Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study.

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

The cost of Alzheimer's disease in China and re-estimation of costs worldwide.

INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-to-moderate Alzheimer's disease: a Phase II multicenter randomised controlled trial.

Background: inhibition of acetylcholinesterase (AChE) has been a effective treatment for Alzheimer's disease (AD). Octohydroaminoacridine, a new AChE inhibitor, is a potential treatment for AD. Method: we conducted a multicenter, randomised, double blind, placebo-controlled, parallel-group Phase II clinical trial to investigate the effects of octohydroaminoacridine in patients with mild-to-moderate AD. Patients were randomised to receive placebo thrice daily, octohydroaminoacridine 1 mg/thrice daily (TID) (low-dose group), 2 mg/TID (middle-dose group) or 4 mg/TID (high-dose group). Doses in the middle-dose and high-dose group were titrated over 2-4 weeks. Changes from baseline to Week 16 were assessed with the AD Assessment Scale-Cognitive Subscale (ADAS-cog), Clinician's Interview-Based Impression of Change Plus (CIBIC+), activities of daily living (ADL) and the neuropsychiatric inventory (NPI). ADAS-cog was the primary end point of the study. A two-way analysis of covariance and least squares mean t-test were used. Results: at Week 16, the changes from baseline in ADAS-cog were 1.4, -2.1, -2.2 and -4.2 for placebo, low-, middle- and high-dose groups, respectively. Patients in the high-dose group had better performance in CIBIC+ and ADL scores at the end of the study. There was no significant difference in the change in NPI score among the groups. The effects of octohydroaminoacridine were dose dependent, and were effective within 16 weeks of treatment. No evidence was found for more adverse events that occurred in different drug groups than placebo group. Conclusions: octohydroaminoacridine significantly improved cognitive function and behaviour in patients with mild-to-moderate AD and this effect was dose dependent.

The prevalence of mild cognitive impairment and its etiological subtypes in elderly Chinese.

BACKGROUND: Epidemiologic studies on mild cognitive impairment (MCI) are limited in China. METHODS: Using a multistage cluster sampling design, a total of 10,276 community residents (6096 urban, 4180 rural) aged 65 years or older were evaluated and diagnosed with normal cognition, MCI, or dementia. MCI was further categorized by imaging into MCI caused by prodromal Alzheimer's disease (MCI-A), MCI resulting from cerebrovascular disease (MCI-CVD), MCI with vascular risk factors (MCI-VRF), and MCI caused by other diseases (MCI-O). RESULTS: The prevalences of overall MCI, MCI-A, MCI-CVD, MCI-VRF, and MCI-O were 20.8% (95% confidence interval [CI] = 20.0-21.6%), 6.1% (95% CI = 5.7-6.6%), 3.8% (95% CI = 3.4-4.2%), 4.9% (95% CI = 4.5-5.4%), and 5.9% (95% CI = 5.5-6.4%) respectively. The rural population had a higher prevalence of overall MCI (23.4% vs 16.8%, P < .001). CONCLUSIONS: The prevalence of MCI in elderly Chinese is higher in rural than in urban areas. Vascular-related MCI (MCI-CVD and MCI-VRF) was most common.

The prevalence of dementia in urban and rural areas of China.

OBJECTIVE: The Chinese population has been aging rapidly and the country's economy has experienced exponential growth during the past three decades. The goal of this study was to estimate the changes in the prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) among elderly Chinese individuals and to analyze differences between urban and rural areas. METHODS: For the years 2008 to 2009, we performed a population-based cross-sectional survey with a multistage cluster sampling design. Residents aged 65 years and older were drawn from 30 urban (n = 6096) and 45 rural (n = 4180) communities across China. Participants were assessed with a series of clinical examinations and neuropsychological measures. Dementia, AD, and VaD were diagnosed according to established criteria via standard diagnostic procedures. RESULTS: The prevalence of dementia, AD, and VaD among individuals aged 65 years and older were 5.14% (95% CI, 4.71-5.57), 3.21% (95% CI, 2.87-3.55), and 1.50% (95% CI, 1.26-1.74), respectively. The prevalence of dementia was significantly higher in rural areas than in urban ones (6.05% vs. 4.40%, P < .001). The same regional difference was also seen for AD (4.25% vs. 2.44%, P < .001) but not for VaD (1.28% vs. 1.61%, P = .166). The difference in AD was not evident when the sample was stratified by educational level. Moreover, the risk factors for AD and VaD differed for urban and rural populations. CONCLUSIONS: A notably higher prevalence of dementia and AD was found in rural areas than in urban ones, and education might be an important reason for the urban-rural differences.

