Pharmacogenomics and therapeutic prospects in dementia

  • Ramón CacabelosEmail author


Dementia is a major problem of health in developed countries. Alzheimer’s disease (AD) is the main cause of dementia, accounting for 50–70% of the cases, followed by vascular dementia (30–40%) and mixed dementia (15–20%). Approximately 10–15% of direct costs in dementia are attributed to pharmacological treatment, and only 10–20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype–phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20–95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.

Key words

dementia Alzheimer’s disease APOE CYP2D6 pharmacogenetics pharmacogenomics multifactorial treatments  



There is no conflict of interest. The corresponding author assures that there is no association with a company whose product is named in the article or a company that markets a competitive product. The presentation of the topic is impartial, and the representation of the contents are product neutral.


  1. 1.
    Aerssens J, Raeymaekers P, Lilienfeld S, Geerts H, Konings F, Parys W (2001) APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer’s disease. Dement Geriatr Cogn Disord 2:69–77CrossRefGoogle Scholar
  2. 2.
    Almkvist O, Jelic V, Amberla K, Hellstrom-Lindahl E, Meurling L, Nordberg A (2001) Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients. Dement Geriatr Cogn Disord 12:22–32PubMedCrossRefGoogle Scholar
  3. 3.
    Alvarez XA, Mouzo R, Pichel V et al (1999) Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer’s disease patients. Effects on cognitive performance, brain bioelectrical activity, and cerebral perfusion. Methods Find Exp Clin Pharmacol 21:633–644PubMedCrossRefGoogle Scholar
  4. 4.
    Alvarez XA, Pichel V, Pérez PA et al (2000) Double-blind, randomized, placebo-controlled pilot study with anapsos in senile dementia: effects on cognition, brain bioelectrical activity and cerebral hemodynamics. Methods Find Exp Clin Pharmacol 22:585–594PubMedCrossRefGoogle Scholar
  5. 5.
    Arranz MJ, Collier D, Kerwin RW (2001) Pharmacogenetics for the individualization of psychiatric treatment. Am J Pharmacogenomics 1:3–10PubMedCrossRefGoogle Scholar
  6. 6.
    Atkinson A, Singleton AB, Steward A et al (1999) CYP2D6 is associated with Parkinson’s disease but not with dementia with Lewy bodies or Alzheimer’s disease. Pharmacogenetics 9:31–35PubMedCrossRefGoogle Scholar
  7. 7.
    Austin CP (2004) The impact of the completed human genome sequence on the development of novel therapeutics for human disease. Annu Rev Med 55:1–13PubMedCrossRefGoogle Scholar
  8. 8.
    Bellivier F, Laplanche JL, Schurhoff F et al (1997) Apolipoprotein E gene polymorphism in early and late onset bipolar patients. Neurosci Lett 233:45–48PubMedCrossRefGoogle Scholar
  9. 9.
    Bentue-Ferrer D, Tribut O, Polard E, Allain H (2003) Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists. CNS Drugs 17:947–963PubMedCrossRefGoogle Scholar
  10. 10.
    Bernal ML, Sinues B, Johansson I et al (1999) Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics 9:657–660PubMedCrossRefGoogle Scholar
  11. 11.
    Bernard S, Neville KA, Nguyen AT, Flockhart DA (2006) Interethnic differences in genetic polymorphisms of CYP2D6 in the US population: clinical implications. Oncologist 11:126–135PubMedCrossRefGoogle Scholar
  12. 12.
    Bizzarro A, Marra C, Acciarri A et al (2005) Apolipoprotein E epsilon-4 allele differentiates the clinical response to donepezil in Alzheimer’s disease. Dement Geriatr Cogn Disord 20:254–261PubMedCrossRefGoogle Scholar
  13. 13.
    Borroni B, Colciaghi F, Pastorino L et al (2002) ApoE genotype influences the biological effects of donepezil on APP metabolism in Alzheimer disease: evidence from a peripheral model. Eur Neuropsychopharmacol 12:195–200PubMedCrossRefGoogle Scholar
  14. 14.
    Cacabelos R (2002) Pharmacogenomics in Alzheimer’s disease. Mini Rev Med Chem 2:59–84PubMedCrossRefGoogle Scholar
