Allelic frequencies at the ACE and LRPAP1 loci suggest age-related relationships in a northern Italian population

The present work attempts to determine the distribution of ACE and LRPAP1 genotypes and allele frequencies in a sample of the population of north-western Italy and to examine the age-related association of these polymorphisms. ACE D allele frequency found in this work further confirms data obtained in previous studies of Northern Italian populations. Regarding the LRPAP1 gene, high frequencies of the deleted allele in European populations were also confirmed. In order to analyse the relationship between ACE and LRPAP1 gene polymorphisms and age, the sample was subdivided into four age groups: 1-30 (n= 99), 31-50 (n= 165), 51-79 (n= 146) and 80-100 years old (n= 57). For the ACE gene, significant difference in D/D genotype frequency was found only between the younger and the 51-79 age groups (p<0.05), the latter showing the lower frequency value. Significant differences were found, for both the I/D and D/D LRPAP1 genotypes, between the first and the second age group (p < 0.02) and between the first and the third age group (p < 0.01), with the 51-79 age group showing the higher D/D and the lower I/D genotype frequency values.     

Endothelin-Converting Enzyme-1 Promoter Polymorphisms and Susceptibility to Sporadic Late-Onset Alzheimer's Disease in a Chinese Population

Endothelin converting enzyme (ECE-1) is a candidate Alzheimer disease susceptibility gene. It was previously reported that western individuals homozygous for the C-338A polymorphism (AA) within the ECE1 gene promoter region are at reduced risk of developing late onset Alzheimer disease (LOAD). A further polymorphism, T-839G, is present within the ECE1 promoter region but a potential association with LOAD has not been studied. We therefore studied possible associations between these ECE1 polymorphisms and LOAD in a Chinese population. Subjects comprised 376 Chinese LOAD patients and 376 age- and sex-matched controls; all subjects were typed for the ECE1 C-338A and the T-839G polymorphisms. We report that the frequency of the 338A allele was decreased in LOAD patients compared to controls (adjusted OR =0.73; 95% CI=0.54–0.98; P=0.03). There was no significant association between T-839G genotype and LOAD, however the combined 839T/338A haplotype was significantly associated with decreased risk of LOAD (OR=0.73; 95% CI=0.57–0.93; P=0.01). This study argues that the ECE1 338A allele is protective against LOAD in a Chinese population.     

Butyrylcholinesterase,ApoE and Alzheimer's disease in a population from the Canary Islands (Spain)

Aim: Cholinergic dysfunction is a major neurochemical feature in Alzheimer's disease (AD), accountable for many cognitive dysfunctions and some psychiatric symptoms. Butyrylcholinesterase (BChE) is one of the cholinesterases with increased activity in the brain of Alzheimer's patients. Several mutations code for different BChE, such as the K variant, which is the most common and is capable of reducing BChE activity by 30%. We studied the relationship between this K variant and Alzheimer's disease in our population from the Canary Islands (Spain). Patients and methods: We used DNA PCR-RFLP techniques to compare 282 patients who had been diagnosed with probable Alzheimer's disease – according to NINCS-ADRDA criteria – with 312 control subjects confirmed to be free of cognitive impairment as assessed by using the CAMDEX cognitive subscale CAMCOG. Results: In our population the K variant of BChE is linked to the age of diagnosis of Alzheimer's disease, since AD individuals with this allele presented the disease at a later stage. No other susceptibility relations are exposed in this study. In addition, the BChE allelic frequencies in our population are higher than those previously reported.     

Familial Alzheimer's disease coding mutations reduce Presenilin-1 expression in a novel genomic locus reporter model

We have generated a physiologically relevant bacterial artificial chromosome (BAC)-based genomic DNA expression model to study PS1 gene expression and function. The PS1-WT-BAC construct restored γ-secretase function, whereas the mutant PS1 BACs demonstrated partial to complete loss of enzymatic activity when stably expressed in a PS double knock-out clonal cell line. We then engineered WT and mutant human PS1-BAC-Luciferase whole genomic locus reporter transgenes, which we transiently transduced in mouse and human non-neuronal and neuronal-like cells, respectively. PS1 ΔE9 and C410Y FAD were found to lower PS1 gene expression in both cell lines, whereas PS1-M146V showed a neuron-specific effect. The nonclinical γ-secretase inactive PS1-D257A mutation did not alter gene expression in either cell line. This is the first time that pathogenic coding mutations in the PS1 gene have been shown to lower PS1 gene expression. These findings may represent a pathologic mechanism for PS1 FAD mutations independent of their effects on γ-secretase activity and demonstrate how dominant PS1 mutations may exert their pathogenic effects by a loss-of-function mechanism.     