GAB2 is not associated with late-onset Alzheimer's disease in Chinese Han.

It has recently been shown that GAB2 alleles modify the risk for late-onset Alzheimer disease (LOAD) in apolipoprotein E (ApoE)epsilon4 allele carriers in a genome-wide association study. Some studies subsequently in Caucasians population, though not all, have demonstrated that GAB2 polymorphisms might be associated with LOAD susceptibility. The aim of this study is to evaluate the reported polymorphisms (rs2373115 and rs1385600) and GAB2 haplotypes (rs2373115-rs1385600) for an interaction with the ApoEepsilon4 allele in a cohort of Chinese LOAD. We conducted a case-control study in 292 LOAD and 227 non-demented controls from the Chinese Han population. Our study does not find any association between the two tested SNPs and GAB2 haplotypes and LOAD or any synergetic interaction between the SNPs and ApoE either. However, since the sample size required to show this point is large, our finding needs to be confirmed by a large independent sample of Chinese population.

Comparative Study of Cognitive Function Between Treatment-Resistant Depressive Patients and First-Episode Depressive Patients.

OBJECTIVE: Despite reports of cognitive dysfunction during the acute phase of depression, there is a lack of studies in patients with treatment-resistant depression (TRD). The aim of this study was to investigate the cognitive function profile of TRD and compare cognitive dysfunction between subjects with TRD and first-episode depression. PATIENTS AND METHODS: The study included 31 patients with TRD and 53 with first-episode depression. Cognitive function was assessed by a series of neuropsychological tools such as the verbal fluency test, Modified Wisconsin Card Sorting Test (M-WCST), Tower of Hanoi test, Chinese-revision of the Wechsler Adult Intelligence Scale (WAIS-RC), and Trail Making Test A and B. RESULTS: There were no significant demographic differences between the TRD, first-episode depression, and normal control groups (gender, age, years of education). The full-scale, verbal, and performance intelligence quotients measured with the WAIS-RC were also not significantly different (p>0.05). The normal group scores were all significantly better than TRD and first-episode depression, and the TRD group performed significantly worse than subjects with first-episode depression on Trail Making Test B, two WCST subscales, and the profile score of the Tower of Hanoi test (all p<0.05). CONCLUSION: Patients with depression exhibited global impairments in cognitive function, and these were more common in TRD. Poor executive function may play an important role in TRD.

Evaluation of choline acetyltransferase gene polymorphism (2384 G/A) in Alzheimer's disease and mild cognitive impairment.

BACKGROUND/AIMS: It has been hypothesized that choline acetyltransferase (ChAT) activity might be associated with cognitive impairment in Alzheimer's disease (AD). A functional single nucleotide polymorphism (2384 G/A) of ChAT was proposed to be associated with AD risk and age of onset. The aim of this study was to evaluate this polymorphism in a cohort of Chinese AD patients and patients with mild cognitive impairment (MCI). METHODS: We conducted a case-control study in 273 cases of sporadic AD, 97 MCI patients and 271 nondemented controls from the Chinese Han population. RESULTS: In AD, ChAT 2384 A carriers had a significantly earlier age of onset and worse individual cognitive function in Fuld Object-Memory Evaluation; in MCI, the carriers of both 2384 A and ApoE epsilon4 had a significantly earlier age of onset. CONCLUSION: ChAT 2384 A allele is a risk factor for AD and MCI.

Prevalence of mild cognitive impairment and its subtypes in community-dwelling residents aged 65 years or older in Guangzhou, China.

