Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer's disease in a southern Chinese population.

In this case-controlled study, we tested susceptible genetic variants for Alzheimer's disease (AD) in CR1, CLU and PICALM from genome-wide association studies (GWAS) in a southern Chinese population. Eight hundred twelve participants consisting of 462 late-onset Alzheimer's disease (LOAD) patients and 350 nondemented control subjects were recruited. We found by multivariate logistic regression analysis, that single nucleotide polymorphisms (SNPs) in CR1 (rs6656401 adjusted allelic p = 0.035; adjusted genotypic p = 0.043) and CLU (rs2279590 adjusted allelic p = 0.035; adjusted genotypic p = 0.006; rs11136000 adjusted allelic p = 0.038; adjusted genotypic p = 0.009) were significantly different between LOAD patients and nondemented controls. For PICALM, LOAD association was found only in the APOE ε4 (-) subgroup (rs3851179 adjusted allelic p = 0.028; adjusted genotypic p = 0.013). Our findings showed evidence of CR1, CLU, and PICALM and LOAD susceptibility in an independent southern Chinese population, which provides additional evidence for LOAD association apart from prior genome-wide association studies in Caucasian populations.

CYP46A1 functional promoter haplotypes decipher genetic susceptibility to Alzheimer's disease.

We here demonstrate that promoter polymorphisms rs8003602 and rs3783320 of cholesterol 24S-hydroxylase (CYP46A1) were significantly associated with Alzheimer's disease (AD) in Chinese subjects. Haplotype analyses showed that haplotype CG is the risk haplotype. Either single marker or haplotypic association was found only in the APOE ε4 negative group. The association was then replicated in an independent set of case-control samples in Mongolians. We also investigated the function of promoter haplotypes and found that luciferase expression for TA promoter construct exhibited significantly higher expression level than the risk CG promoter construct. This finding might indicate individuals bearing the CG haplotype are genetically more susceptible to AD compared to those with TA haplotype. Further, we found MYT1 could be the potential transcription factor binding to the significant promoter polymorphism and mediated gene transcriptional activity. In general, our results show that promoter haplotypes could significantly affect CYP46A1 gene transcription level possibly through interacting with certain transcription factors.

Bioavailable testosterone predicts a lower risk of Alzheimer's disease in older men.

There is a paucity of data on the relationship between testosterone and Alzheimer's disease (AD) in older men. The objective of the present study was to investigate the effects of serum total testosterone (TT), bioavailable testosterone (BT), and sex hormone binding globulin (SHBG) levels on the subsequent risk of AD in nondemented Chinese older men. This was a one-year prospective cohort study. 153 ambulatory community-living nondemented Chinese older men, aged 55 years or over, were recruited and followed for one year. Morning serum TT, BT, and SHBG levels were measured at baseline. At one-year of followup, assessment for dementia and AD were performed. AD was diagnosed by the NINCDS-ADRDA criteria for probable AD. Overall, the mean age of the subjects was 72.7 (SD 6.9). 6.5% (n = 10) developed dementia (converters), all having AD. 93.5% (n = 143) did not develop dementia (non-converters). Logistic regression analysis for independent predictors of AD showed that the baseline serum BT level, systolic blood pressure (SBP) and ApoE "4 genotype were significant independent predictors, after adjustment for age, education, BMI, fasting plasma glucose, and serum HDLC levels. The baseline serum BT level predicted a reduced risk of AD (adjusted relative risk (RR) 0.22, 95% CI: 0.07-0.69)). Baseline SBP and ApoE "4 genotype but not SHBG were independent risk factors, with RRs of 1.04 and 5.04 respectively. In conclusion, the serum level of bioavailable testosterone in late life predicts a lower risk of future AD development in older men.

A study on the association of the chromosome 12p13 locus with sporadic late-onset Alzheimer's disease in Chinese.

Recent linkage and association studies have implicated the chromosome 12p13 locus as possibly harboring genetic variants predisposed to Alzheimer's disease (AD). We attempted to replicate this association in a Chinese data set comprised of 256 AD cases and 264 age-matched normal controls. A total of 14 single nucleotide polymorphisms (SNPs) were examined. Single marker association revealed the two SNPs in NCAPD2 (rs7311174 and rs2072374) as showing nominal significant p values (p = 0.0491 and 0.0116, respectively). Haplotype analysis found LD block one to be significantly associated with AD (global p = 0.0250). Haplotypes CGGATG and CAGTCG were also significantly associated with AD (p = 0.0498 and p = 0.0482, respectively). These genetic analyses provide evidence that the chromosome 12p13 locus is associated with AD in Chinese.

