. Lenzen HJ, Assmann G, Buchwalsky R, Schulte H,. Association of apolipoprotein E polymorphism, low-density-lipoprotein cholesterol, and coronary disease. Clin. Chem. 1986; 32: 778-781.
43. Garces C, Benavente M, Ortega H, et al. Influence of birth weight on the apo E genetic determinants of plasma lipid levels in children. Pediatr. Res. 2002; 52: 873-978.
44. Sullivan PM, Mace BE, Maeda N, Schmechel DE,. Marked regional differences of brain human apolipoprotein E expression in targeted replacement mice. Neuroscience 2004; 124: 725-733.
45. Ji Y, Gong Y, Gan W, Beach T, Holtzman DM, Wisniewski T,. Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E mice and Alzheimer's disease patients. Neuroscience 2003; 122: 305-315.
46. Harris FM, Tesseur I, Brench WJ, et al. Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease. J. Biol. Chem. 2004; 279: 3862-3868.
47. Saunders AM, Strittmatter WJ, Schamechel D, et al. Association of apolipoprotein E allele E4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993; 43: 1467-1472.
48. Corder EH, Saunders AM, Risch NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 1994; 7: 180-184.
49. Daw EW, Payami H, Nemens EJ, et al. The number of trait loci in late-onset Alzheimer disease. Am. J. Hum. Genet. 2000; 66: 196-204. Note: Erratum: Am. J. Hum. Genet. 2000; 66: 1728.
50. Perry RT, Collins JS, Harrell LE, et al. Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to aged-matched controls. Am. J. Med. Genet. 2001; 105: 332-342.
51. Schachter F, Faure-Delanef L, Guenot F, et al. Genetic association with human longevity at the APOE and ACE loci. Nat. Genet. 1994; 6: 29-32.
52. Graves AB, Mortimer JA, Bowen JD, et al. Head circumference and incident Alzheimer's disease: modification by apolipoprotein E. Neurology 2001; 57: 1453-1460.
53. Brecht WJ, Harris FM, Chang S, et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 2004; 24: 2527-2534.
54. Glockner F, Ohn TG,. Hippocampal apolipoprotein D level depends on Braak stage and APOE genotype. Neuroscience 2003; 122: 103-110.
55. Colton CA, Needham LK, Brown C, et al. APOE genotype-specific differences in human and mouse macrophage nitric oxide production. J. Neuroimmunol. 2004; 147: 62-67.
56. Strittmatter WJ, Roses AD,. Apolipoprotein E and Alzheimer disease. Proc. Natl. Acad. Sci. USA 1995; 92: 4724-4727.
57. Ledesma MD, Moreno FJ, Pérez MM, Avila J,. Binding of apolipoprotein E3 to tau protein: effects on tau glycation, tau phosphorylation and tau-microtubule binding in vitro. Alzheimer Res. 1996; 2: 85-88.
58. Olichney JM, Hansen LA, Galasko D, et al. The apolipoprotein E epsylon-4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology 1996; 47: 190-196.
59. Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. New Engl. J. Med. 1995; 333: 1242-1247.
60. Lambert L, Mann D, Goumidi L, et al. Effects of the APOE promoter polymorphisms on cerebral amyloid peptide deposition in Alzheimer's disease. Lancet 2001; 357: 608-609.
61. Strittmatter WJ, Saunders AM, Schmechel D, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993; 90: 8098-8102.
62. O'Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N. Engl. J. Med. 2000; 342: 240-245.
63. Reiman EM, Caselli RJ, Yun LS, et al. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon-4 allele for apolipoprotein E. N. Engl. J. Med. 1996; 334: 752-758.
64. Corzo L, Fernández-Novoa L, Zas R, et al. Apolipoprotein E genotype-related serum apolipoprotein E and lipid levels in Alzheimer's disease. Ann. Psychiatr. 1999; 7: 99-107.
65. Corzo L, Fernández-Novoa L, Zas R, et al. Influence of the APOE genotype on serum ApoE levels in Alzheimer's disease patients. In:, Fisher A, Hanin I, Yoshida M, (eds). Progress in Alzheimer's and Parkinson's Diseases. Plenum Press, New York, 1998; 765-771.
66. Mouzo R, Álvarez XA, Pichel V, Alcaraz M, Cacabelos R,. Apolipoprotein E-related blood pressure parameters in senile dementia. Ann. Psychiatr. 1999; 7: 93-97.