Allelic association at the D14S43 locus in early onset Alzheimer's disease

The D14S43 marker is closely linked to the major gene for early onset autosomal dominant Alzheimer's disease on chromosome 14. Allelic frequencies at the D14S43 locus were compared in 113 familial and isolated cases of early onset Alzheimer's disease (<60 years of age at onset) (EOAD) and 109 unaffected individuals of the same geographic origin. Allele 7 was significantly (P = 0.033) more frequent in type 1 EOAD patients (13.2%), defined by the presence of at least another first degree relative with EOAD, than in controls (4.1%). Since an autosomal dominant gene is probably responsible for type 1 patients, allelic association may reflect linkage disequilibrium at the D14S43 locus. This would mean that some patients share a common ancestral mutation. However, since multiple tests were carried out, this result must be interpreted with caution, and needs confirmation in an independent sample. © 1995 Wiley-Liss, Inc.     

Lack of evidence for association of a UCH-L1 S18Y polymorphism with Parkinson's disease in a Han-Chinese population

Mutation in UCH-L1 has been reported as a rare cause of autosomal dominant Parkinson's disease (PD). A S18Y polymorphism in the same gene has been associated with sporadic PD. We investigated the frequency of this polymorphism among the Han-Chinese ethnic population in a case-control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR-restriction fragment length polymorphism analysis. We did not observe any difference in allele or genotype frequencies between the cases and the controls (P>0.05). Our results do not support a role for this variant in sporadic PD.     

Association between promoter polymorphisms in anterior pharynx-defective-1a and sporadic Alzheimer's disease in the North Chinese Han population

Amyloid β-peptide (Aβ) deposition in brain is important in the development of sporadic Alzheimer's disease (SAD) and Aβ is produced through sequential cleaving of amyloid precursor protein (APP) by β-secretase and γ-secrease. Anterior pharynx-defective-1 (APH-1) is an important subunit of the gamma-secretase complex, and its expression level was associated with the activity of γ-secrease. We hypothesized that alterations in the APH-1 promoter region might alter APH-1 expression and the activity of γ-secrease, thus be involved in the SAD process. In the present study, we sequenced APH-1a promoter region in 20 randomly selected controls and 20 SAD patients and detected two polymorphisms which were −980C/G (rs3754048) and −21C/A (rs2275780). Then, we investigated genotypes and allele of these two polymorphisms as well as apolipoprotein ?4 (APOE ?4) status in 256 SAD patients and 276 normal controls with restriction fragment length polymorphisms analysis and sequencing. Results showed the GG genotype and G allele of −980C/G polymorphism were more frequent in the SAD group than that in the controls not only in the whole subjects (genotype P = 0.038, allele P = 0.01 respectively) but also in the APOE ?4 + subjects (genotype P = 0.048, allele P = 0.016 respectively). There was no statistical difference between SAD group and controls regarding to the frequency of alleles and genotypes of −21C/A whenever before or after stratification by APOE ?4. Our results suggest that there is an association between −980C/G and the development of SAD in the Northern Han Chinese population and that allele G may interact synergistically with the APOE ?4 allele to increase the risk of SAD.     

Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families

An association between the ϵ4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset AD families. We found an association of familial AD to the APOE ϵ4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE ϵ4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis. © 1996 Wiley-Liss, Inc.     

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Aβ and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3′ un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein ?4 (APOE ?4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p = 0.042). In subjects with the APOE ?4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p = 0.027, allele p = 0.011). In the whole study group, the age, sex, and APOE ?4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI = 1.068–2.234, p = 0.027) whereas within only APOE ?4 allele carriers, the adjusted OR increased to 2.734 (95%CI = 1.236–5.862, p = 0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE ?4 allele.     

