Abstract
AbstractAlthough there is evidence for the involvement of genes of serotonergic and dopaminergic systems in the manifestation of the Behavioural and Psychological Symptoms in Dementia (BPSD), genetic association studies are contradictory. We used 1008 probable AD patients from the UK and applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of 11 polymorphisms in the serotonergic and dopaminergic systems, on four behavioural sub-phenotypes, namely "psychosis"," moods", "agitation" and "behavioural dyscontrol", as well as on 12 NPI items. Significant findings included the association of DRD1 A48G with "psychosis" (p=0.037), the association of DAT1 VNTR with "agitation" (p=0.006) and the association of DRD4 with "moods" sub-phenotype (p=0.008). In addition, associations were identified between DRD1 A48G and DAT1 VNTR with aberrant motor behaviour (AMB) symptoms (p=0.001 and p=0.015 respectively), between DRD4 and sleep disturbances (p=0.018) and between 5HTTLPR and apathy (p=0.033). Finally, significant interactions were observed between COMT Val158Met and 5HTTLPR with "psychosis" (p=0.026), between HTTLPR and STin2 with "psychosis" (p=0.005), between DAT1 3'UTR VNTR and COMT Val158Met with "agitation" (p=0.0001) and between DAT1 3'UTR VNTR and 5HTTLPR with the "moods" factor (p=0.0027). The complexity of the interrelations between genetic variation, behavioural symptoms and clinical variables was efficiently captured by this MIMIC model.
Highlights
Behavioural and psychological symptoms such as hallucinations, agitation or depression occur in the majority of people with Alzheimer’s Disease and are associated with considerable morbidity to patients and distress to carers (1-3)
For the 5HTTLPR polymorphism we investigated for the presence of short allele or genotype (S or SS & LS), whereas for STin2 we examined the association between Behavioural and Psychological Symptoms in Dementia (BPSD) and presence of (12R) repeats
We investigated whether the dopamine transporter gene (DAT) polymorphism interacts with DRD1 or DRD4 polymorphisms, whether the DRD1 polymorphism interacts with DRD3 or DRD4 polymorphisms, whether the Catechol-O-methyl transferase gene (COMT) polymorphism interacts with HTTLPR, Monoamine Oxidase A gene (MAOA), or DAT polymorphisms, whether HTTLPR interacts with DAT, MAOA, DRD4 or STin2 polymorphisms and whether the MAOA polymorphism interacts with DRD4 polymorphism
Summary
Behavioural and psychological symptoms such as hallucinations, agitation or depression occur in the majority of people with Alzheimer’s Disease and are associated with considerable morbidity to patients and distress to carers (1-3). This study aimed to investigate associations between risk alleles/genotypes and the presence of behavioural symptoms and sub-phenotypes, using data on eleven polymorphisms from ten genes, in a large cohort (n = 1008) of patients with probable AD. In the current study we aimed to use this model as a platform to test the association between risk alleles/genotypes with these behavioural symptoms and sub-phenotypes in the presence of covariates. This is a powerful approach which allows us to perform a simultaneous analysis of the entire system of variables, by forming specific hypotheses.
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