67. Lombardi VRM, Amado L, Fernández-Novoa L, Etcheverría I, Seoane S, Cacabelos R,. Flow cytometry analysis of CD28-/CD8+ supressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of Alzheimer's disease patients. In:, Hanin I, Fisher A, Cacabelos R, (eds). New Trends in Alzheimer- and Parkinson-Related Disorders. Monduzzi Editore, Bologna, 2003; 57-61.
68. Lombardi VRM, Fernández-Novoa L, Etcheverría I, Seoane S, Cacabelos R,. Association between APOE ε4 allele and increased expression of CD95 on T cells from patients with Alzheimer's disease. Methods Find. Exp. Clin. Pharmacol. 2004; 26: 523-529.
69. Reiman EM, Casselli RJ, Chen K, et al. 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. Proc. Natl. Acad. Sci. USA 2001; 98: 3334-3339.
70. Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc. Natl. Acad. Sci. USA 2004; 101: 284-289.
71. Dubelaar EJ, Verwer RW, Hofman MA, Van Heerikhuize JJ, Ravid R, Swaab DE,. ApoE epsilon4 genotype is accompanied by lower metabolic activity in nucleus basalis of Meynert neurons in Alzheimer patients and controls as indicated by the size of the Golgi apparatus. J. Neuropathol. Exp. Neurol. 2004; 63: 159-169.
72. Cacabelos R,. Molecular pathology and pharmacogenomics in Alzheimer's disease: polygenic-related effects of multifactorial treatments on cognition, anxiety, and depression. Methods Find. Exp. Clin. Pharmacol. 2007; 29 (Suppl. B): 1-91.
73. Sanan DA, Weisgraber KH, Russell SJ, et al. Apolipoprotein E associates with beta-amyloid peptide of Alzheimer's disease to from novel monofibrils: isoform apoE4 associates more efficiently than apoeE4. J. Clin. Invest. 1994; 94: 860-869.
74. Tabaton M, Rolleri M, Masturzo P, et al. Apolipoprotein E epsilon-4 allele frequency is not increased in progressive supranuclear palsy. Neurology 1995; 45: 1764-1765.
75. Ghebremedhin E, Schultz C, Thal DR, et al. Gender and age modify the association between APOE and AD-related neuropathology. Neurology 2001; 56: 1696-1701.
76. Lambert J-C, Mann D, Goumidi L, et al. Effect of the APOE promoter polymorphism on cerebral amyloid peptide deposition in Alzheimer's disease. Lancet 2001; 357: 608-609.
77. Xu Q, Brecht WJ, Weisgraber KH, Mahley RW, Huang Y,. Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer. J. Biol. Chem. 2004; 279: 25511-15516.
78. Mariani SM,. ApoE and Alzheimer's disease: 10 years later. Med. Gen. Med. 2004; 6: 1-5.
79. Ji ZS, Miranda RD, Newhouse YM, Weisgraber KH, Huang Y, Mahley RW,. Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells. J. Biol. Chem. 2002; 277: 21821-21828.
80. Harris FM, Bretch WJ, Xu Q, et al. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. USA 2003; 100: 10966-10971.
81. Huang ZH, Gu D, Mazzone T,. Oleic acid modulates the post-translational glycosylation of macrophage ApoE to increase its secretion. J. Biol. Chem. 2004; 279: 29195-29201.
82. Noguchi S, Murakami K, Yamada N,. Apolipoprotein E genotype and Alzheimer's disease. Lancet 1993; 342: 737.
83. Frikke-Schmidt R, Nordestgaard BG, Thudium D, Moes Gronholdt ML, Tybjaerg-Hansen A,. APOE genotype predicts AD and other dementia but not ischemic cerebrovascular disease. Neurology 2001; 56: 194-200.
84. Engelborghs S, Dermaut B, Goeman J, et al. Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects. J. Neurol. Neurosurg. Psychiatry 2003; 74: 1148-1151.
85. Weiringa GE, Burlinson S, Rafferty JA, Gowland E, Burns A,. Apolipoprotein e genotypes and serum lipid levels in Alzheimer's disease and multi-infarct dementia. Int. J. Geriatr. Psychiatry 1997; 12: 349-362.