  15. 15.
    Cacabelos R (2002) Pharmacogenomics for the treatment of dementia. Ann Med 34:357–379PubMedCrossRefGoogle Scholar
  16. 16.
    Cacabelos R (2003) The application of functional genomics to Alzheimer’s disease. Pharmacogenomics 4:597–621PubMedCrossRefGoogle Scholar
  17. 17.
    Cacabelos R (2005) Pharmacogenomics and therapeutic prospects in Alzheimer’s disease. Exp Opin Pharmacother 6:1967–1987CrossRefGoogle Scholar
  18. 18.
    Cacabelos R (2005) Pharmacogenomics, nutrigenomics and therapeutic optimization in Alzheimer’s disease. Aging Health 1:303–348CrossRefGoogle Scholar
  19. 19.
    Cacabelos R (2007) Molecular pathology and pharmacogenomics in Alzheimer’s disease: Polygenic-related effects of multifactorial treatments on cognition, anxiety, and depression. Methods Find Exp Clin Pharmacol 29(Suppl B):1–91PubMedGoogle Scholar
  20. 20.
    Cacabelos R (2007) Donepezil in Alzheimer’s disease: from conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat 3:303–333Google Scholar
  21. 21.
    Cacabelos R, Alvarez A, Fernández-Novoa L, Lombardi VRM (2000) A pharmacogenomic approach to Alzheimer’s disease. Acta Neurol Scand 176(Suppl):12–19CrossRefGoogle Scholar
  22. 22.
    Cacabelos R, Alvarez XA, Lombardi V et al (2000) Pharmacological treatment of Alzheimer disease: from phychotropic drugs and cholinesterase inhibitors to pharmacogenomics. Drugs Today 36:415–499PubMedGoogle Scholar
  23. 23.
    Cacabelos R, Fernández-Novoa L, Corzo L et al (2004) Phenotypic profiles and functional genomics in dementia with a vascular component. Neurol Res 26:459–480PubMedCrossRefGoogle Scholar
  24. 24.
    Cacabelos R, Fernández-Novoa L, Lombardi V, Kubota Y, Takeda M (2005) Molecular genetics of Alzheimer’s disease and aging. Methods Find Exp Clin Pharmacol 27(Suppl A):1–573PubMedGoogle Scholar
  25. 25.
    Cacabelos R, Fernández-Novoa L, Pichel V, Lombardi V, Kubota Y, Takeda M (2004) Pharmacogenomic studies with a combination therapy in Alzheimer’s disease. In: Takeda M, Tanaka T, Cacabelos R (eds) Molecular neurobiology of Alzheimer Disease and related disorders. Karger, Basel, pp 94–107CrossRefGoogle Scholar
  26. 26.
    Cacabelos R, Kubota Y, Isaza C et al (2005) Functional genomics and pharmacogenetics in Alzheimer’s disease. In: Hanin I, Cacabelos R, Fisher A (eds) Recent progress in Alzheimer’s and Parkinson’s Disease. Taylor & Francis, London, pp 89–102Google Scholar
  27. 27.
    Cacabelos R (2007) Pleiotropic effects of APOE in dementia: influence on functional genomics and pharmacogenetics. In: Fisher A, Hanin I, Stocchi F, Memo M (eds) Advances in Alzheimer’s and Parkinson’s disease. Insights, progress, and perspectives. Springer, Secaucus (NJ) (in press)Google Scholar
  28. 28.
    Cacabelos R, Rodríguez B, Carrera C, Beyer K, Lao JI, Sellers MA (1997) Behavioral changes associated with different apolipoprotein E genotypes in dementia. Alzheimer Dis Assoc Disord 11(Suppl 4):S27–S37PubMedGoogle Scholar
  29. 29.
    Cacabelos R, Takeda M (2006) Pharmacogenomics, nutrigenomics and future therapeutics in Alzheimer’s disease. Drugs Future 31(Suppl B):5–146Google Scholar
  30. 30.
    Cervilla JA, Russ C, Holmes C et al (1999) CYP2D6 polymorphisms in Alzheimer’s disease, with and without extrapyramidal signs, showing no apolipoprotein E epsilon 4 effect modification. Biol Psychiatry 45:426–429PubMedCrossRefGoogle Scholar
  31. 31.
    Chen X, Xia Y, Alford M et al (1995) The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer’s disease. Ann Neurol 38:653–658PubMedCrossRefGoogle Scholar
  32. 32.
    Craig D, Hart DJ, McIlroy SP, Passmore AP (2005) Association analysis of apolipoprotein E genotype and risk of depressive symptoms in Alzheimer’s disease. Dement Geriatr Cogn Disord 19:154–157PubMedCrossRefGoogle Scholar
  33. 33.
