Dominic J. Hart

Association Analysis of Apolipoprotein E Genotype and Risk of Depressive Symptoms in Alzheimer’s Disease

Objectives: Behavioural and psychological symptoms of dementia (BPSD) are potent predictors of carer distress and admission to institutional care. In Alzheimer’s disease (AD), depressive symptoms are one of the most common complaints affecting around 50% of all patients. There is speculation these symptoms result from known genetic risk factors for AD, therefore we investigated the role of apolipoprotein E Ε4 in the aetiology of depression in AD. Methods: In this well-characterised cohort (n = 404) from the relatively genetically homogeneous Northern Ireland population, we tested the hypothesis that genetic variants of apolipoprotein E influence the risk for depressive symptoms in AD patients using the Neuropsychiatric Inventory (NPI-D) to determine the presence of depressive symptoms during the dementing illness. Results: A total of 55% of patients exhibited a history of depression/dysphoria during the course of the illness as gathered by the NPI-D questionnaire. Forty-six percent were suffering from depression/dysphoria when the analysis was restricted to the month prior to interview. No statistically significant association between genotypes or alleles of apolipoprotein E and depression/dysphoria in AD was observed, nor was any association noted between the presence of severe symptoms and genotypes/alleles of apolipoprotein E. Conclusions: These results suggest apolipoprotein E genotype creates no additional risk for depressive symptoms in AD.

The interleukin 1β gene promoter polymorphism (−511) acts as a risk factor for psychosis in Alzheimer's dementia

The explanation for why some patients develop psychotic change in Alzheimers disease (AD) is unclear. “Psychosis‐modifier genes” may act in the setting of neurodegeneration to produce AD plus psychosis in a similar way to how genetic modulation during neurodevelopment leads to schizophrenia. Because there is increasing interest in the common disruption of cytokine pathways seen in both AD and schizophrenia, we tested the association between the functional interleukin‐1β −511 promoter polymorphism with delusions and hallucinations in AD. Significant associations between psychotic symptoms and the CC genotype (p = 0.001 ‐ p = 0.043) and C allele (p = 0.014 vs p = 0.048) were found, thus confirming the previously noted increased risk in schizophrenia.

Psychotic symptoms in Alzheimer’s disease are not influenced by polymorphic variation at the dopamine receptor DRD3 gene

It has been suggested that genetic influences unmasked during neurodevelopment to produce schizophrenia may appear throughout neurodegeneration to produce AD plus psychosis. Risk of schizophrenia and psychosis in Alzheimers disease (AD) has been linked to polymorphic variation at the dopamine receptor DRD3 gene implying similar causative mechanisms. We tested this association in a large cohort of Alzheimers disease patients with a diagnosis of probable AD of 3 years or more duration from the relatively genetically homogenous Northern Irish population. We assessed relationships between genotypes/alleles of the DRD3 BalI polymorphism and the presence or absence of psychotic symptoms (delusions, hallucinations) in AD patients during the month prior to interview and at any stage during the dementia. No significant associations were found when delusions and hallucinations were cross-tabulated against S and G alleles and SS, SG and GG genotypes. Logistic regression failed to detect any influence of APOE, gender, family history or prior psychiatric history. In conclusion, we were unable to confirm previously reported associations between the DRD3 BalI polymorphism and psychotic symptoms in AD.

Analysis of the 5HT-2A T102C receptor polymorphism and psychotic symptoms in Alzheimer's disease†

Although the aetiology of psychotic symptoms in Alzheimers disease (AD) is multi‐factorial, alterations in serotonergic neurotransmission are often implicated. Polymorphisms of the serotonin receptor 5HT‐2A are associated with hallucinatory symptoms and delusions in demented and non‐demented cohorts. This study examined the role of the 5HT‐2A T102C polymorphism in influencing psychotic symptoms in a large Northern Ireland AD population (n = 406, mean MMSE 13/30). Forty‐eight percent of patients experienced delusional symptoms and 28% experienced hallucinations during the course of their dementia. No significant association was found either in frequency of genotype or allelic variation for either set of symptoms. Furthermore, the mean delusional and hallucinatory severity scores did not differ significantly among the three genotype groups. The lack of influence of the T102C polymorphism of the 5HT‐2A receptor on the emergence of psychotic symptoms in AD contrasts with previous reports in other cohorts involving smaller numbers of subjects.

Allelic variation at the A218C tryptophan hydroxylase polymorphism influences agitation and aggression in Alzheimer's disease

The behavioural and psychological symptoms of dementia are common, distressing to carers, and directly linked to the requirement for institutional care. Symptoms of aggression and agitation are particularly difficult for carers to tolerate. The origin of these features is unclear although genetic and environmental modification of pre-frontal serotonergic circuitry which regulates the control of negative emotions is proposed. Following the suggestion that the A218C intronic polymorphism of the tryptophan hydroxylase gene influences aggression and anger in non-demented individuals, we tested the influence of A218C on symptoms of agitation/aggression in 396 Alzheimers disease patients using the Neuropsychiatric Inventory. Overall, 50% of participants experienced agitation/aggression in the month prior to interview. It was observed that male patients with a history of agitation/aggression were more likely to possess C-containing genotypes (P = 0.044, OR = 1.65, CI = 0.98-2.76). We conclude that aggression in male subjects with Alzheimers disease may be genetically linked to polymorphic variation at the tryptophan hydroxylase gene.

P3-209: Genetic variation in the alpha 7 nicotinic acetylcholine receptor is associated with delusional symptoms in Alzheimer's disease

PLINK gave an adjusted p-value of 1.3x10 for the chisq test. Rs5984894 maps to a 102-kb LD block on Xq21.3 that is entirely within the gene encoding protocadherin 11, X-linked (PCDH11X). The PCDH11X gene is a member of the protocadherin subfamily of calcium-dependent cell adhesion and recognition proteins, which are particularly prevalent in the central nervous system. Conclusions: Our two-stage LOAD GWAS shows genome-wide significance for rs5984894, a variant that maps to a 102-kb LD block entirely within PCDH11X. These results warrant further examination of PCDH11X as a LOAD susceptibility gene.