Endoplasmic reticulum (ER) chaperone heat shock 70 kDa protein 5 (HSPA5/GRP78) is known to be involved in the metabolism of amyloid precursor protein and neuronal death in Alzheimer's disease (AD) could arise from dysfunction of the ER. Through a case-control study and an expression assay, we investigated the association of HSPA5 -415 G/A (rs391957), -370 C/T (rs17840761) and -180 del/G (rs3216733) polymorphisms with Taiwanese AD. The overall genotype and allele frequency distribution at the completely linked -415 G/A and -180 del/G sites showed significant difference between AD cases and controls (P = 0.020 and 0.009, respectively). A decrease in risk of developing AD was demonstrated for -415 AA/-180 GG genotype [OR = 0.38, 95% confidence interval (CI) = 0.18-0.75, P = 0.007] and -415 A/-180 G allele (OR = 0.69, 95% CI = 0.51-0.91, P = 0.009). The HSPA5 transcriptional activity of the -415 A/-180 G allele was significantly lower than that of the -415 G/-180 del alleles, whereas induction of HSPA5 expression after ER stress was markedly increased in the cells with the -415 A/-180 G allele. Therefore, our preliminary results may suggest a protective role of the HSPA5 -415 A/-180 G allele in Taiwanese AD susceptibility.

Lipoproteins and vascular factors may play roles in the development of Alzheimer's disease (AD) and/or vascular dementia (VaD). In this study, odd ratios (ORs) and 95% confidence intervals (CIs) for apolipoprotein E (APOE), angiotensin-converting enzyme (ACE), and kallikrein (KLK1) polymorphisms were computed to test their association with the disease by a case-control study. The risk of AD was significantly increased for individuals with APOE varepsilon4 allele (OR = 3.73, 95% CI = 2.38-5.98). The risk of AD was also significant for people with ACE DD genotype, D allele, or T-D haplotype [OR (95% CI) = 4.29 (1.96-10.23), 1.90 (1.35-2.70), or 2.91 (1.71-5.10), respectively]. The above association between ACE-VaD was also strong (p = 0.0012, 0.0050, 0.0007, respectively). Reporter constructs containing the -240 A or T allele displayed similar transcriptional activity in both HEK-293 and IMR-32 cells. Thus, another putative pathogenic marker that is linked with the Alu D allele might affect the risk of AD and VaD in Taiwan.

This study was to determine whether polymorphisms of heat shock protein 70-1 (HSP70-1) and tumor necrosis factor α (TNF-α) are associated with the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). Using the criteria of the NINCDS-ADRDA and NINDS-AIREN, 125 AD patients, 57 VaD patients and 109 ethnically matched nondemented controls were enrolled. The HSP70-1 –110 A/C and TNF-α –1031 T/C, –863 C/A and –857 C/T polymorphisms were analyzed by means of genotype or haplotype association methods. None of the four genotypes examined showed a statistically significant difference in genotype distribution between the AD cases and controls. However, the HSP70-1 –110 CC genotype occurred more frequently among AD cases (p = 0.0821; odds ratio: 2.08; 95% confidence interval, CI: 0.92–4.98). The overall genotype distribution among the VaD cases tended to be different at the HSP70-1 –110 and TNF-α –1031 sites (p = 0.0604 and 0.0316, respectively). The HSP70-1 –110 CC genotype was more frequent (p = 0.0459), and the association of the –110 CC genotype with VaD was evident (p = 0.0207; odds ratio: 3.22; 95% CI: 1.20–8.87). The more frequent TNF-α –1031 TC genotype (p = 0.0614) was also evidently associated with VaD (p = 0.0209; odds ratio: 2.32; 95% CI: 1.14–4.78). Multivariate analysis demonstrated the synergistic effect of the HSP70-1 –110 CC and TNF-α –1031 TC/CC genotypes on VaD (p = 0.0091; odds ratio: 10.09; 95% CI: 2.01–75.97). Haplotype analysis among TNF-α –1031, –863, –857 sites revealed that –1031C–857C may act as a risk haplotype among VaD cases (p = 0.0132, odds ratio: 2.26; 95% CI: 1.19–4.33). Our results suggest a potential protective role for HSP70 in both VaD and AD, whereas TNF-α may act as a risk factor only for VaD, and not for AD.