[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) patients commonly suffer from behavioral and psychological symptoms of dementia (BPSD). Variants within the neuregulin-1 (NRG1) gene have been investigated both in early onset psychiatric disorders, such as schizophrenia and recently in AD patients with psychosis. In this study, we analyzed NRG1 variants in AD patients with and without psychosis. Our large cohort of 399 probable AD patients had longitudinal information on the BPSD, which was used to dichotomize patients into whether they had ever suffered from psychotic symptoms within the study period. The NRG1 single nucleotide polymorphisms rs3924999, rs35753505 (SNP8NRG221533) and the microsatellites 478B14-848 and 420M9-1395 were investigated for association with psychosis using genotype, allele, and haplotype analyses. No associations were found between any of these variants or haplotypic combinations with delusions, hallucinations, psychosis, or elation/mania in our cohort. Positive associations with polymorphisms and haplotype combinations of NRG1 have been reported in psychiatric disorders. One previous study found an association with psychosis in AD, with a SNP outside the haplotype block first reported for association with schizophrenia. We found no association with any of these variants in our cohort. Further investigations of this region on chromosome 8 are clearly required, with replication in different large longitudinal cohorts.
[Show abstract][Hide abstract] ABSTRACT: Since previous observations indicated that the urea cycle may have a role in the Alzheimer's disease (AD) process, we set out to quantify the expression of each gene involved in the urea cycle in control and AD brains and establish whether these genes could be genetic determinants of AD. We first confirmed that all the urea cycle enzyme genes are expressed in the AD brain. The expression of arginase 2 was greater in the AD brain than in the control brain. The presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age-at-onset for both genders. None of the other genes in the pathway appeared to be differentially expressed in the AD brain or act as genetic determinants of the disease.
[Show abstract][Hide abstract] ABSTRACT: The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.
[Show abstract][Hide abstract] ABSTRACT: Several observations suggest that neurotoxicity in Alzheimer's disease (AD) can be partly attributed to beta-amyloid (Abeta) and senile plaques. Recent work has suggested that the FISH (five SH3 domains) adapter protein and ADAM12 (a disintegrin and metalloprotease) may mediate the neurotoxic effect of Abeta. Both genes are located on chromosome 10, within a region linked to AD (for SH3PXD2A) or nearby (for ADAM12). A recent study reported a statistically significant interaction between 2 variants of these genes (rs3740473 for SH3PXD2A and rs11244787 for ADAM12) with respect to the risk of developing AD. With a view to replicating this observation, we genotyped the two SNPs in four European case-control cohorts of Caucasian origin (1913 cases and 1468 controls) but were unable to confirm the initial results.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to the development of BPSD in AD has been supported. Polymorphisms within dopamine receptors DRD1, DRD2, DRD3 and DRD4 have previously been investigated in a few interesting studies that are reviewed here and extended using our patient cohort.
Our large cohort of 395 probable AD patients had longitudinal information on the BPSD (Neuropsychiatric Inventory), which was used to dichotomise patients into whether they had ever suffered from a given symptom within the study period, or not. These measures were related to the DRD1 (A-48G), DRD2 (ser311cys; C-ins/del), DRD3 (ser9gly) and DRD4 (VNTR) genotype and allele frequencies.
Associations were revealed between DRD3 and elation, and between DRD4 with agitation/aggression and with depression; however, these findings do not remain significant after correction for multiple testing. No associations were found with the other genetic variants and these symptoms and no associations were observed between any of the polymorphic variants examined and delusions, hallucinations, psychosis and aberrant motor behaviour.
Our data, in combination with a review of the literature, reveal a potential role for the VNTR variant of DRD4 in the development of depression in AD patients. The findings presented here need to be replicated in large, well characterised longitudinal cohorts.
International Journal of Geriatric Psychiatry 09/2009; 24(9):1020-5. DOI:10.1002/gps.2214 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10(-5)) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 x 10(-9) for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 x 10(-9) for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of beta amyloid (Abeta) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.
[Show abstract][Hide abstract] ABSTRACT: Because the action of thyroid hormone (T3) is involved in adult cognitive functions, we wanted to assess the association between THRA gene polymorphisms, which encodes the T3 nuclear receptor TRα1, and Alzheimer's disease (AD) risk. We analysed 5 single nucleotide polymorphisms (SNPs) of THRA, covering the known common genetic variability of the gene, in the Lille AD case-control study (710 cases/597 controls). We observed that subjects bearing the rs939348 TT genotype had a tendency to have a higher risk of developing AD (adjusted OR [95%CI]=1.71 [0.99-2.95] p=0.06). We extended our finding to three other independent AD case-control studies and observed similar trends. When combining the 4 studies (1749 cases/1339 controls), we observed an overall significant higher risk of AD in TT subjects (adjusted OR [95%CI]=1.42 [1.03-1.96], p=0.03) compared with C allele bearers. However, when combining our data with the available data coming from 2 American genome wide association studies on AD, we observed a weak and not significant association (OR=1.19 [0.97-1.45], p=0.10). The relationship between the genetic variability of the THRA gene and AD risk remains uncertain but cannot be entirely excluded.
Neurobiology of aging 06/2009; 32(4):624-30. DOI:10.1016/j.neurobiolaging.2009.04.007 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE epsilon 4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE epsilon 4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the A beta(40) peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD); a genetic component to the development of BPSD has been demonstrated. Genetic risk factors for other psychiatric disorders have been implicated in BPSD; however, this is the first known investigation of the dopamine transporter (DAT1) gene in BPSD.
