Genetic studies on chromosome 12p11-12 in late onset Alzheimer's disease

CONTEXT: The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report has suggested a second locus on chromosome 12p11-12. OBJECTIVE: To look for evidence of linkage on chromosome 12 and to test for the presence of the new locus in an independent sample of familial late-onset AD cases. DESIGN: Retrospective cohort study. As part of a 20-centimorgan genome screen (approximately equal to 200 markers), we tested a series of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. SETTING: Clinic populations in the continental United States selected from the National Institute of Mental Health AD Genetics Consortium. PATIENTS: We selected samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable or definite AD with onset ages older than 60 years (mean+/-SD, 75+/-6 years). Within the families, we used the 2 probable or definitely affected individuals. In families with more than 2 such cases available, we used all of them; in families with only 2 such cases in which unaffected individuals were available, we also sampled the oldest unaffected individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. MAIN OUTCOME MEASURE: Presence of linkage or locus on chromosome 12. RESULTS: Although linkage analyses confirmed the presence of a genetic susceptibility factor at the APOE locus in these families with late-onset AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the alpha2-macroglobulin locus in the affected pairs in which both members did not possess an APOE epsilon4 allele. CONCLUSIONS: APOE remains the only locus established to be a risk factor for late-onset AD. We were unable to confirm that a locus on chromosome 12p11-12 has a major effect on risk for late-onset AD, although an effect smaller than that for APOE cannot be excluded

The Tourist Area Life Cycle (TALC) and Its Effect on the Quality-of-Life (QOL) of Destination Community

This chapter examines the connection between tourism area life cycle (TALC) and its effects on the quality-of-life (QOL) of destination communities. We posit that as destinations go through structural changes over time, the extent to which the dynamics of change affect the QOL of the resident community varies with the stages of the life cycle. The chapter consists of four major sections. After a brief introduction, the first section presents the concept of TALC and describes the development phases and the indicators that help understand tourism area development. The second section provides a brief discussion on the impact of tourism on the community in relation to TALC, which is then followed by the third section which focuses on the adjustment to change and maintaining the QOL of the community. Section four reviews related literature to support the relation between TALC and QOL of communities. The chapter ends with delineating critical issues for future research, outlining some of the difficulties moving forward, and formulating relevant policy implications that may help the researchers and destination management organizations to further examine the issues that may surround TALC and QOL connections

γ-Secretase-Regulated Mechanisms Similar to Notch Signaling May Play a Role in Signaling Events, Including APP Signaling, Which Leads to Alzheimer’s Disease

Although gamma-secretase was first identified as a protease that cleaves amyloid precursor protein (APP) within the transmembrane domain, thus producing A beta peptides that are thought to be pathogenic in Alzheimer\u27s disease (AD), its physiological functions have not been fully elucidated. In the canonical Notch signaling pathway, intramembrane cleavage by gamma-secretase serves to release an intracellular domain of Notch that shows activity in the nucleus through binding to transcription factors. Many type 1 transmembrane proteins, including Notch, Delta, and APP, have recently been shown to be substrates for gamma-secretase, and their intracellular domains are released from the cell membrane following cleavage by gamma-secretase. The common enzyme gamma-secretase modulates proteolysis and the turnover of possible signaling molecules, which has led to the attractive hypothesis that mechanisms similar to Notch signaling contribute widely to proteolysis-regulated signaling pathways. APP is also likely to have a signaling mechanism, although the physiological functions of APP have not been elucidated. Indeed, we have shown that the intracellular domain of APP alters gene expression and induces neuron-specific apoptosis. These results suggest that APP signaling responds to the onset of AD. Here, we review the possibility of gamma-secretase-regulated signaling, including APP signaling, which leads to AD