Alzheimer's disease and Parkinson's disease genome-wide association study top hits and risk of Parkinson's disease in Korean population

Alzheimer's disease (AD) and Parkinson's disease (PD) have overlapping clinical and pathological features, suggesting a common pathway for these 2 neurodegenerative disorders. Here we investigated the association of both AD and PD GWAS top hits with PD susceptibility. We selected 25 single nucleotide polymorphisms (SNPs) in 9 genes (ABCA7, APOE, BST1, CLU, CR1, LRRK2, PARK16, PICALM, and SNCA) that were genotyped in 1036 PD case patients and 1208 controls. Case patients and controls were all ethnic Koreans. Logistic regression analysis was performed to calculate age- and sex-adjusted odds ratios. None of the AD-susceptibility loci (ABCA7, APOE, CLU, CR1, and PICALM) showed statistically significant association with PD susceptibility. In contrast, we replicated associations of SNCA, LRRK2, BST1, and PARK16 with PD susceptibility in Koreans. Of those, the SNCA SNP rs11931074 showed the most significant association with PD susceptibility (adjusted odds ratio = 1.48; 95% confidence interval = 1.31–1.67; p = 2.20E-10). In a logistic regression analysis with SNPs coded under an additive model, there was no significant genetic interaction between the LRRK2 and the PARK16 locus gene RAB7L1 in PD risk. Our results confirm the associations of SNCA, LRRK2, BST1, and PARK16 with PD susceptibility and fail to show significant associations of AD genome-wide association study (GWAS) top hits with PD susceptibility in a Korean population.     

Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene

The amyloid beta protein (Aβ) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 2 (TLR2) is thought to contribute to Aβ clearance. Studies have reported the presence and functional implications of guanine-thymine (GT) repeat microsatellite polymorphisms in intron II of the human TLR2 gene. The present study evaluated the association of the microsatellite polymorphism and sporadic late-onset AD (LOAD) in the Han Chinese population. The numbers of (GT) repeats were counted in 137 AD patients and in 137 non-AD control subjects, using polymerase chain reaction and genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele, (GT)17 to (GT)22 as the M allele, and (GT)23 or more as the L allele. Patients with AD had more S alleles (P < 0.001; odds ratio (OR) = 2.32; 95% confidence interval (CI) = 1.57–3.42) and fewer L alleles (P = 0.02; OR = 0.66; 95% CI = 0.46–0.93) than did healthy controls. Genotypes SS and SM were more common, whereas ML and SL were less common in patients with AD. In subgroup analyses, the genotypes including S alleles were associated with an increased risk of LOAD (OR = 2.05, 95% CI = 1.26–3.34), and this association was influenced by the presence of APOE ?4 alleles. This study demonstrates an association of microsatellite polymorphisms in intron II of the human TLR2 gene with risk for LOAD in Han Chinese.     

Association studies of cholesterol metabolism genes (CH25H, ABCA1 and CH24H) in Alzheimer's disease

Recent studies have demonstrated that cholesterol metabolism has an important role in Alzheimer's disease (AD) pathogenesis, suggesting that cholesterol-related genes may be significant genetic risk factors for AD. Based on the results of genome-wide screens, along with biological studies, we selected three genes as candidates for AD risk factors: ATP-binding cassette transporter A1 (ABCA1), cholesterol 25-hydroxylase (CH25H) and cholesterol 24-hydroxylase (CH24H). Case-control of North American Caucasians and AD families of Caribbean Hispanic origin were examined. Although excellent biological candidates, the case-control dataset did not support the hypothesis that these three genes were associated with susceptibility to AD. Similarly, no association was found in the Caribbean Hispanic families for CH25H. However, we did observe a possible interaction between ABCA1 and APOE in the Hispanics.     