    Egger SS, Bachmann A, Hubmann N, Schlienger RG, Krähenbühl S (2006) Prevalence of potentially inappropriate medication use in elderly patients. Comparison between general medicine and geriatric wards. Drugs Aging 23:823–837PubMedCrossRefGoogle Scholar
  34. 34.
    Emilien G, Ponchon M, Caldas C, Isacson O, Maloteux JM (2000) Impact of genomics on drug discovery and clinical medicine. QJ Med 93:391–423Google Scholar
  35. 35.
    Evans WE, McLeod HL (2003) Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 348:538–549PubMedCrossRefGoogle Scholar
  36. 36.
    Flicker L, Martins RN, Thomas J et al (2004) Homocysteine, Alzheimer genes and proteins, and measures of cognition and depression in older men. J Alzheimer Dis 6:329–336Google Scholar
  37. 37.
    Furuno T, Kawanishi C, Iseki E et al (2001) No evidence of an association between CYP2D6 polymorphisms among Japanese and dementia with Lewy bodies. Psychiatry Clin Neurosci 55:89–92PubMedCrossRefGoogle Scholar
  38. 38.
    Gabryelewicz T, Religa D, Styczynska M et al (2002) Behavioural pathology in Alzheimer’s disease with special reference to apolipoprotein E genotype. Dement Geriatr Cogn Disord 14:208–212PubMedCrossRefGoogle Scholar
  39. 39.
    Gaikovitch EA, Cascorbi I, Mrozikiewicz PM et al (2003) Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 59:303–312PubMedCrossRefGoogle Scholar
  40. 40.
    Giacobini E (2006) Cholinesterases in human brain: the effect of cholinesterase inhibitors on Alzheimer’s disease, related disorders. In: Giacobini E, Pepeu G (eds) The Brain Cholinergic System in health and disease. Informa Healthcare, Oxon, pp 235–264Google Scholar
  41. 41.
    Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781PubMedCrossRefGoogle Scholar
  42. 42.
    Goldstein DB, Tate SK, Sisodiya SM (2003) Pharmacogenetics goes genomic. Nat Rev Genet 4:937–947PubMedCrossRefGoogle Scholar
  43. 43.
    Griese E-U, Zanger UM, Brudermanns U et al (1998) Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 8:15–26PubMedCrossRefGoogle Scholar
  44. 44.
    Hedlund E, Gustafsson JA, Warner M (2001) Cytochrome P450 in the brain: a review. Curr Drug Metabol 2:245–263CrossRefGoogle Scholar
  45. 45.
    Hickie I, Naismith S, Ward PB et al (2005) Reduced hippocapal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry 186:197–202PubMedCrossRefGoogle Scholar
  46. 46.
    Hogan DB, Goldlist B, Naglie G, Patterson C (2004) Comparison studies of cholinesterase inhibitors for Alzheimer’s disease. Lancet Neurol 3:622–628PubMedCrossRefGoogle Scholar
  47. 47.
    Hollingworth P, Hamshire ML, Moskvina V et al (2006) Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer’s disease. J Am Geriatr Soc 54:1348–1354PubMedCrossRefGoogle Scholar
  48. 48.
    Hunter DJ (2005) Gene–environment interactions in human diseases. Nat Rev Genet 6:287–298PubMedCrossRefGoogle Scholar
  49. 49.
    International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945CrossRefGoogle Scholar
  50. 50.
    Isaza CA, Henao J, López AM, Cacabelos R (2000) Isolation, sequence and genotyping of the drug metabolizer CYP2D6 gene in the Colombian population. Methods Find Exp Clin Pharmacol 22:695–705PubMedCrossRefGoogle Scholar
  51. 51.
    Kim JM, Stewart R, Shin IS, Yoon JS (2004) Vascular/risk and late-life depression in a Korean community population. Br J Psychiatry 185:102–107PubMedCrossRefGoogle Scholar
  52. 52.
    Levenson JM, Sweatt JD (2005) Epigenetic mechanisms in memory formation. Nat Rev Neurosci 6:108–118PubMedCrossRefGoogle Scholar
  53. 53.
    Loveman E, Green C, Kirby J et al (2006) The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease. Health Technol Assess 10:1–176Google Scholar
  54. 54.
    MacGowan SH, Wilcock GK, Scott M (1998) Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer’s disease. Int J Geriatr Psychiatry 13:625–630PubMedCrossRefGoogle Scholar
  55. 55.
    Meyer UA (2004) Pharmacogenetics—five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 5:669–676PubMedCrossRefGoogle Scholar
  56. 56.