BACKGROUND: Prevalence of mild cognitive impairment (MCI) has been reported substantial variations, and mostly in Western countries. Less is known about MCI in the south of China. The study is to estimate the prevalence of MCI and its subtypes in residents aged 65year or older in community-dwelling residents of Guangzhou, China. METHODS: The study was a community-based, cross-sectional study conducted in rural and urban areas of Guangzhou between April and October 2009. Eight communities were randomly selected using a cluster sampling method. Each elderly was interviewed with Montreal Cognitive Assessment, the Mini-Mental state examination, Auditory Verbal Learning Test, the Clinical Dementia Rating scale et al. MCI was classified as amnestic MCI (a-MCI) or nonamnestic MCI (na-MCI). RESULTS: 2427 individuals were contacted, but in-person interviews were conducted with 2111 participants. 299 participants with MCI were identified. The prevalence of MCI, a-MCI and na-MCI was 14.2%, 12.2%, 2.0% respectively. The prevalence of MCI and a-MCI increased with age, decreased with education level, and was higher in rural areas than in urban areas. The difference of prevalence of MCI and a-MCI between women with men wasn't statistically significant(MCIχ2=1.0, OR 0.9, 95%CI=0.6-1.2; a-MCIχ2=1.0, OR 0.9, 95%CI=0.6-1.2), when controlling for education by logistic regression analysis. CONCLUSIONS: The results suggest that 14.2% of elderly individuals are affected by MCI in Guangzhou, China. And MCI was dominated by a-MCI. The prevalence of MCI and a-MCI increased with age, decreased with education level, and was higher in the rural population compared to the urban population.

Genome-wide DNA methylation analysis in obsessive-compulsive disorder patients.

Literatures have suggested that not only genetic but also environmental factors, interactively accounted for susceptibility of obsessive-compulsive disorder (OCD). DNA methylation may regulate expression of genes as the heritable epigenetic modification. The examination for genome-wide DNA methylation was performed on blood samples from 65 patients with OCD, as well as 96 healthy control subjects. The DNA methylation was examined at over 485,000 CpG sites using the Illumina Infinium Human Methylation450 BeadChip. As a result, 8,417 probes corresponding to 2,190 unique genes were found to be differentially methylated between OCD and healthy control subjects. Of those genes, 4,013 loci were located in CpG islands and 2,478 were in promoter regions. These included BCYRN1, BCOR, FGF13, HLA-DRB1, ARX, etc., which have previously been reported to be associated with OCD. Pathway analyses indicated that regulation of actin cytoskeleton, cell adhesion molecules (CAMs), actin binding, transcription regulator activity, and other pathways might be further associated with risk of OCD. Unsupervised clustering analysis of the top 3,000 most variable probes revealed two distinct groups with significantly more people with OCD in cluster one compared with controls (67.74% of cases v.s. 27.13% of controls, Chi-square = 26.011, df = 1, P = 3.41E-07). These results strongly suggested that differential DNA methylation might play an important role in etiology of OCD.

The effectiveness and safety of amisulpride in Chinese patients with schizophrenia: An 8-week, prospective, open-label, multicenter, single-arm study.

INTRODUCTION: This study evaluated the effectiveness and safety of amisulpride in Chinese schizophrenia patients. METHODS: A multicenter, single-arm Phase IV study (NCT01795183). Chinese patients with schizophrenia received amisulpride for 8 weeks. The primary endpoint was ≥50% decrease in Positive and Negative Syndrome Scale total score from Baseline to Week 8. RESULTS: A total of 316 patients were enrolled; 295 were included in the effectiveness analysis; 66.8% (197/295) achieved ≥50% decrease in Positive and Negative Syndrome Scale total score from Baseline to Week 8. Nine patients discontinued treatment because of adverse events. DISCUSSION: Amisulpride had clinical effectiveness and was relatively well tolerated in Chinese patients with schizophrenia.

Characteristics of suicide attempters and nonattempters with schizophrenia in a rural community.

In this study, demographic and clinical characteristics of individuals with schizophrenia in a Chinese rural community who had attempted suicide at some time in their lives and those who had not made a suicide attempt were compared. Among individuals with schizophrenia, subjects with (n = 38) and without (n = 472) a lifetime history of suicide attempt were assessed with the Present State Examination. The results indicate that attempters had a significantly younger age, higher level of education, higher rate of lifetime depressed mood and hopelessness, and a larger number of positive symptoms than patients without suicide attempts. The logistic regression models also indicated that hopelessness, the number of positive symptoms and age were the most important predictors. Early interventions focusing on reducing hopelessness and controlling positive symptoms may help reduce the risk of suicide attempts among patients with schizophrenia.

[The C224T polymorphism in the cathepsin D gene is not associated with sporadic Alzheimer's disease in Chinese].

