Robyn Carson

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.

α7 Nicotinic acetylcholine receptor gene and reduced risk of Alzheimer’s disease

Background: Sporadic Alzheimer’s disease (AD) is a common disabling disease of complex aetiology for which there are limited therapeutic options. We sought to investigate the role of the α7 nicotinic acetylcholine receptor gene (CHRNA7) in influencing risk of AD in a large population. CHRNA7 is a strong candidate gene for AD for several reasons: (1) its expression is altered differentially in the AD brain; (2) it interacts directly with β amyloid peptide (Aβ42); and (3) agonist activation induces several neuroprotective pathways. Methods: In this study we used a genetic haplotype approach to assess the contribution of common variation at the CHRNA7 locus to risk of AD. Fourteen single nucleotide polymorphisms (SNPs) were genotyped in 764 AD patients and 314 controls. Results: Three blocks of high linkage disequilibrium (LD) and low haplotype diversity were identified. The block 1 TCC haplotype was significantly associated with reduced odds of AD (p = 0.001) and was independent of apolipoprotein E (APOE) status. Individual SNPs were not associated with risk for AD. Conclusions: We conclude that genetic variation in CHRNA7 influences susceptibility to AD. These results provide support for the development of α7nAChR agonists or modulators as potential drug treatments for AD. Further work is necessary to replicate the findings in other populations.

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.

Apolipoprotein epsilon4 and neuropsychological performance in Alzheimer's disease and vascular dementia

The apolipoprotein (APOE) epsilon4 allele is a genetic risk factor for the development of Alzheimers disease (AD). It has also been associated with vascular dementia (VaD) in some but not all studies. Previous studies have examined the role of APOE in predicting performance on cognitive tests in both demented and non-demented populations. In cognitively intact individuals, statistically significant group differences between APOE epsilon4 carriers and non-carriers have been demonstrated for several cognitive domains. In AD studies of the impact of APOE epsilon4 on cognition have been conflicting while no previous study has assessed cognition and impact of APOE epsilon4 in VaD. In this study we investigated the impact of APOE epsilon4 on performance in neuropsychological tests including information processing speed in patients with mild-moderate AD and VaD. We incorporated both computerized and pen and paper tests to ensure a sensitive method of assessing cognition. 109 patients participated in the study (VaD=41, AD=68). Neurocognitive performance of 44 epsilon4 present AD patients was compared to 24 epsilon4absent patients and performance of 23 epsilon4 present VaD patients was compared to 18 epsilon4 absent patients. There was evidence that APOE epsilon4 conferred a risk of poorer cognitive functioning in both patient groups. In the AD group presence of epsilon4 conferred a negative impact on some measures of speed of information processing and immediate recall while in the VaD group epsilon4 present patients had evidence of poorer accuracy on tasks such as choice reaction time and spatial working memory. In AD and VaD groups epsilon4 present patients showed impairment in selective attention. These findings provide further support of the negative impact of the epsilon4 allele in cognition.

Age-Related Macular Degeneration–Associated Genes in Alzheimer Disease

OBJECTIVES Given the clinical and pathological similarities between age-related macular degeneration (AMD) and Alzheimer disease (AD), to assess whether AMD-associated single nucleotide polymorphisms (SNPs), including those from complement-related genes, are associated with AD. DESIGN A case-control association study-type design. SETTING A UK tertiary care dementia clinic. PARTICIPANTS 322 cognitively normal participants and 258 cases with a clinical diagnosis of AD. MEASUREMENTS Polymorphisms in the following genes were studied: CFH, ARMS2, C2/CFB, C3, CFI/PLA2G12a, SERPING1, TLR3, TLR4, CRP, APOE, and TOMM40. Haplotypes were analysed for CFH, TOMM40, and APOE. Univariate analysis was performed for each genetic change and case-comparator status, and then correction for multiple testing performed. RESULTS The presence of an ε4 APOE allele was significantly associated with AD. No association was evident between CFH SNPs or haplotypes, or other AMD-associated SNPs tested, and AD. The exceptions were TOMM40 SNPs, which were associated with AD even after correction for multiple comparisons. The associations disappeared, however, when entered into a regression model including APOE genotypes. CONCLUSIONS The results for most SNPs tested, as well as CFH haplotypes, are novel. The functional effects of abnormal complement activity in ADs pathogenesis may be contradictory, but methodological reasons may underlie the lack of association-for example, genetic changes other than SNPs being involved.

Introduction to genetic epidemiology.

Genetic epidemiology is of topical and increasingly practical relevance. The subject attempts to answer 2 questions: (1) is there a genetic component to a disease, and (2) what genes are involved? This article summarizes genetic epidemiologic methods, describing family- and population-based methods used to locate and identify genes and the advantages and disadvantages of each approach. Health care professionals are faced with more and more genetic information, both from interested patients and from the media, and understanding the principles underlying genetic studies allows such information to be placed in context.

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.