86. Frisoni GB, Geroldi C, Bianchetti A, et al. Apolipoprotein E epsilon-4 allele frequency in vascular dementia and Alzheimer's disease. Stroke 1994; 25: 1703.
87. Slooter AJC, Breteler MB, Ott A, Van Broeckhoven C, Van Duijn CM,. APOE genotyping in differential diagnosis of Alzheimer's disease. Lancet 1996; 348: 334.
88. Nicoll JAR, Burnett C, Love S, et al. High frequency of apolipoprotein E epsilon-2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann. Neurol. 1997; 41: 716-721.
89. Nicoll JAR, Burnett C, Love S, et al. High frequency of apolipoprotein E epsilon-2 in patients with cerebral hemorrhage due to cerebral amyloid angiopathy. Ann. Neurol. 1996; 39: 682.
90. Lin HF, Lai CL, Tai CT, Lin RT, Liu CK,. Apolipoprotein E polymorphism in ischemic cerebrovascular disease and vascular dementia patients in Taiwan. Neuroepidemiology 2004; 23: 129-134.
91. Greenberg SM, Vonsattel JPG, Segal AZ, et al. Association of apolipoprotein E epsilon-2 and vasculopathy in cerebral amyloid angiopathy. Neurology 1998; 50: 961-965.
92. Love S, Nicoll JA, Hughes A, Wilcock GK,. APOE and cerebral amyloid angiopathy in the elderly. Neuroreport 2003; 14: 1535-1536.
93. Broderick J, Lu M, Jackson C, et al. Apolipoprotein E, phenotype and the efficacy of intravenous tissue plasminogen activator in acute ischemic stroke. Ann. Neurol. 2001; 49: 736-744.
94. Arai H, Higuchi S, Muramatsu T, Iwarsubo T, Sasaki H, Trojanowski Q,. Apolipoprotein E gene in diffuse Lewy body disease with or without co-existing Alzheimer's disease. Lancet 1994; 344: 1307.
95. Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL,. Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J. Med. Genet. 1999; 36: 108-111.
96. Verpillat P, Camuzat A, Hannequin D, et al. Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis. Eur. J. Hum. Genet. 2002; 10: 399-405.
97. Waring SC, O'Brien PC, Kurland LT, et al. Apolipoprotein E allele in Chamorros with amyotrophic lateral sclerosis/parkinsonism-dementia complex. Lancet 1994; 343: 611.
98. Itabashi S, Arai H, Higuchi S, Sasaki H, Trojanowski JQ,. APOE e4 allele in Alzheimer's and non-Alzheimer's dementias. Lancet 1996; 348: 960-961.
99. Chalabi AI, Enayat ZE, Bakker MC, et al. Association of apolipoprotein E e4 allele with bulbar-onset motor neuron disease. Lancet 1996; 347: 159-160.
100. Smith G, Haverkamp LJ, Case S, Appel V, Appel SH,. Apolipoprotein E ε4 in bulbar-onset motor neuron disease. Lancet 1996; 348: 334-348.
101. Mui S, Rebeck GW, McKenna-Yasek D, Hyman BT, Brown RH Jr,. Apolipoprotein E epsilon 4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis. Ann. Neurol. 1995; 38: 460-463.
102. Hyman BT, West HL, Rebeck GW, et al. Quantitative analysis of senile plaques in Alzheimer's disease: observation of log-normal size distribution and molecular epidemiology of differences associates with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc. Natl. Acad. Sci. USA 1995; 92: 3586-3590.
103. Royston MC, Mann D, Pickering-Brown S, et al. Apolipoprotein E epsilon-2 allele promotes longevity and protects patients with Down's syndrome from dementia. Neuroreport 1994; 5: 2583-2585.
104. Van Gool WA, Evenhuis HM, Van Duijin CM,. A case-control study of apolipoprotein E genotypes in Alzheimer's disease associated with Down's syndrome. Ann. Neurol. 1995; 38: 225-230.
105. Hardy J, Crook R, Perry R, Raghavan R, Roberts G,. ApoE genotype and Down's syndrome. Lancet 1994; 343: 979-980.
106. Harrington CR, Roth M, Xuereb JH, McKenna PJ, Wischik CM,. Apolipoprotein E type 4 allele frequency is increased in patients with schizophrenia. Neurosci. Lett. 1995; 202: 101-104.