    Mizutani T (2003) PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev 35:99–106PubMedCrossRefGoogle Scholar
  57. 57.
    Muller-Thomsen T, Artl S, Ganzer S et al (2002) Depression in Alzheimer’s disease might be associated with apolipoprotein E epsilon 4 allele frequency in women but not in men. Dement Geriatr Cogn Disord 14:59–63PubMedCrossRefGoogle Scholar
  58. 58.
    Naismith S, Hickie I, Ward PB et al (2002) Caudate nucleus volumes and genetic determinants of homocysteine metabolism in the prediction of psychomotor speed in older persons with depression. Am J Psychiatry 159:2096–2098PubMedCrossRefGoogle Scholar
  59. 59.
    Nebes RD, Vora IJ, Meltzer CC et al (2001) Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression. Am J Psychiatry 158:878–884PubMedGoogle Scholar
  60. 60.
    Need AC, Motulsky AG, Goldstein DB (2005) Priorities and standards in pharmacogenetic research. Nat Genet 37:671–681PubMedCrossRefGoogle Scholar
  61. 61.
    Nicholl DJ, Bennett P, Hiller L et al (1999) A study of five candidate genes in Parkinson’s disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism. Neurology 53:1415–1421PubMedGoogle Scholar
  62. 62.
    O’Brien JT, Lloyd A, McKeith I, Gholkar A, Ferrier N (2004) A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am J Psychiatry 161:2081–2090PubMedCrossRefGoogle Scholar
  63. 63.
    Petersen RC, Thomas RG, Grundman M et al (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388PubMedCrossRefGoogle Scholar
  64. 64.
    Philips KA, Van Bebber SL (2005) Measuring the value of pharmacogenomics. Nat Rev Drug Discov 4:500–509CrossRefGoogle Scholar
  65. 65.
    Poirier J (1999) Apolipoprotein E4, cholinergic integrity and the pharmacogenetics of Alzheimer’s disease. J Psychiatry Neurosci 24:147–153PubMedGoogle Scholar
  66. 66.
    Poirier J, Delisle M-C, Quirion R et al (1995) Apolipoprotein E4 allele as a predictor of cholinergic deficits treatment outcome in Alzheimer disease. Proc Natl Acad Sci USA 92:12260–12264PubMedCrossRefGoogle Scholar
  67. 67.
    Raimundo S, Fischer J, Eichelbaum M, Griese EU, Schwab M, Zanger (2000) Elucidation of the genetic basis of the common intermediate metabolizer phenotype for drug oxidation by CYP2D6. Pharmacogenetics 10:577–581PubMedCrossRefGoogle Scholar
  68. 68.
    Raskind MA, Peskind ER, Wessel T, Yuan W (2000) Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 54:2261–2268PubMedGoogle Scholar
  69. 69.
    Rasmussen JO, Christensen M, Svendsen JM, Skausig O, Hansen EL, Nielsen KA (2006) CYP2D6 gene test in psychiatric patients and healthy volunteers. Scand J Clin Lab Invest 66:129–136PubMedCrossRefGoogle Scholar
  70. 70.
    Rigaud AS, Traykov L, Caputo L et al (2000) The apolipoprotein E epsilon 4 allele and the response to tacrine therapy in Alzheimer’s disease. Eur J Neurol 7:255–258PubMedCrossRefGoogle Scholar
  71. 71.
    Rigaud AS, Traykov L, Latour F et al (2002) Presence of absence of least one epsilon 4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer’s disease. Pharmacogenetics 12:415–420PubMedCrossRefGoogle Scholar
  72. 72.
    Risner ME, Saunders AM, Altman JF et al (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics 6:246–254Google Scholar
  73. 73.
    Roses AD (2004) Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet 5:645–656PubMedCrossRefGoogle Scholar
  74. 74.
    Sachse C, Brockmoller J, Bauer S, Roots I (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295PubMedGoogle Scholar
  75. 75.
    Saito S, Ishida A, Sekine A et al (2003) Catalog of 680 variants among eight cytochrome P450 (CYP) genes: nine esterase genes, and two other genes in the Japanese population. J Hum Genet 48:249–270PubMedCrossRefGoogle Scholar
  76. 76.
    Saunders AM, Trowers MK, Shimkets RA et al (2000) The role of apolipoprotein E in Alzheimer’s disease: pharmacogenomic target selection. Biochem Biophys Acta 1502:85–94PubMedGoogle Scholar
  77. 77.
