Longfei Jia

The prevalence of dementia in urban and rural areas of China

The Chinese population has been aging rapidly and the countrys 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, Alzheimers disease (AD), and vascular dementia (VaD) among elderly Chinese individuals and to analyze differences between urban and rural areas.

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

Epidemiologic studies on mild cognitive impairment (MCI) are limited in China.

Promoter polymorphisms which modulate APP expression may increase susceptibility to Alzheimer's disease

Increasing evidence indicates that variants in promoter of the beta-amyloid precursor protein (APP) gene could up-regulate the APP gene expression and aggravate the amyloid beta protein (A beta) accumulation, thus contributing to the development of Alzheimers disease (AD). In Chinese Han populations we found three polymorphisms in APP promoter: -877T/C(rs466433), -955A/G(rs364048) and -9G/C. The -877T and -955A alleles were over-represented in 209 sporadic AD (SAD) patients when compared to those in 437 healthy individuals. Furthermore, -877T/C and -955A/G were in strong linkage disequilibrium and they constructed a relatively risky -877T/-955A and a relatively protective -877C/-955G. Luciferase reporter assay indicated -877T/-955A had four times higher transcriptional activity than -877C/-955G. A more marked increase in -877T/-955A transcriptional activity was seen when under A beta(25-35) treatment. As for the -9G/C polymorphism, significant differences between the two alleles were not observed either in genetic evaluation or in functional assay. The present study provides strong evidence that APP promoter polymorphisms that significantly increase APP expression levels are associated with development of SAD.

Association between polymorphisms in the apolipoprotein D gene and sporadic Alzheimer's disease

Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein that is increased in the hippocampus and cerebrospinal fluid of patients with Alzheimers disease (AD), which implies that apoD might be involved in the pathogenesis of AD. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing techniques to screen all exons (1-5) and the flanking exon-intron boundaries of the apoD gene (APOD). Thirty subjects [15 sporadic AD (SAD) patients and 15 controls] were randomly selected and tested for APOD variations by direct sequencing. Two APOD polymorphisms (rs5952T/C and rs1568566C/T) were detected. We further investigated APOD polymorphisms in 256 SAD patients and 294 healthy subjects from a North Chinese population to investigate whether they affect the risk of SAD. Logistic analysis revealed that both rs5952 C and rs1568566 T alleles increase the risk of SAD [rs5952, adjusted odds ratio (OR) 1.817, 95% confidence interval (CI) 1.237-2.669, P = 0.002; rs1568566, adjusted OR 1.563, 95% CI 1.060-2.306, P = 0.024). The rs5952T-rs1568566C haplotype showed lower risk of SAD (OR 0.421, 95% CI 0.305-0.583, P = 0.000). Case-control analysis revealed that the rs5952T-rs1568566C haplotype could serve as a novel defendant factor against SAD. APOD polymorphisms might play an important role in modifying SAD risk in some way.

A Lifespan Observation of a Novel Mouse Model: In Vivo Evidence Supports Aβ Oligomer Hypothesis

Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.

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

Alzheimers 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 Alzheimers disease in Han Chinese.

Genetic association between polymorphisms of Pen2 gene and late onset Alzheimer's disease in the North Chinese population

UNLABELLED Presenilin enhancer 2 (Pen2) is a subunit of the gamma-secretase complex which cleaves amyloid precursor protein (APP) to generate amyloid beta (Abeta). We performed a systematic screening of all Pen2 exons and introns using direct sequencing to assess its role in the risk of developing late onset Alzheimers disease (LOAD). 947 subjects (LOAD: 467; CONTROLS 480) were recruited for this study. We obtained three polymorphisms: rs10402601, rs3817622, and rs2293688. Among these three polymorphisms, there was an interaction between rs3817622 and apolipoprotein E (APOE) genotypes (P=0.002). In the subjects with APOE 4 allele, there was a significant difference in the distribution of alleles (P=0.003) and genotypes (P=0.007) between LOAD and control groups. ORs [95% confidence interval (CI)] of allele A and T/A+A/A genotypes were respectively 4.720 (1.517-10.654) and 3.886 (1.381-10.932) with allele T and genotype T/T as a reference. Our results suggest that there is an association between rs3817622 and the development of LOAD in APOE epsilon4 carriers within the northern Chinese population. It is possible allele A of the Pen2 gene increases the risk for LOAD.

Association between presenilin 1 intronic polymorphism and late onset Alzheimer's disease in the North Chinese population

The association between presenilin 1 intronic polymorphism (rs165932) and late onset Alzheimers disease (LOAD) has been a matter of controversy. Within China, varied results have been reported. Therefore, we collected a large sample from the North Chinese population to test the association of the PS1 polymorphism with LOAD. AD patients (467 total, mean age=75.3+/-7.3, age at onset=70.2+/-5.1) and age-matched normal elderly controls (480 total) were recruited. Genotypes of PS1 and apolipoprotein E (APOE) were determined by PCR and RFLP. The results showed that there were significant differences in the distributions of both alleles (chi(2)=45.305, P<10(-5)) and genotypes (chi(2)=53.055, P<10(-5)) of PS1 gene between the AD and control groups. The APOE epsilon4 allele was more prevalent in patients than in controls (chi(2)=46.389, P<10(-5)). It was significantly different when PS1 alleles and genotypes were compared between AD and controls with APOE epsilon4 negative. However, no significance was found when PS1 alleles or genotypes were compared between AD and controls with APOE epsilon4 positive. Furthermore, with PS1 2/2 genotype as a reference, the odds ratios (ORs) of LOAD with PS1 1/2, 1/1+1/2 and 1/1 genotypes gradually increased allele 1 copy number, suggesting that allele 1 is a crucial risk for LOAD. In summary, we found an association between presenilin 1 intronic polymorphism and LOAD, but no influence of APOE epsilon4 on the distribution of the PS1 intronic polymorphism. In addition, the larger sample size raises the possibility that ethnic and regional differences in China may explain the differences in reported results.