Cumulative effect of COMT and 5-HTTLPR polymorphisms and their interaction with disease severity and comorbidities on the risk of psychosis in Alzheimer disease.

OBJECTIVE The objective of this study was to investigate the cumulative effect of the genes likely involved in Alzheimer disease (AD)-related psychosis and their interaction with disease stage and environmental factors. METHODS Two hundred thirty-four patients with AD underwent clinical and neuropsychologic examination, behavioral and psychiatric disturbances evaluation, and were subsequently divided into two subgroups according to the presence (AD-P) or the absence (AD-nP) of psychotic symptoms. Cathecol-O-methyltransferase (COMT), serotonin gene-linked promoter region (5-HTTLPR), and Apolipoprotein E (ApoE) genotypes were performed. RESULTS COMT*H (H/H or H/liter; odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.13-5.11) and 5-HTTLPR*S (S/S or S/liter, OR: 2.14; 95% CI: 1.13-4.07) were associated with AD-P. A gene dose effect was observed; in fact, carriers of both polymorphisms showed a fivefold risk for psychosis compared with patients bearing no polymorphisms. An interaction between these two genetic variations with disease stage and ischemic cardiomyopathy was found, the latter influencing AD-P risk only if "at-risk" genetic polymorphisms were present. The combined trend effect of COMT*H plus 5-HTTLPR*S and advance disease stage on AD-P risk was approximately 200% greater than that predicted by assuming additive effects, whereas the one obtained by COMT*H plus 5-HTTLPR*S and ischemic cardiomyopathy was 50% greater. ApoE genotype did not influence AD-P risk. CONCLUSIONS These findings claim for a synergic effect of COMT*H and 5-HTTLPR*S polymorphisms on the risk of psychosis in AD and for their interaction with disease stage and ischemic cardiomyopathy. This study suggests that considering both the genetic background and the environmental correlates might provide new insight for understanding psychosis mechanisms related to AD.

[1]  M. Mega,et al.  The Neuropsychiatric Inventory , 1994, Neurology.

[2]  David R. Anderson,et al.  Model selection and multimodel inference : a practical information-theoretic approach , 2003 .

[3]  B. Kolachana,et al.  Catechol-O-Methyltransferase Genotype and Dopamine Regulation in the Human Brain , 2003, The Journal of Neuroscience.

[4]  B. Pollock,et al.  The 5-HTTPR*S/*L polymorphism and aggressive behavior in Alzheimer disease. , 2001, Archives of neurology.

[5]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[6]  David R. Anderson,et al.  Model selection and inference : a practical information-theoretic approach , 2000 .

[7]  K. Kendler,et al.  Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families , 2004, Molecular Psychiatry.

[8]  C. Cusin,et al.  Serotonin transporter gene (5-HTTLPR) and major psychoses , 2002, Molecular Psychiatry.

[9]  B. Pollock,et al.  Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. , 2002, The American journal of psychiatry.

[10]  S. Faraone,et al.  Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. , 2003, The American journal of psychiatry.

[11]  J. Cummings,et al.  Assessing the Impact of Neuropsychiatric Symptoms in Alzheimer's Disease: The Neuropsychiatric Inventory Caregiver Distress Scale , 1998, Journal of the American Geriatrics Society.

[12]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[13]  D. Geschwind,et al.  Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease. , 2004, Archives of neurology.

[14]  B. Devlin,et al.  Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype , 2003, Molecular Psychiatry.

[15]  M. Garcia-Alloza,et al.  Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease , 2005, Neuropsychologia.

[16]  C. Lyketsos,et al.  Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. , 2002, JAMA.

[17]  K J Rothman,et al.  Synergy and antagonism in cause-effect relationships. , 1974, American journal of epidemiology.

[18]  T. Shimomura,et al.  Factors associated with psychotic symptoms in Alzheimer’s disease , 1998, Journal of neurology, neurosurgery, and psychiatry.

[19]  M. Luca,et al.  Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer Disease , 2004, Neuroscience Letters.

[20]  C. Lyketsos,et al.  The epidemiology of psychosis in dementia. , 2003, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[21]  P Riederer,et al.  Allelic Variation of Human Serotonin Transporter Gene Expression , 1996, Journal of neurochemistry.

[22]  J. Duchek,et al.  Reliability of the Washington University Clinical Dementia Rating. , 1988, Archives of neurology.

[23]  P. S. St George-Hyslop,et al.  Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer's disease. , 1999, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[24]  R. Tamura,et al.  Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. , 2000, Archives of general psychiatry.

[25]  W. Hauser,et al.  Predictors of disease course in patients with probable Alzheimer's disease , 1987, Neurology.

[26]  R. Doody,et al.  Positive and negative neuropsychiatric features in Alzheimer's disease. , 1995, The Journal of neuropsychiatry and clinical neurosciences.

[27]  L. Thal,et al.  Neuromotor abnormalities and risk for psychosis in Alzheimer’s disease , 2003, Neurology.

[28]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[29]  J. Beckmann,et al.  A highly significant association between a COMT haplotype and schizophrenia. , 2002, American journal of human genetics.

[30]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[31]  I. Skoog,et al.  Psychotic symptoms and paranoid ideation in a nondemented population-based sample of the very old. , 2002, Archives of general psychiatry.

[32]  M J Khoury,et al.  Commentary: facing the challenge of gene-environment interaction: the two-by-four table and beyond. , 2001, American journal of epidemiology.

[33]  J. Becker,et al.  The apolipoprotein E ϵ4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease , 1997, Neurology.

[34]  M. Albert,et al.  Association between the APOE genotype and psychopathologic symptoms in Alzheimer’s disease , 2002, Neurology.

[35]  Jane S. Paulsen,et al.  Incidence of and risk factors for hallucinations and delusions in patients with probable AD , 2000, Neurology.