Our large cohort of 395 patients with probable Alzheimer's disease was dichotomised into whether they had ever suffered from a given symptom over the study period or not, based on longitudinal data using the BPSD (Neuropsychiatric Inventory). These measures were related to the DAT1 3'-untranslated region (UTR) variable number tandem repeat (VNTR) polymorphism.
Potential associations were revealed between the 9-repeat allele and presence of irritability and between the 10-repeat allele and aberrant motor behaviour (AMB); however, these do not remain significant after correction for multiple testing. No associations were observed with delusions, hallucinations, depression, agitation/aggression or elation.
Our data suggest that the DAT1 3'-UTR VNTR could play a role in susceptibility to irritability and AMB. The findings presented here require replication in large well-characterised cohorts.
[Show abstract][Hide abstract] ABSTRACT: Expression of ornithine transcarbamylase (OTC) is strongly induced in the brain of individuals suffering from Alzheimer's Disease (AD). Association studies in a population from northern France have revealed that two SNPs -389 G/A (rs5963409) and -241 A/G (rs5963411) located in the promoter of the OTC gene are associated with the risk of developing AD. In the present work, these association studies were extended to a population of 2113 AD cases and 1580 controls from northern France, western France, the United Kingdom and Italy. The rs5963409 minor allele was weakly but significantly associated with an increased risk of developing AD (OR=1.19, p=0.004). This association was independent of age and ApoE status. Our results support that the OTC gene may be a minor genetic determinant of AD.
[Show abstract][Hide abstract] ABSTRACT: Caregiver burden is a key measure in caregiver research and is frequently used as a baseline measure in intervention studies. Previous research has found numerous factors associated with caregiver burden such as the relationship quality between carer and patient, the patient's cognitive ability, behavioural and psychological symptoms displayed by the patient, caregiver gender, adverse life events to name a few. Many studies have investigated these factors singularly however current thought suggests a multi-factorial role and inter-dependence of these factors. Based on this it was decided to investigate factors associated with caregiver burden using a multiple regression analysis in order to ascertain the predictive quality of these factors of caregiver burden.
Cross-sectional study using validated measures of a patient's cognitive ability, ability to carry out day-to-day tasks and behavioural and psychological symptoms. Caregiver outcomes used are caregiver burden, relationship quality, caregiver confidence, experience of adverse life events, neuroticism, age and gender. Interviews and questionnaires were carried out on 74 patients diagnosed with dementia and their main caregivers from the Midlands of England.
Multiple regression analysis showed that caregiver overload, carer-patient relationship quality, the experience of adverse life events, caregiver gender, caregivers' level of neuroticism, caregiver role captivity and the level of caregiver confidence accounted for over 80% of the variance in caregiver burden.
These results confirm previous correlational research on caregiver burden. Furthermore, due to the use of multiple regression analysis the findings also show factors that are clear predictors of caregiver burden and we offer possible suggestions from these findings on future clinical practice interventions on caregiver burden.
International Journal of Geriatric Psychiatry 10/2008; 23(10):1078-85. DOI:10.1002/gps.2071 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is biochemical and animal model evidence supporting a pathological role of the ACT gene in AD. However, direct genetic evidence remains controversial and has been mostly limited to individual single nucleotide polymorphism (SNP) analysis. To resolve this apparent conflict we have used a high-density ACT SNP map, constructed haplotypes and explored correlations with phenotype. SNPs were identified by sequencing and used to construct haplotypes in 668 AD patients and 419 controls and a case-control association study was performed. Five SNPs, comprising five common haplotypes, represented 93% of ACT gene variation. Although no single SNP or haplotype was associated with AD status, a SNP in intron 2 was associated with later onset and more rapid cognitive decline (P=0.04). This SNP was both individually associated with severe astrocytosis (P=0.004) in AD patients and when combined with the signal sequence SNP (P=0.002). This suggests that astrocytosis may have a protective function for a limited period in some patients. These SNP associations either support a direct role for the ACT gene, in AD pathology or alternatively reflect linkage with polymorphisms in other genes nearby.
Neurobiology of aging 09/2008; 29(8):1167-76. DOI:10.1016/j.neurobiolaging.2007.02.021 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common neurodegenerative disorders in the elderly, have been hypothesized to share genetic determinants. Recently, Li et al. proposed that a variant in the NEDD9 gene may be one of these common genetic factors. We attempted to confirm this initial observation by conducting an equivalent analysis in terms of pathologies and sample size. We genotyped the NEDD9 rs760678 SNP in three independent AD case-control studies (n = 3176) and two independent PD case-control studies (n = 1855). However, we failed to detect an association of this SNP with the risk of developing AD or PD, in any of these populations. In conclusion, these data indicate that the rs760678 SNP of the NEDD9 gene is at best a weak genetic determinant of AD or PD. Yes Yes
Human Molecular Genetics 06/2008; 17(18). DOI:10.1093/hmg/ddn183 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The first genome-wide association in Alzheimer's disease (AD) suggested that the GAB2 gene rs2373115 polymorphism may be a strong risk factor in APOE varepsilon4-carriers. We failed to detect an association of rs2373115 with the risk of developing AD in three populations (totalling 1406 controls and 1749 AD cases) whatever the APOE status, even if we observed a slight tendency for an increase of the GG genotype (OR (GG versus GT+TT)=1.3, 95% CI 1.0-1.6, p=0.09) and the G allele frequency (OR=1.3, 95%CI 1.0-1.6, p=0.05) in varepsilon4-carriers. In addition, the rs2373115 did not modulate the extent of tau phosphorylation in the brain of 89 AD cases. The GAB2 gene is at best a minor genetic determinant of AD.
Neurobiology of Disease 05/2008; 30(1):103-6. DOI:10.1016/j.nbd.2007.12.006 · 5.08 Impact Factor