Cathepsin D is the major lysosomal/endosomal aspartic protease and exhibits beta- and gamma-secretase-like activity in vitro. Data from German suggest that the C224T polymorphism in the Cathepsin D gene (CTSD) exon 2 is strongly associated with the risk for Alzheimer's disease (AD). Meanwhile other studies have not been able to replicate the result. It's necessary to determine the genotype of the polymorphism in CTSD in Chinese sporadic AD patients and age-matched controls with normal cognition and examine possible association of the polymorphism with the disease. We find no strong evidence of association between the CTSD C224T polymorphism and Chinese sporadic AD. Whereas there may be a weak synergistic interaction between ApoE epsilon4 and CTSD T allele.

[Analysis on association between the polymorphisms in apolipoprotein E, interleukin-1 alpha genes and Alzheimer's disease in Chengdu area].

OBJECTIVE: To investigate the correlation between the polymorphisms of apolipoprotein E(APOE), the interleukin-1 alpha (IL-1 alpha ) genes and the susceptibility to Alzheimer's disease(AD). METHODS: Association study was performed in 114 AD patients and 113 healthy elderly individuals from Chengdu, China. Polymorphisms of APOE and IL-1 alpha genes were analyzed with polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of APOE-epsilon 4-carrying genotype in moderate to severe AD patients (28.6%) was higher than that of mild patients (18.5%) and the controls (14.2%), and the difference between moderate to severe AD group and the control group was significant (OR=2.4, 95%CI: 1.1-5.5). The frequency of epsilon 4 was also of significant difference between the group of moderate to severe dementia and the control group (OR=2.6, 95%CI: 1.3-5.3). However, no significant difference in distribution of IL-1 alpha polymorphism between AD patients and controls was observed. CONCLUSION: The APOE epsilon 4 allele was associated with moderate to severe AD while no association between the IL-1 alpha gene polymorphism and AD was found.

[A caregiver survey in Beijing, Xi'an, Shanghai and Chengdu: health services status for the elderly with dementia].

OBJECTIVE: In order to rationally allocate resources and to improve the quality of life of people with dementia, it is necessary to assess their current health services status. METHODS: A population-based door-to-door caregiver survey was conducted in Beijing, Xi'an, Shanghai and Chengdu in 1998. Totally 1 141 individuals with dementia were found among 34 807 residents aged 55 years and over on the basis of national prevalence study of dementia. Then 428 families with demented patients were randomly selected for questionare interview. Interviews were completed in 405 but refused by 23 families. Measurements included demographic characteristics of patients and their caregivers, perspective of the victim of the disease, current awareness of the disease and medical and welfare services provided. RESULTS: Among 405 cases of dementia (including 298 cases of AD and 81 cases of VaD), mean MMSE scores were 16.3 +/- 5.3 for 157 mild cases, 12.7 +/- 5.4 for 135 moderate cases, and 6.2 +/- 5.8 for 110 severe cases. Most patients (96%) were cared for at home by family members. Among caregivers, 189 (48.8%) considered the impairment of cognition, behavior and daily living activity in demented persons as a result of normal aging. Half of the caregivers spend over 8 hours each day looking after the patient. Whether the caregivers brought their relatives with dementia to a doctor was determined by disease severity, i.e. 8.3% for mild, 13.5% for moderate, and 19.4% for severe in 1996 to approximately 1997 and 14.4%, 25.6% and 33.6%, respectively in 1998-1999. Of those, only 26.9% reported receiving a dementia diagnosis, and only 21.3% received a recommedation to take medication. However, there was no established standard treatment and only 2% patient's used Ache-I. CONCLUSIONS: General education is needed to increase the public awareness of dementia. For patients with dementia, early diagnosis, early treatment and optimal care are important to improve their quality of life.

Methodology of China's national study on the evaluation, early recognition, and treatment of psychological problems in the elderly: the China Longitudinal Aging Study (CLAS).