107. Jönsson E, Lannfelt L, Engvall B, Sedvall G,. Lack of association between schizophrenia and the apolipoprotein E epsilon 4 allele. Eur. Arch. Psychiatry Clin. Neurosci. 1996; 246: 182-184.
108. Zhu S, Nöthen MM, Uhlhaas S, et al. Apolipoprotein E genotype distribution in schizophrenia. Psychiatr. Genet. 1996; 6: 75-79.
109. Arnold SE, Joo E, Martinoli MG, et al. Apolipoprotein E genotype in schizophrenia: frequency, age and onset, and neuropathological features. Neuroreport 1997; 8: 1523-1526.
110. Igata-Yi R, Igata T, Ishizuka K,. Apolipoprotein E genotype and psychosis. Biol. Psychiatry 1997; 41: 906-908.
111. Lan TH, Hong CJ, Chen JY, Sim CB,. Apolipoprotein E-epsilon 4 frequency in patients with schizophrenia. Biol. Psychiatry 1997; 42: 225-227.
112. Martorell L, Virgos C, Valero J, et al. Schizophrenic women with the ApoE ε4 allele have a worse prognosis than those without it. Mol. Psychiatry 2001; 6: 307-310.
113. Sáiz PA, Morales B, G-Portilla MP, et al. Apolipoprotein E genotype and schizophrenia: further negative evidence. Acta Psychiatr. Scand. 2002; 105: 71-75.
114. Kampman O, Antilla S, Illi A, et al. Apolipoprotein E polymorphism is associated with age of onset in schizophrenia. J. Hum. Genet. 2004; 49: 355-359.
115. Pickard D, Malhotra AK, Rooney W, et al. Apolipoprotein E epsilon 4 and clinical phenotype in schizophrenia. Lancet 1997; 350: 930-931.
116. Rietchel M, Krau H, Müller DJ, et al. Apolipoprotein E ε4 and clinical phenotype in schizophrenia. Lancet 1997; 350: 1857-1858.
117. Ohara K, Nagai M, Ohara K,. Apolipoprotein Eε and clinical phenotype in schizophrenia. Lancet 1997; 350: 1857.
118. Chen J, Hong CJ, Chiu HJ, et al. Apolipoprotein E genotype and schizophrenia. Biol. Psychiatry 1999; 39: 141-143.
119. Kimura T, Shono M, Yakota S, et al. Apolipoprotein E-4 and tardive dyskinesia in a Japanese population. J. Psychiatry 2000; 34: 329-332.
120. Kimura T, Yokota S, Igata-Yi R, Shono M, Takamatsu J, Miyakawa T,. Apolipoprotein E ε2 allele and early onset schizophrenia. Neurosci. Lett. 1997; 231: 53-55. (Pubitemid 27366287)
121. Durany N, Riederer P, Cruz-Sánchez FF,. Apolipoprotein E genotype in Spanish schizophrenic patients. Psychiatr. Genet. 2000; 10: 73-77.
122. Schurhoff F, Krebs MO, Szoke A, et al. Apolipoprotein E in schizophrenia: a French association study and meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003; 119: 18-23.
123. Howard R, Dennehey J, Lovestone S, et al. Apolipoprotein e genotype and late paraphrenia. Int. J. Geriatr. Psychiatry 1995; 10: 147-150.
124. Scarmeas N, Brandt J, Albert M, et al. Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease. Neurology 2002; 58: 1182-1188. (Pubitemid 34411861)
125. Cacabelos R, Rodríguez B, Carrera C, et al. APOE-related frequency of cognitive and noncognitive symptoms in dementia. Methods Find. Exp. Clin. Pharmacol. 1996; 18: 693-706.
126. Dean B, Laws SM, Hone E, et al. Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia. Biol. Psychiatry 2003; 54: 616-622.
127. Enzinger C, Ropele S, Smith S, et al. Accelerated evolution of brain atrophy and 'black holes' in MS patients with APOE-epsilon-4. Ann. Neurol. 2004; 55: 563-569.
128. Savettieri G, Andreoli V, Bonavita S, et al. Apolipoprotein E genotype does not influence the progression of multiple sclerosis. J. Neurol. 2003; 250: 1094-1098.
129. Enzinger C, Ropele S, Strasser-Fuchs S, et al. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon-4 allele. Arch. Neurol. 2003; 60: 65-70.
