Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells.

Mutations in the presenilin 1 (PS1) gene lead to early-onset Alzheimer's disease with the S170F mutation causing the earliest reported age of onset. Expression of this, and other PS1 mutations, in SH-SY5Y cells resulted in significant loss of cellular viability compared to control cells. Basal Ca2+ concentrations in PS1 mutants were never lower than controls and prolonged incubation in Ca2+ -free solutions did not deplete Ca2+ stores, demonstrating there was no difference in Ca2+ leak from endoplasmic reticulum (ER) stores in PS1 mutants.

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

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).

No association between neuregulin 1 and psychotic symptoms in Alzheimer's disease patients.

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.

A study of the association between the ADAM12 and SH3PXD2A (SH3MD1) genes and Alzheimer's disease.

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 common biological mechanism in cancer and Alzheimer's disease?

Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition.

Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.

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).

Determinants of burden in those who care for someone with dementia.

Objectives: 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.

A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.

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.

Association study of the NEDD9 gene with the risk of developing Alzheimer's and Parkinson's disease.

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.

Association study of the GAB2 gene with the risk of developing Alzheimer's disease.

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.

Cognitive phenotypes in Alzheimer's disease and genetic risk.

Variation in the clinical characteristics of patients with Alzheimer's disease (AD) is increasingly recognised, although the factors underlying variation are not fully understood. The study examined the cognitive characteristics of 523 AD patients at the time of their presentation to a neurological dementia clinic and explored the relationship to family history and apolipoprotein E (APOE) genotype. Distinct profiles were identified, which were mirrored by topographical differences on neuroimaging.

Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients.

Background/aims: Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD.

Evidence for the association of the S100beta gene with low cognitive performance and dementia in the elderly.

Variations in the S100beta gene may be instrumental in producing a continuum from mild cognitive decline to overt dementia. After screening 25 single nucleotide polymorphisms (SNPs) in S100beta, we observed association of the rs2300403 intron 2 SNP with poorer cognitive function in three independent populations. Moreover, we detected a significant association of this SNP with increased risk of developing dementia or Alzheimer's disease (AD) in six independent populations, especially in women and in the oldest.

A SNP in the ACT gene associated with astrocytosis and rapid cognitive decline in AD.

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.

Platelet glycoprotein polymorphisms: risk, in vivo expression and severity of atherothrombotic stroke in Chinese.

Background: Polymorphisms in platelet glycoprotein (GP) receptors Ia, Ib and IIIa may be heritable risk factors for platelet-dependent thrombosis leading to death. The precipitation of stroke by occlusive thrombi has led to the investigation of the platelet surface GP receptors, that are involved in critical steps in the activation of platelets. Three polymorphisms in the GP Iba gene and one in each of GPIIIa, GP Ia were selected based on the evidence of functional effects on structure or expression as candidates for risk.

Role of 5HT 2A and 5HT 2C polymorphisms in behavioural and psychological symptoms of Alzheimer's disease.

Objective: Alzheimer's disease (AD) patients suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. Polymorphisms within serotonin receptors 5HT(2A) and 5HT(2C) have been previously investigated in a few interesting studies reviewed here, however, their role remains unclear.

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease.

Background: Patients with Alzheimer's disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer's disease has been demonstrated. Several studies have investigated whether the exon 4 epsilon2/epsilon3/epsilon4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype.

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD.