Gene-gene functional relationships in Alzheimer's disease: CELF1 regulates KLC1 alternative splicing.

The causes of Alzheimer's disease (AD) are poorly understood, although many genes are known to be involved in this pathology. To gain insights into the underlying molecular mechanisms, it is essential to identify the relationships between individual AD genes. Previous work has shown that the splice variant E of KLC1 (KLC1_vE) promotes AD, and that the CELF1 gene, which encodes an RNA-binding protein involved in splicing regulation, is at a risk locus for AD. Here, we identified a functional link between CELF1 and KLC1 in AD pathogenesis. Transcriptomic data from human samples from different ethnic groups revealed that CELF1 mRNA levels are low in AD brains, and the splicing pattern of KLC1 is strongly correlated with CELF1 expression levels. Specifically, KLC1_vE is negatively correlated with CELF1. Depletion and overexpression experiments in cultured cells demonstrated that the CELF1 protein down-regulates KLC1_vE. In a cross-linking and immunoprecipitation sequencing (CLIP-seq) database, CELF1 directly binds to KLC1 RNA, following which it likely modulates terminal exon usage, hence KLC1_vE formation. These findings reveal a new pathogenic pathway where a risk allele of CELF1 is associated with reduced CELF1 expression, which up-regulates KLC1_vE to promote AD.

Characteristics of very late-onset schizophrenia-like psychosis classified with the biomarkers for Alzheimer's disease: a retrospective cross-sectional study.

OBJECTIVES: We aimed to investigate the association between very late-onset schizophrenia-like psychosis (VLOSLP), a schizophrenia spectrum disorder with an onset of ≥60 years, and Alzheimer's disease (AD) using biomarkers. DESIGN: Retrospective cross-sectional study. SETTING: Neuropsychology clinic of Osaka University Hospital in Japan. PARTICIPANTS: Thirty-three participants were classified into three groups: eight AD biomarker-negative VLOSLP (VLOSLP-AD), nine AD biomarker-positive VLOSLP (VLOSLP+AD), and sixteen amnestic mild cognitive impairment due to AD without psychosis (aMCI-P+AD) participants. MEASUREMENTS: Phosphorylated tau levels in the cerebrospinal fluid and 18F-Florbetapir positron emission tomography results were used as AD biomarkers. Several scales (e.g. the Mini-Mental State Examination (MMSE), Wechsler Memory Scale-Revised (WMS-R) Logical Memory (LM) I and II, and Neuropsychiatric Inventory (NPI)-plus) were conducted to assess clinical characteristics. RESULTS: Those in both VLOSLP-AD and +AD groups scored higher than those in aMCI-P+AD in WMS-R LM I. On the other hand, VLOSLP+AD participants scored in between the other two groups in the WMS-R LM II, with only VLOSLP-AD participants scoring significantly higher than aMCI-P+AD participants. There were no significant differences in sex distribution and MMSE scores among the three groups or in the subtype of psychotic symptoms between VLOSLP-AD and +AD participants. Four VLOSLP-AD and five VLOSLP+AD participants harbored partition delusions. Delusion of theft was shown in two VLOSLP-AD patients and five VLOSLP+AD patients. CONCLUSION: Some VLOSLP patients had AD pathology. Clinical characteristics were different between AD biomarker-positive and AD biomarker-negative VLOSLP, which may be helpful for detecting AD pathology in VLOSLP patients.

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-ß accumulation in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-ß (Aß) in human brain is still not well understood. To identify novel genes that cause accumulation of Aß in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aß level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aß accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.

Atlas stumbled: kinesin light chain-1 variant E triggers a vicious cycle of axonal transport disruption and amyloid-ß generation in Alzheimer's disease.

Substantial evidence implicates fast axonal transport (FAT) defects in neurodegeneration. In Alzheimer's disease (AD), it is controversial whether transport defects cause or arise from amyloid-ß (Aß)-induced toxicity. Using a novel, unbiased genetic screen, Morihara et al. identified kinesin light chain-1 splice variant E (KLC1vE) as a modifier of Aß accumulation. Here, we propose three mechanisms to explain this causal role. First, KLC1vE reduces APP transport, leading to Aß accumulation. Second, reduced transport of APP by KLC1vE triggers an ER stress response that activates the amyloidogenic pathway. Third, KLC1vE impairs transport of other KLC1 cargos that regulate amyloidogenesis, promoting Aß retention within the secretory pathway. Collectively, KLC1vE perpetuates a vicious cycle of Aß generation, kinase dysregulation, and global FAT impairment that inevitably leads to cellular toxicity. These concepts implicate alternative splicing of KLC1 in AD and suggest that the reciprocal influence of transport mechanisms on disease states contributes to neurodegeneration.

