Yi-Min Chu

Association between air pollutants and dementia risk in the elderly

The aging rate in Taiwan is the second highest in the world. As the population ages quickly, the prevalence of dementia increases rapidly. There are some studies that have explored the association between air pollution and cognitive decline, but the association between air pollution and dementia has not been directly evaluated.

Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease.

BACKGROUND In addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ)-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimers disease (AD). Palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα). FINDINGS In the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ1-42 and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons. CONCLUSIONS In line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.

Sequence Variants of Toll Like Receptor 4 and Late-Onset Alzheimer's Disease

Background Toll like receptor 4 (TLR4) has been related to inflammation and beta-amyloid deposition in Alzheimers disease (AD) brain. No study has explored the association between haplotype-tagging single nucleotide polymorphisms (htSNPs) of TLR4 and AD risk previously and ApoE e4 status alone showed low sensitivity in identifying late-onset AD (LOAD) patients. Methods A total of 269 LOAD patients were recruited from three hospitals in northern Taiwan (2007–2010). Controls (n = 449) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) TLR4 htSNPs were selected to assess the association between TLR4 polymorphisms and the risk of LOAD in the Chinese ethnic population. Results Homozygosity of TLR4 rs1927907 was significantly associated with an increased risk of LOAD [TT vs. CC: adjusted odds ratio (AOR) = 2.45, 95% confidence interval (CI) = 1.30–4.64]. After stratification, the association increased further in ApoE e4 non-carriers (AOR = 3.07) and in hypertensive patients (AOR = 3.60). Haplotype GACGG was associated with a decreased risk of LOAD (1 vs. 0 copies: AOR = 0.59, 95% CI = 0.36–0.96; 2 vs. 0 copies: AOR = 0.31, 95% CI = 0.14–0.67) in ApoE e4 non-carriers. ApoE e4 status significantly modified this association (p interaction = 0.01). These associations remained significant after correction for multiple tests. Conclusions Sequence variants of TLR4 were associated with an increased risk of LOAD, especially in ApoE e4 non-carriers and in hypertensive patients. The combination of TLR4 rs1927907 and ApoE e4 significantly increased the screening sensitivity in identifying LOAD patients from 0.4 to 0.7.

Body mass index (BMI) at an early age and the risk of dementia.

BMI change and BMI at an early age have not been investigated as risks for dementia. This case-control study included 286 dementia patients and 268 controls from two medical centers between 2007 and 2009. BMI information was collected from medical records and questionnaires. Men and women with low BMIs at the time of the study, in their 20s, and in their 40s had significantly increased risks of Alzheimers disease (AD) (odds ratio = OR = 2.62-3.97) and increased vascular dementia (VaD) risk (20s and 40s: OR = 6.23-11.11) compared with those with normal BMIs. High BMI in the 20s and 40s was associated with increased VaD risk (OR = 15.29 and 10.32) among women. For BMI changes from the 20s or 40s, the second and third tertiles were significantly associated with decreased AD risk among women (OR = 0.15-0.35) compared to the first tertile. The third tertile of BMI change from the 20s or 40s was associated with decreased VaD risk among women (OR = 0.06 and 0.14). Low BMIs in the 20s and 40s were stronger predictors of AD and VaD. There was a U-shaped association between BMI at different ages and dementia among participants with VaD.

Genetic polymorphisms of clusterin gene are associated with a decreased risk of Alzheimer’s disease