130. Chapman J, Korczyn AD, Karussis DM, Michaelson DM,. The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology 2001; 57: 1482-1485.
131. Chapman J, Vinokurov S, Achiron A, et al. APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 2001; 56: 312-316.
132. Santos M, Do Carmo Costa M, Edite Rio M, et al. Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin. Mult. Scler. 2004; 10: 153-157.
133. Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K,. Polymorphisms of apolipoprotein E and Japanese patients with multiple sclerosis. Mult. Scler. 2003; 9: 382-386. (Pubitemid 36958021)
134. Teasdale GW, Nicoll JAR, Murray G, Fiddes M,. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997; 350: 1069-1071. (Pubitemid 27437858)
135. Crawford FC, Vanderploeg RD, Freeman MJ, et al. APOE genotype influences acquisition and recall following traumatic brain injury. Neurology 2002; 58: 1115-1118.
136. Liberman JN, Stewart WF, Wesnes K, Troncoso J,. Apolipoprotein E epsilon-4 and short-term recovery from predominantly mild brain injury. Neurology 2002; 58: 1038-1044.
137. Kay AD, Petzold A, Kerr M, Keir G, Thompson E, Nicoll JA,. Alterations in cerebrospinal fluid apolipoprotein E and amyloid beta-protein after traumatic brain injury. J. Neurotrauma 2003; 20: 943-952. (Pubitemid 37288554)
138. Egensperger R, Bancher C, Kosel S, et al. The apolipoprotein E epsilon-4 allele in Parkinson's disease with Alzheimer's lesions. Biochem. Biophys. Res. Commun. 1996; 224: 484-486.
139. Marder K, Maestre G, Cote L, et al. The apolipoprotein E4 allele in Parkinson's disease with and without dementia. Neurology 1994; 44: 1330-1331.
140. Zareparsi S, Comicioli R, Sexton G, et al. Age at onset of Parkinson disease and apolipoprotein E genotypes. Am. J. Med. Genet. 2002; 107: 156-161.
141. Amouyel P, Vidal O, Launay JM, Laplanche JL,. The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. Lancet 1994; 344: 1315-1318.
142. Garlepp MJ, Tabarias H, Van Bockxmeer FM, Zilko PJ, Laing B, Mastaglia FL,. Apolipoprotein E epsilon 4 in inclusion body myositis. Ann. Neurol. 1995; 38: 957-959.
143. Kadotani H, Kadotani T, Young T, et al. Association between apolipoprotein E epsilon-4 and sleep-disordered breathing in adults. JAMA 2001; 285: 2888-2890.
144. Matsumoto S, Nishimura M, Sakamoto T, et al. Modulation of the onset age in primary dystonia by APOE genotype. Neurology 2003; 60: 2003-2005.
145. Copin B, Brezin AP, Valtot F, Dascotte JC, Bechetoille A, Garchon HJ,. Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene. Am. J. Hum. Genet. 2002; 70: 1575-1581.
146. Bunce C, Hitchings RA, Bhattacharya SS, Lehmann OJ,. Single-nucleotide polymorphisms and glaucoma severity. Am. J. Hum. Genet. 2003; 72: 1593-1594.
147. Ressiniotis T, Griffiths PG, Birch M, Keers S, Chinnery PF,. The role of apolipoprotein E gene polymorphisms in primary open-angle glaucoma. Arch. Ophthalmol. 2004; 122: 258-261.
148. Schultz DW, Klein ML, Humpert A, et al. Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch. Opthalmol. 2003; 121: 679-683.
149. Baird PN, Guida E, Chu DT, Vu HT, Guymer RH,. The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2004; 45: 1311-1315.
150. Zareparsi S, Reddick AC, Branham KE, et al. Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest. Ophthalmol. Vis. Sci. 2004; 45: 1306-1310.
151. Anderson DH, Ozaki S, Nealon M, et al. Local cellular sources of apolipoprotein E in the human and retinal pigmented epithelium: implications for the process of drusen formation. Am. J. Ophthalmol. 2001; 131: 767-781.
152. Higuchi S, Matsushita S, Hasegawa Y, Maramatsu T, Arai H, Hayashida M,. Apolipoprotein E e4 Allele and pupillary response to tropicamide. Am. J. Psychiatry 1997; 154: 694-696.