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-ß accumulation modifier.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of Aß accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aß accumulation. To avoid detecting secondarily affected genes by Aß, we used non-Tg mice in the absence of Aß pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an Aß modifier, indicating a role for intracellular trafficking in Aß accumulation. Aß levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of Aß, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aß pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.

Sleep Disturbance Caused by Step Changes in Railway Noise Exposure and Earthquakes.

Kyushu Shinkansen and conventional railway lines run parallel in the areas 5 km north of Kumamoto Station (northern area) and 12 km south of the station (southern area). Following the operation of the Kyushu Shinkansen Line in 2011, the adjacent conventional railway line in the north was elevated, a new station was operated in the south, and large earthquakes struck the Kumamoto area from March to April 2016. Sleep disturbances were compared before and after the interventions and earthquakes based on noise source (Shinkansen and conventional railways), area (northern and southern), and house type (detached and apartment) through socio-acoustic surveys from 2011 to 2017. The Shinkansen railway caused significantly less sleep disturbances in detached houses in the north after compared to before the earthquakes, presumably due to more frequent closures of bedroom windows in northern detached houses following the earthquakes. The Shinkansen railway caused significantly more sleep disturbances in apartments in the south after compared to before the earthquakes, presumably because the Shinkansen slowed down immediately after the earthquakes and returned to normal speed during the survey, suddenly increasing the noise exposure. There was no significant difference in the other six cases investigated. Overall, the interventions may not have caused significant differences in sleep disturbances. This article expands on the congress paper by Morihara et al. presented in the "Community Response to Noise" session at the 52nd International Congress and Exhibition on Noise Control Engineering in Makuhari, Japan, organized by the International Institute of Noise Control Engineering.

Ribavirin Treatment for Severe Schizophrenia with Anti-Borna Disease Virus 1 Antibodies 30 Years after Onset.

Objective: Borna disease virus 1 (BoDV-1) was proven to cause fatal encephalitis in humans in 2018. However, the effects of persistent infections remain unclear. Here, we present the case of a 50-year-old woman with a 30-year history of severe schizophrenia, who was exposed to fleas from stray cats prior to disease onset, suggesting the possibility of zoonosis including BoDV-1 infection. The patient had experienced significant social impairment, thought deterioration, delusions, and hallucinations for more than 20 years. Method: A radioligand assay was used to test the patient for IgG and IgM antibodies against BoDV-1 nucleoprotein (N) and phosphoprotein (P). Based on the protocol for hepatitis C, we treated the patient with 400 mg/day ribavirin, which was later increased to 600 mg/day. Results: The serological examination revealed anti-BoDV-1 N IgG. Although only subtle changes were observed over the 24 weeks of treatment, the family noticed that the patient's Cotard delusions had disappeared 7 months after completing the treatment, accompanied by some improvements in the relationship with the family. Conclusion: Though definite proof was not obtained, this presumed suppression of BoDV-1 by ribavirin leading to improvements in Cotard syndrome-like symptoms suggests that intractable schizophrenia might be one of the BoDV-1 infection phenotypes. Further studies are needed to clarify the effect of persistent BoDV-1 infections in humans.

Models of Aviation Noise Impact in the Context of Operation Decrease at Tan Son Nhat Airport.

Air traffic bans in response to the spread of the coronavirus have changed the sound situation of urban areas around airports. This study aimed to investigate the effect of this unprecedented event on the community response to noise before and after the international flight operation at Tan Son Nhat Airport (TSN) in March 2020. The "before" survey was conducted in August 2019, and the two "after" surveys were conducted in June and September 2020. Structural equation models (SEMs) for noise annoyance and insomnia were developed by linking the questionnaire items of the social surveys. The first effort aimed to achieve a common model of noise annoyance and insomnia, corresponding to the situation before and after the change, respectively. Approximately, 1200 responses were obtained from surveys conducted in 12 residential areas around TSN in 2019 and 2020. The average daily flight numbers observed in August 2019 during the two surveys conducted in 2020 were 728, 413, and 299, respectively. The sound pressure levels of the 12 sites around TSN decreased from 45-81 dB (mean = 64, SD = 9.8) in 2019 to 41-76 dB (mean = 60, SD = 9.8) and 41-73 dB (mean = 59, SD = 9.3) in June and September 2020, respectively. The SEM indicated that the residents' health was related to increased annoyance and insomnia.

