Corinne Lendon

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimers disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.

A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk

Alzheimers 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.

Cognitive Phenotypes in Alzheimer's Disease and Genetic Risk

Variation in the clinical characteristics of patients with Alzheimers 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. Clinical distinctions were maintained over time. Two-thirds of patients showed a constellation of deficits at presentation which included memory, language, visuospatial and constructional difficulties. However, a quarter had circumscribed presentations of amnesia, aphasia, perceptuospatial disorder or apraxia. The rare presence of frontal lobe characteristics was associated with a younger age of onset, an increased incidence of myoclonus at presentation, a positive family history but not with possession of APOE epsilon4 allele. An amnestic presentation (severe, yet circumscribed amnesia) was strongly associated with an older age of onset, a positive family history and the presence of APOE epsilon4 allele. Posterior cortical presentations showed a female bias, were typically sporadic, and showed no association with APOE epsilon4. The findings support the notion of phenotypic variation in AD, and show that genetic risk factors can influence clinical presentation. The findings draw attention to the specific association between APOE epsilon4 allele and memory but challenge the commonly held notion that the presence of the epsilon4 allele inevitably reduces onset age. The findings indicate that risk factors other than APOE epsilon4 allele underlie the non-familial, early onset posterior hemisphere presentations of AD.

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22

Objective The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. Background Several dementing disorders have clinical and pathologic similarities with AD, Picks disease, and the “nonspecific” dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. Methods The authors performed a clinical assessment gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. Results HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Picks disease. Salient clinical features are global dementia with disproportionate dysphasia and “frontotemporal” symptoms. A linkage between HDDD and 17q 21–22 was shown, with a maximum lod score of 3.68 at zero recombination. Conclusions Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Determinants of burden in those who care for someone with dementia

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 patients 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.

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimers disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

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 Alzheimers disease (AD) is the ɛ4 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 ɛ4 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 ɛ4 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 Aβ40 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.

Variation at the serotonin transporter gene influences susceptibility to bipolar affective puerperal psychosis

Up to half of parous females with bipolar disorder (manic depression) develop an episode of severe psychiatric disturbance, usually called puerperal psychosis, within a few days of giving birth. We report significant evidence (p<0.003) that variation at the serotonin transporter gene exerts a substantial (odds ratio=4) and important (population attributable fraction=69%) influence on susceptibility to such episodes.

E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin‐1 (PS‐1) gene on chromosome 14 in affected individuals in each of seven Colombian early‐onset Alzheimers disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two‐point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS‐1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997.

Are the estrogen receptors involved in Alzheimer's disease?

Retrospective analysis shows that women who took estrogen replacement therapy may have less risk of cognitive decline and of developing Alzheimers disease (AD). The greater risk associated with female gender and these observations suggest that estrogen may be implicated in the aetiology of AD. Estrogen is one of a family of sex steroids that exerts many of its genomic effects through the activation of the nuclear estrogen receptors, ERalpha and ERbeta. Previously, increased risk for AD has been reported for polymorphisms in the ERalpha gene in a Japanese cohort, however, this association has not been systematically replicated. We have further investigated polymorphisms in the ERalpha and have extended this to investigate an association with a polymorphism within the ERbeta gene in an independent UK Caucasian population. We found no independent association of these polymorphisms with the risk of developing AD in the total sample nor within either gender. However, we did detect a significant interaction between the ERalpha and ERbeta polymorphisms and the risk for AD (OR=0.22 95% CI (0.05-0.88), P=0.02). If this finding can be supported in other independent studies, it may suggest that the risk for AD may be modulated only when both ERalpha and ERbeta have particular variations in their expression and/or biological activities.