Late-life body mass index and waist circumference in amnestic mild cognitive impairment and Alzheimer's disease.

We investigated the progressive associations of late-life body mass index (BMI) and waist circumference (WC) with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) in Chinese older adults in a case-control study. Late-life BMI and WC were measured. AD was diagnosed by the NINCDS-ADRDA criteria for probable AD and aMCI by the Petersen's criteria. 426 Chinese older adults [125 AD, 125 aMCI and 176 controls with normal cognition (NC)], aged 55 to 93 years old, were recruited. Both BMI and WC decreased significantly across the normal, aMCI, and AD groups (dementia diagnostic group: p for trend < 0.001 and 0.016 respectively, 1-way ANOVA). After adjustment for significant confounders, multivariate general linear model analyses showed that the dementia diagnostic group (AD/aMCI/NC) was a significant independent predictor of both the late-life BMI and late-life WC (p = 0.002 and 0.018 respectively). In conclusion, late-life BMI and WC progressively decrease in older adults with normal cognition, aMCI, and AD. Low late-life BMI and WC represent potentially useful pre-clinical markers of aMCI and AD.

Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men.

OBJECTIVE: We investigated the risk of amnestic mild cognitive impairment (aMCI) in relation to serum bioavailable (BT) and total testosterone (TT) levels in older men. DESIGN, SETTING AND SUBJECTS: A cross-sectional study in an ambulatory setting, with older men aged 55-93 years with normal cognition, aMCI and Alzheimer's disease (AD). MEASUREMENTS: Morning serum BT and TT levels were determined. AD was diagnosed by the Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD and aMCI by the Petersen criteria. RESULTS: We recruited 203 Chinese older men (48 aMCI, 66 AD and 89 with normal cognition). Mean serum BT, but not TT, levels were significantly lower in the aMCI (mean BT +/- SEM 1.06 +/- 0.10 nmol/l) and AD (0.99 +/- 0.08 nmol/l) groups than in the normal controls (1.82 +/- 0.12 nmol/l) (P < 0.001, one-way anova) with no significant difference between the aMCI and AD groups. After adjustment for education, age and apolipoprotein E (apoE) genotype, logistic regression analyses showed that the serum BT level [adjusted odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.32-0.85] was an independent protective factor for aMCI. For the combined outcome of aMCI and AD, the serum BT level was an independent protective factor but age and apoE epsilon4 were independent risk factors. There was no interaction between BT and age. CONCLUSIONS: In older men, serum BT, but not TT, levels were associated with a lower risk of aMCI and AD.

A novel intronic polymorphism of ABCA1 gene reveals risk for sporadic Alzheimer's disease in Chinese.

Recent genetic studies have shown that variants of the ATP-binding cassette transporter A1, ABCA1, may be implicated in the pathogenesis of Alzheimer's disease (AD). In this case-control study, a panel of 19 single nucleotide polymorphisms (SNP) (including three amino-acid-coding SNPs used for replication of previous work, and 16 newly selected intronic tag SNPs) was genotyped. Nominally significant single marker P-values were observed in four SNPs, with the highest score of 0.003 for rs2297404 (OR = 1.88, 95%CI 1.23-2.87). In addition, six distinct linkage disequilibrium (LD) blocks were detected. LD block1 harbored three nominally significant SNPs (rs2297404, rs2230808, and rs2020927), and showed a different haplotype structure in the affected and unaffected groups. Of the four haplotypes identified, haplotype2 (CAC) was more prevalent in the disease group (0.323 in AD vs. 0.202 in control); while haplotype1 (TGG) was over-represented in the healthy controls (0.595 in control vs. 0.493 in AD), indicating disease risk conferring possibility of haplotype2. After doubling the sample size, the three nominally significant SNPs were still significantly associated with AD. Although coding SNP (rs2230808) was confirmed to have a significant association with AD, prediction of the effects of an amino acid substitution SNP rs2230808 (R1587K) on the three-dimensional structure and function of the ABCA1 protein using PolyPhen program revealed that it is unlikely to be functionally significant. However, the adjacent rs2297404 in the same LD block is potentially functionally significant because of its position in the immediate vicinity of a splicing branch site. Further functional analysis of this polymorphism should be a high priority.