Functional genetic variation at the NRGN gene and schizophrenia: evidence from a gene-based case-control study and gene expression analysis.

Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia.

Protein synthesis in the posterior cingulate cortex in Alzheimer's disease.

BACKGROUND: Neuroimaging studies using (18) F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and single photon emission computed tomography (SPECT) have shown that the posterior cingulate cortex (PCC) is the primary and most prominent area of cerebral metabolic and perfusional decrement in early Alzheimer's disease (AD). We carried out the present preliminary study to investigate whether a decline of cerebral blood flow (CBF) in the PCC in early to moderate AD was accompanied with that of cerebral protein synthesis (CPS). METHODS: We carried out both N-isopropyl-p-[123I] iodoamphetamine SPECT (IMP-SPECT) and L-[methyl-11C] methionine positron emission tomography (MET-PET) in eight AD patients with apolipoprotein E epsilon 4 allele in the early to moderate stage. We also carried out IMP-SPECT in eight healthy controls (HC). We located 32 regions of interest (ROI), and values of regional MET or IMP uptakes were averaged in five regions; the frontal lobe (FL), the parietal lobe (PL), the medial temporal lobe (MTL), PCC and the occipital lobe. Furthermore, the values in the FL, PL, MTL and PCC were divided by values in the occipital areas, and normalized values of regional CBF (rCBF) and CPS (rCPS) were calculated. Then, the rCBF in the FL, PL, MTL and PCC were compared between AD and HC. In addition, the rCBF and rCPS were compared in the FL, PL, MTL and PCC of AD. RESULTS: The rCBF in the PCC, but not in the other three regions, was significantly lower in AD than in HC. The rCBF was significantly lower than rCPS in the PCC, but rCBF and rCPS were comparable in the other three regions in AD. CONCLUSIONS: The CBF reduction in the PCC in AD was partly caused by neuronal loss in the PCC and partly supported the hypothesis that CBF reduction in the PCC was a result of functional deafferentation by neural degeneration in areas other than the PCC.

Protein kinase C stabilizes X-linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser(87) to suppress apoptotic cell death.

BACKGROUND: Multiple protein kinases have been shown to be involved in the apoptotic neuronal loss of Alzheimer's disease (AD). Although some studies support the role of protein kinase C (PKC) in amyloid precursor protein processing as well as in tau phosphorylation, a direct role for PKC in apoptotic neuronal death remains to be clarified. In the present study, we report on the possible role of PKC in cell survival during conditions of stress through phosphorylation of the X-linked inhibitor of apoptosis protein (XIAP). METHODS: Phosphorylation of XIAP at Ser87 was confirmed by western blot analysis employing phosphorylation dependent anti-XIAP antibody after incubation of recombinant XIAP with active PKC in vitro. And increased phosphorylation of XIAP at the site was also confirmed in SH-SY5Y cells treated with PKC activator, phorbol 12-myristate 13-acetate (PMA). A mutant XIAP construct in which Ser87 was substituted by Ala, was prepared, and transfected to cells. After the transfection of wild or mutant XIAP, cells viability was evaluated by counting living and dead cells treated with PMA during etoposide-induced apoptosis. RESULTS: Recombinant XIAP was phosphorylated at Ser(87) by PKC in vitro and treatment of XIAP-transfected SH-SY5Y cells with a PKC activator, phorbol 12-myristate 13-acetate (PMA) induced phosphorylation of XIAP at Ser(87) . Pulse chase experiments revealed that, when phosphorylated at Ser(87) , wild-type XIAP is more stable than XIAP with a Ser87Ala substitution, which is degraded faster. Importantly, the phosphorylation of XIAP at the site by PKC significantly increased cell survival up to approximately 2.5 times under the condition of apoptosis induced by 25 µg/ml etoposide. CONCLUSION: The findings of the present study indicate a role for PKC, through phosphorylation of XIAP at Ser(87) and its stabilization, in cell survival under conditions of stress and lend strength to the idea that PKC is crucial in regulating neuronal homeostasis, which may be impaired in AD.