    Schuetz EG, Relling MV, Kishi S et al (2004) PharGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5. Pharmacol Rev 56:159PubMedCrossRefGoogle Scholar
  78. 78.
    Scordo MG, Dahl ML, Spina E, Cordici F, Arena MG (2006) No association between CYP2D6 polymorphisms and Alzheimer’s disease in an Italian population. Pharmacol Res 53:162–165PubMedCrossRefGoogle Scholar
  79. 79.
    Selkoe DJ, Podlisny MB (2002) Deciphering the genetic basis of Alzheimer’s disease. Annu Rev Genomics Hum Genet 3:67–99PubMedCrossRefGoogle Scholar
  80. 80.
    Sink KM, Holden KF, Yaffe K (2005) Pharmacological treatment of neuropsychiatric symptoms of dementia. A review of the evidence. JAMA 293:596–608PubMedCrossRefGoogle Scholar
  81. 81.
    Sjögren M, Hesse C, Basun H et al (2001) Tacrine and rate of progression in Alzheimer’s disease—relation to ApoE allele genotype. J Neural Transm 108:451–458PubMedCrossRefGoogle Scholar
  82. 82.
    Steffens DC, Norton MC, Hart AD et al (2003) Apolipoprotein E genotype and major depression in a community of older adults. The Cache County Study. Psychol Med 33:541–547PubMedCrossRefGoogle Scholar
  83. 83.
    Steinberg M, Corcoran C, Tschanz JT et al (2006) Risk factors for neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry 21:824–830PubMedCrossRefGoogle Scholar
  84. 84.
    Suh Y-H, Checler F (2002) Amyloid precursor protein, presenilins, and α-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Phamacol Rev 54:469–525Google Scholar
  85. 85.
    Teter B, Finch CE (2004) Caliban’s heritance and the genetics of neuronal aging. Trends Neurosci 27:627–632PubMedCrossRefGoogle Scholar
  86. 86.
    Tribut O, Lessard Y, Reymann JM, Allain H, Bentue-Ferrer D (2002) Pharmacogenomics. Med Sci Monit 8:152–163Google Scholar
  87. 87.
    Van der Flier Wm, Staekenborg S, Pijnenburg YA et al (2006) Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease. Dement Geriatr Cogn Disord 23:42–6PubMedCrossRefGoogle Scholar
  88. 88.
    Van Dam D, De Deyn PP (2006) Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 5:956–970PubMedCrossRefGoogle Scholar
  89. 89.
    Varsaldi F, Miglio G, Scordo MG et al (2006) Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer’s disease patients. Eur J Clin Pharmacol 62:721–726PubMedCrossRefGoogle Scholar
  90. 90.
    Verrils NM (2006) Clinical proteomics: present and future prospects. Clin Biochem Rev 27:99–116Google Scholar
  91. 91.
    Weinshilboum RM, Wang L (2006) Pharmacogenetics and pharmacogenomics: development, science, and translation. Annu Rev Genomics Hum Genet 7:223–245PubMedCrossRefGoogle Scholar
  92. 92.
    Woo SI, Kim JW, Seo HG et al (2001) CYP2D6*4 polymorphism is not associated with Parkinson’s disease and has no protective role against Alzheimer’s disease in the Korean population. Psychiatry Clin Neurosci 55:373–377PubMedCrossRefGoogle Scholar
  93. 93.
    Wooding SP, Watkins WS, Bamshad MJ et al (2002) DNA sequence variations in a 3.7-kb noncoding sequence 5-prime of the CYP1A2 gene: implications for human population history and natural selection. Am J Hum Genet 71:528–542PubMedCrossRefGoogle Scholar
  94. 94.
    Xie HG, Kim RB, Wood AJ, Stein CM (2001) Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharm Toxicol 41:815–850CrossRefGoogle Scholar
  95. 95.
    Xie HG, Prasad HG, Kim RB, Stein CM (2002) CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 54:1257–1270PubMedCrossRefGoogle Scholar
  96. 96.
    Yamada H, Dahl ML, Viitanen M, Winblad B, Sjoqvist F, Lannfelt L (1998) No association between familial Alzheimer disease and cytochrome P450 polymorphisms. Alzheimer Dis Assoc Disord 12:204–207PubMedCrossRefGoogle Scholar
  97. 97.
  98. 98.
  99. 99.
  100. 100.
  101. 101.

Copyright information

© Springer 2008

Authors and Affiliations

  1. 1.EuroEspes Biomedical Research CenterInstitute for CNS DisordersCoruñaSpain
  2. 2.EuroEspes Chair of Biotechnology and GenomicsCamilo José Cela UniversityMadridSpain

Personalised recommendations