153. Scinto LFM, Daffner KR, Dressler D, et al. A potential noninvasive neurobiological test for Alzheimer disease. Science 1994; 266: 1051-1053.
154. Idiaquez J, Álvarez G, Villagra R, San Martín RA,. Cholinergic supersensitivity of the iris in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 1994; 57: 1544-1545.
155. Treloar A, Assin M, MacDonald A, et al. Pupillary response to topical tropicamide as a marker of Alzheimer's disease. Br. J. Clin. Pharmacol. 1996; 41: 256-257.
156. Yaffe K, Haan M, Byers A, et al. Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 2000; 54: 1949-1954.
157. Taylor RW, Stewart MW, Avery PJ, et al. Apolipoprotein E and familial non-insulin-dependent diabetes mellitus. Lancet 1994; 344: 406.
158. Liu L, Xiang K, Zheng T, Zhang R, Li M, Li J,. Co-inheritance of specific genotypes of HSPG and ApoE gene increases risk of type 2 diabetic nephropathy. Mol. Cell. Biochem. 2003; 254: 353-358.
159. Araki S, Koya D, Makiishi T, et al. APOE polymorphism and the progression of diabetic nephropathy in Japanese subjects with type 2 diabetes: results of a prospective observational follow-up study. Diabetes Care 2003; 26: 2416-2420.
160. Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA,. The role of viruses and of APOE in dementia. Ann. N. Y. Acad. Sci. 2004; 1019: 15-18.
161. Itzhaki RF, Lin WR, Shang D, et al. Herpes simplex virus type 1 in brain and risk for Alzheimer's disease. Lancet 1997; 349: 241-244.
162. Lin W-R, Graham J, MacGowan M, Wilcock GK, Itzhaki RF,. Alzheimer's disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimers Rep. 1998; 1: 173-178.
163. Lin WR, Jennings R, Smith TL, Wozniak MA, Itzhaki RF,. Vaccination prevents latent HSV1 infection of mouse brain. Neurobiol. Aging 2001; 22: 699-703.
164. Corder EH, Robertson K, Lannfelt L, et al. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat. Med. 1998; 4: 1182-1184.
165. Tursen U, Kaya TI, Eskandari G, et al. Apolipoprotein E gene polymorphism and serum lipids in patients with superficial fungal disease. Yonsei Med. 2004; 45: 375-379.
166. Grunenfelder J, Umbehr M, Plass A, et al. Genetic polymorphisms of apolipoprotein E4 and tumor necrosis beta as predisposing for increased inflammatory cytokines after cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 2004; 128: 92-97.
167. Corbo RM, Scacchi R, Cresta M,. Differential reproductive efficiency associated with common apolipoprotein e alleles in postreproductive-aged subjects. Fertil. Steril. 2004; 81: 104-107.
168. Thompson PD, Tsongalis GJ, Seip RL, et al. Apolipoprotein E genotype and changes in serum lipids and maximal oxygen uptake with exercise training. Metabolism 2004; 53: 193-202.
169. Leon AS, Togashi K, Rankinen T, et al. Association of apolipoprotein E polymorphism with blood lipids and maximal oxygen uptake in the sedentary state and after exercise training in the HERITAGE family study. Metabolism 2004; 53: 108-116.
170. Cacabelos R,. The application of functional genomics to Alzheimer's disease. Pharmacogenomics 2003; 4: 597-621.
171. Cacabelos R, Takeda M,. Pharmacogenomics, nutrigenomics and future therapeutics in Alzheimer's disease. Drugs Future 2006; 31 (Suppl. B): 5-146.
172. Cacabelos R,. Pharmacogenomics in Alzheimer's disease. Methods Mol. Biol. 2008; 448: 213-357.
173. Roses AD,. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat. Rev. Genet. 2004; 5: 645-656.
174. Cacabelos R,. Pharmacogenomics and therapeutic strategies for dementia. Expert Rev. Mol. Diagn. 2009; 9: 567-611.
175. Cacabelos R, Llovo R, Fraile C, Fernández-Novoa L,. Pharmacogenetic aspects of therapy with cholinesterase inhibitors: the role of CYP2D6 in Alzheimer's disease pharmacogenetics. Curr. Alzheimer Res. 2007; 4: 479-500.
176. Thomann PA, Roth AS, Dos Santos V, Toro P, Essig M, Schöder J,.