Effects of Noise and Vibration Due to the Hokuriku Shinkansen Railway on the Living Environment: A Socio-Acoustic Survey One Year after the Opening.

One year after the opening of the Hokuriku Shinkansen (high-speed) railway, in 2016, we conducted a social survey targeting the residents of detached houses along the rail. Noise and vibration exposure levels were estimated at outdoor points closest to the noise source side of the houses. Of the 1980 people contacted, there were 1022 valid respondents. The purpose of this research was to investigate the relationship between noise and vibration exposure and community responses. The results demonstrated that the noise annoyance and daily activity disturbances of residents living in areas without a conventional railway are higher than those of residents living in areas running parallel to a conventional railway line. This tendency was remarkable, especially for areas with high vibration exposure caused by the Shinkansen railway. There was no difference between before and after the opening of the Shinkansen railway in the evaluation of housing satisfaction, or regarding the preference for the residential area and quietness around the house. However, since the survey before the opening was conducted only in the Ishikawa site, it will be necessary to conduct before-and-after surveys in areas where there are no conventional railways, and where the speed of the Shinkansen is fast.

Representative Exposure-Annoyance Relationships Due to Transportation Noises in Japan.

This paper focuses on clarifying the relationship between noise exposure and the prevalence of highly annoyed people due to transportation noise in Japan. The authors accumulated 34 datasets, which were provided by Socio-Acoustic Survey Data Archive and derived from the other surveys conducted in Japan. All the datasets include the following micro-data: demographic factors, exposure, and annoyance data associated with specific noise sources. We performed secondary analyses using micro-data and established the relationships between noise exposure (Lden) and the percentage of highly annoyed people (%HA) for the following noise source: road traffic, conventional railway, Shinkansen railway, civil aircraft, and military aircraft noises. Among the five transportation noises, %HA for the military aircraft noise is the highest, followed by civil aircraft noise and Shinkansen railway noise. The %HA for conventional railway noise was higher than that for road traffic noise. To validate the representativeness of the exposure-response curves, we have discussed factors affecting the difference in annoyance. In addition, comparing the Japanese relationship with that shown in the "Environmental Noise Guidelines for the European Region," we revealed that Japanese annoyance is higher than the WHO-reported annoyance.

The Effect of an Alternative Definition of "Percent Highly Annoyed" on the Exposure-Response Relationship: Comparison of Noise Annoyance Responses Measured by ICBEN 5-Point Verbal and 11-Point Numerical Scales.

Since the development of the 5-point verbal and 11-point numerical scales for measuring noise annoyance by the ICBEN Team 6, these scales have been widely used in socio-acoustic surveys worldwide, and annoyance responses have been easily compared internationally. However, both the top two categories of the 5-point verbal scale and the top three ones of the 11-point numerical scale are correspond to high annoyance, so it is difficult to precisely compare annoyance responses. Therefore, we calculated differences in day-evening-night-weighted sound pressure levels (Lden) by comparing values corresponding to 10% highly annoyed (HA) on Lden_%HA curves obtained from measurements in 40 datasets regarding surveys conducted in Japan and Vietnam. The results showed that the Lden value corresponding to 10% HA using the 5-point verbal scale was approximately 5 dB lower than that of the 11-point numerical scale. Thus, some correction is required to compare annoyance responses measured by the 5-point verbal and the 11-point numerical scales. The results of this study were also compared with those of a survey in Switzerland.

How Does a Community Respond to Changes in Aircraft Noise? A Comparison of Two Surveys Conducted 11 Years Apart in Ho Chi Minh City.

There have been many arguments about findings of an increase in noise annoyance over time and a recommendation of stricter limits on aircraft noise levels to protect the health of residents around airports. It is crucial to examine if the established exposure-response relationship is suitable for designing future aircraft noise regulations. This study was focused on identifying changes in response to noise over time by comparing community responses from two surveys conducted in 2008 and 2019 at Tân SÆ¡n Nhat (TSN) international airport. Annoyance was found to significantly reduce in 2019 compared to 2008; however, changes in sleep quality were relatively small. Unexpectedly, a gradual increase in the annoyance due to aircraft noise was not found. Results of multiple regression analysis indicated that differences in the reaction of the residents to noise in the two studies were significantly attributed to nonacoustic factors. Noise sensitivity and dissatisfaction with the living environment (e.g., inconvenience in accessing workplace) considerably affect noise annoyance, whereas noise sensitivity, age, and dissatisfaction with the green environment of living areas affect sleep quality. These findings suggest the fulfillment of desired living environment as effective measures for mitigating noise impacts on residents in the vicinity of busy airports.