SUMMARY: Cognitive and depressive disorders are common in elderly Chinese and are becoming an increasingly important public health problem, partly because of the rapid aging of the population. To help address this issue China's national government has funded a major study to establish national standards for the early identification, evaluation and treatment of common psychological disorders in the elderly. The present paper describes the overall methodology of this study. Fifteen centers in eight provinces will recruit representative samples of subjects aged 60 and over, collect a detailed history, conduct a physical and neurological examination, administer a comprehensive battery of psychological tests, and carry out a diagnostic exam using the Structured Clinical Interview for DSM-IV (SCID). These subjects will participate in follow-up evaluations one year and three years after the initial evaluation. Subsamples of subjects with mild cognitive impairment (MCI) and subclinical depression will be enrolled in randomized controlled trials of a cognitive training program (for MCI) or group cognitive behavioral therapy (for subclinical depression). The results of the study will be used to estimate the prevalence of cognitive and affective disorders in the elderly, to develop a standard screening procedure for these conditions that can be promulgated nationally, and to promote the use of specific interventions that can prevent the development of dementia in persons with MCI and the development of depressive episodes in elderly individuals with subclinical depression.

Exploration of 16 candidate genes identifies the association of IDE with Alzheimer's disease in Han Chinese.

Alzheimer's disease (AD) has a complex pattern of inheritance and many genes have recently been reported to contribute to the disease susceptibility. We selected 106 SNPs within 16 candidate genes and performed a multistage association study using 4 sample sets consisting of 731 AD patients and 738 control subjects to identify genetic factors for AD in Han Chinese. A single nucleotide polymorphism (SNP) in the insulin degrading enzyme gene (IDE), rs3781239, showed a significant association with AD. The C allele increased the risk of AD 1.72-fold than the G allele (odds ratio [OR] = 1.72, 95% confidence interval [CI] = 1.17-2.53, p = 0.006) and CC carriers had a 4.89-fold higher risk for AD than that of the carriers with CG and GG genotypes (odds ratio = 4.89, 95% CI = 1.85-12.91, p = 0.001). Moreover, the CC genotype was significantly associated with earlier age at onset (p = 0.001, hazard ratio [HR] = 2.09, 95% CI = 1.38-3.18). Our data suggest that the polymorphism of IDE is associated with susceptibility to Alzheimer's disease in Han Chinese.

The Q7R polymorphism in the saitohin gene is rare in a southern Chinese population.

Saitohin (STH) is thought to be involved in the pathogenesis of many neurodegenerative diseases. Recent reports were inconclusive in showing that the Q7R polymorphism in the STH gene is associated with late-onset Alzheimer's disease (LOAD). We examined the Q7R polymorphism in 500 subjects (LOAD: 280; controls: 220) from Guangdong, China, by the Restriction Fragment Length Polymorphism method. Only one QR heterozygous and no RR homozygous variants were found. Our results suggest that the frequency of the R allele in the Han population is lower than that in Caucasian and African populations. The Q7R polymorphism is unlikely to contribute significantly to Alzheimer's disease susceptibility of the Han population in south China and the variation of the Q7R polymorphism among different ethnic groups might account for the varied clinical manifestations of some STH-related diseases.

[The prevalence of mild cognitive impairment among residents aged 55 or over in Chengdu area].

OBJECTIVE: To study the prevalence of mild cognitive impairment (MCI) in the urban and the rural areas in Chengdu, Southwest China. METHODS: Residents aged 55 or over were selected by stratified random cluster sampling from 19 districts, cities, and counties of Chengdu area in Sichuan province. A two-stage survey was carried out. In the first stage, CMMSE, CES-D were used as screening instruments. In the second stage, Diagnostic questionnaires of dementia and CDR were used as diagnostic instruments. The diagnostic criteria of mild cognitive impairment adopted from Petersen's were: (1) memory complaint; (2) normal activities of daily living; (3) normal general cognitive function; (4) memory impairment incompatible with age; (5) not demented; (6) CDR = 0.5 and (7) exclusion of the reversible cognitive impairment caused by other factors (i.e. depression). RESULTS: Three thousand, nine hundred and ten subjects were examined. The prevalence rates of MCI was 2.4%. The MCI prevalence rates in the urban and the rural areas were 1.5%, 2.5% respectively, without significant difference. The MCI prevalence in males and females were 1.8%, 2.9% respectively. Prevalence rate in female was higher than in males with significant difference. Prevalence of illiteracy (4.0%) was the highest among different educational levels. The accumulated prevalence increased with age. CONCLUSION: The prevalence of MCI (2.4%) was slightly higher than the prevalence of AD (2.05%) in the same areas of Chengdu. MCI seemed to be a high risk factor for AD which should to be followed up. Early intervention in MCI might be helpful in the prevention of AD.