Clusterin (CLU) is located on chromosome 8p21–p12. The binding of CLU to Ab facilitates Ab clearance and transporting of CLUAb complex. Recent Caucasian genomewide association studies (GWASs) found that CLU rs11136000 is the only SNP consistently associated with a reduced risk of Alzheimer’s disease (AD) [odds ratio (OR) = 0.85–0.86] [1–3], similar findings were observed in two Caucasian candidate-gene studies [4, 5], while the other two Caucasian studies did not observe this association [6, 7]. In contrast, a Chinese study observed an opposite association (OR = 1.39) [8]. This study was aimed to explore the association between CLU polymorphisms and the risk of AD using a set of haplotype-tagging SNPs (htSNPs) in a Taiwanese population. Furthermore, stratified analyses were performed to evaluate how ApoE e4 status and vascular risk factors modified this association. This is a case-control study with a total of 268 AD cases recruited from the Department of Neurology at three teaching hospitals in northern Taiwan from 2007 to 2010. Controls (n = 389) were recruited from the elderly health checkup and volunteers in the hospital during the same period of time. All study participants were Taiwanese aged 60 and older. A well-trained personnel administered questionnaires to obtain detailed information on demography, lifestyle, and comorbidity. Neurologists used MiniMental State Examination and Clinical Dementia Rating to assess the cognitive function of AD patients. Diagnosis of AD was made by using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the criteria of

Genetic Polymorphisms of a Novel Vascular Susceptibility Gene, Ninjurin2 (NINJ2), Are Associated with a Decreased Risk of Alzheimer's Disease

Background Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously. Methods A total of 275 Alzheimers disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association. Results Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI)  = 0.23–0.80; rs12425791: AOR  = 0.33, 95% CI  = 0.12–0.96]. Five common haplotypes (cumulative frequency  = 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR  = 0.32, 95% CI  = 0.11–0.94). No associations were observed for VaD. Conclusion Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk.

Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease

BackgroundLoss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimers disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies.MethodsThis was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD.ResultsVariant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (Pinteraction < 0.05).ConclusionInherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.

CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease

Background CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimers disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. Methods Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment. Results AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47–8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38–8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. Conclusion For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice.

CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking

α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-β. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, apolipoprotein E (APOE) ε4 status and smoking on dementia risk. This case-control study recruited 254 late-onset Alzheimer’s disease (LOAD) and 115 vascular dementia (VaD) cases (age ≥65) from the neurology clinics of three teaching hospitals in Taiwan during 2007–2010. Controls (N = 435) were recruited from health checkup programs and volunteers during the same period. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among APOE ε4 non-carriers, CHRNA7 rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio = 0.29, 95% confidence interval = 0.13–0.64, P = 0.002). Similar findings were observed for carriers of GT haplotype in CHRNA7 block4. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. These findings help to understand dementia pathogenesis.

Religious affiliation and the risk of dementia in Taiwanese elderly

INTRODUCTION Religious affiliations vary across ethnic groups because of different cultural backgrounds. Some studies have explored the association between religious affiliation and cognitive decline. Only a small portion of patients with cognitive decline progress to dementia. However, the association between religious affiliation and dementia risk remains unclear. METHODS In this case-control study, we recruited 280 patients with Alzheimers disease (AD) and 138 with vascular dementia (VaD) (both aged ≥60 years) from three teaching hospitals in northern Taiwan between 2007 and 2010. Age-matched healthy controls (n=466) were recruited from an elderly health checkup program and from volunteers visiting the hospital during the same period. Three religious affiliations-Taoism, Buddhism, and Christianity-were evaluated. The study also assessed the effect of important factors such as gender or leisure activities on the association of religious affiliation with dementia risk. RESULTS Participants with Christianity affiliation showed decreased AD risk (adjusted odds ratio [AOR]=0.46, 95% confidence interval [CI]=0.25-0.87) compared with those without any religious affiliation. Moreover, this effect was stronger in women (AOR=0.38, 95% CI=0.15-0.92) and in participants who exercised regularly (>3 times/week; AOR=0.33, 95% CI=0.14-0.77). No significant association was observed among participants with Taoism and Buddhism affiliations. Affiliation to none of the religions was associated with VaD risk. CONCLUSIONS Thus, Chinese participants having Christianity affiliation showed decreased AD risk. Moreover, the protective effect was more evident in women and in participants who exercised regularly.