Case Report: Usefulness of Biomarkers for Alzheimer's Disease in Two Cases With Very-Late-Onset Schizophrenia-Like Psychosis.

The association between primary psychotic disorders emerging in later life and neurodegenerative diseases, including Alzheimer's disease (AD), is controversial. We present two female non-demented cases of psychosis with onset above the age of 60 years. Cases 1 and 2 were aged was 68 and 81 years, respectively. They suffered from persecutory delusions and scored 28 on the Mini-Mental State Examination (MMSE) at the first examination. Although detailed neuropsychological tests detected amnesia, they had preserved daily life function. Brain magnetic resonance imaging, N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) single-photon emission computed tomography, and cardiac [123I]-metaiodobenzylguanidine (123I-MIBG) scintigraphy showed no specific abnormalities in either case. We diagnosed them with very-late-onset schizophrenia-like psychosis (VLOSLP) because there was no evidence that their psychoses were derived from organic diseases or affective disorders. Upon close inspection, the AD biomarkers, cerebrospinal fluid (CSF) testing and Florbetapir F 18 positron emission tomography (PET), were positive in Case 1 and negative in Case 2. Case 1 scored 25 1 year later and 23 2 years later on the MMSE and was finally diagnosed as AD dementia. These two cases suggest that some clinically diagnosed VLOSLPs may be a prodromal AD. Although VLOSLP is a disease entity supposed to be a primary psychotic disorder, some are probably secondary psychosis with insidious neurodegeneration. Advanced biomarkers such as amyloid PET and CSF may contribute to the detection of secondary psychosis from clinically diagnosed VLOSLP.

KIBRA genetic polymorphism influences episodic memory in Alzheimer's disease, but does not show association with disease in a Japanese cohort.

BACKGROUND/AIMS: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer's disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort. METHODS: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT). RESULTS: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort. CONCLUSION: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve.

Apolipoprotein E and central nervous system disorders: reviews of clinical findings.

Dementia is a major health problem in developed countries with over 25 million people affected worldwide and probably over 75 million people at risk during the next 20 years. Alzheimer's disease (AD) is the most frequent cause of dementia (50-70%), followed by vascular dementia (30-40%), and mixed dementia (15-20%). AD pathogenesis is still to be elucidated but it is believed to be the complex interaction between genetic and environmental factors in later life. Three causative genes for familial AD have been identified: amyloid precursor protein, presenilin-1, and presenilin-2. There are 150 genes involved with increased neuronal vulnerability to premature death in the AD brain. Among these susceptibility genes, the apolipoprotein E (ApoE) gene is the most prevalent as a risk for AD pathogenic process in which complex interactions between genetic and environmental factors are involved, leading to a cascade of pathogenic events converging in final pathways to premature neuronal death. Some of these mechanisms are common to several neurodegenerative disorders that differ depending upon the genes affected and the involvement of environmental conditions. ApoE is a key lipoprotein in lipid and cholesterol metabolism and it is also the major risk gene for AD and many other central nervous system disorders. The pathogenic role of ApoE-4 is still to be clarified; however, diverse evidence suggests that ApoE may play pleiotropic functions in dementia and central nervous system disorders.

Laughter and humor as complementary and alternative medicines for dementia patients.

BACKGROUND: The number of dementia patients has increased worldwide, with an estimated 13.7 million dementia patients in the Asia Pacific region alone. This number is expected to increase to 64.6 million by the year 2050. DISCUSSION: As a result of advances in research, there several pharmacological therapies available for the treatment of dementia patients. However, current treatments do not suppress the disease process and cannot prevent dementia, and it will be some time before these goals are realized. In the meantime, complementary and alternative medicine (CAM) is an important aspect in the treatment of dementia patients to improve their quality of life throughout the long course of the disease. Considering the individuality of dementia patients, applicability of laughter and humor therapy is discussed. Even though there are many things that need to be elucidated regarding the mechanisms underlying the beneficial effects of laughter and humor, both may be good CAM for dementia patients if they are applied carefully and properly. SUMMARY: In this debate article, the physiological basis and actual application of laughter and humor in the treatment of dementia patients are presented for discussion on the applicability to dementia patients.