Association between the macrophage inflammatory protein-l alpha gene polymorphism and Alzheimer's disease in the Chinese population

Genetic polymorphisms in chemokine receptor and their natural ligand genes have been shown to modify the disease progression of Alzheimer's disease (AD). Human macrophage inflammatory protein-1 alpha (MIP-1alpha) is a chemotactic cytokine which plays a considerable role in AD pathogenesis, but its genetic contribution to AD has never been investigated. Recently, a biallelic dinucleotide microsatellite repeat (TA repeat) polymorphism has been found in the MIP-1alpha gene promoter region at position -906. We investigated whether this promoter polymorphism of MIP-1alpha gene might be responsible for susceptibility to AD in a Chinese population, utilizing a clinically well-defined group of 138 sporadic AD patients and 180 age-matched controls. We also examined the combined gene effects between the MIP-1alpha and apolipoprotein E (APOE) genes. The overall distribution of MIP-1alpha-906 alleles and genotypes was significantly different between AD cases and controls (P<0.05). The odds ratio for AD associated with the (TA)(6)/(TA)(6) versus non-(TA)(6)/(TA)(6) genotype was 1.893 (95% CI=1.208-2.967), while that for APOE varepsilon4 and MIP-1alpha (TA)(6)/(TA)(6) carriers was 7.140 (95% CI=3.222-15.823). In addition, we found that serum MIP-1alpha levels in patients with (TA)(6)/(TA)(6) genotype were increased significantly when compared with non-(TA)(6)/(TA)(6) genotype. The results indicate that the MIP-1alpha-906 (TA)(6)/(TA)(6) genotype, either by itself or interacting with the APOE varepsilon4 gene seems to be a genetic risk factor for AD. This genotype is associated with elevated serum MIP-1alpha levels in patients, which can contribute to increase the inflammatory process occurring in AD.     

A SNP site in pri-miR-124 changes mature miR-124 expression but no contribution to Alzheimer's disease in a Mongolian population

Increasing evidence shows that single nucleotide polymorphisms (SNPs) or mutations in microRNAs (miRNAs) sequence may affect the processing and function of miRNAs and participate in the occurrence of diseases. Although many SNPs of miRNAs were found, their functions in the pathological process of nerve cells were only just emerging. In the present study, the effect of the SNP of one neuronal miRNA, miR-124, on miRNA biogenesis and human genetic disease was investigated using in vitro cell line model and Alzheimer's disease (AD) in the Mongolian population. Bioinformatics prediction showed that a common G/C polymorphism designated rs531564 was found in the pri-miR-124 and the G allele changed the formation of a ring-shaped structure in the predicted secondary structure of the pri-miRNA for miR-124-1. Northern blot and real-time PCR analysis showed that the amount of mature miR-124 from the C/G heterozygosity of rs531564 was increased compared with the CC or GG homozygosity of rs531564. The expression of mature miR-124 from GG homozygosity was also higher than that from CC homozygosity. But in an association study of AD patients and controls, neither genotype nor allele distribution difference was found in AD patients compared with controls. Collectively, the present study is the first to evaluate the relationship between miR-124 and AD in the Mongolian population. SNP rs531564 of miR-124 may not represent a risk factor in the development of AD among Mongolian population.     

Butyrylcholinesterase K variant is genetically associated with late onset Alzheimer's disease in Northern Ireland

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E epsilon4 (APOE epsilon4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (chi(2)=23.68, df=2, p<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (chi(2)=16.39, df=1, p<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2. 20-6.07). This risk increased in subjects 75 years and older (OR=5. 50, 95% CI 2.56-11.87). At the same time the APOE epsilon4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE epsilon4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.     

Episodic-like and procedural memory impairments in histamine H1 Receptor knockout mice coincide with changes in acetylcholine esterase activity in the hippocampus and dopamine turnover in the cerebellum

We investigated episodic-like (ELM) and procedural memory (PM) in histamine H1 receptor knockout (H1R-KO) mice. In order to relate possible behavioral deficits to neurobiological changes, we examined H1R-KO and wild-type (WT) mice in terms of acetylcholine esterase (AChE) activity in subregions of the hippocampus and AChE and tyrosine hydroxylase (TH) expression in the striatum. Furthermore, we analyzed acetylcholine (ACh), 5-HT and dopamine (DA) levels, including metabolites, in the cerebellum of H1R-KO and WT mice. The homozygous H1R-KO mice showed impaired ELM as compared with the heterozygous H1R-KO and WT mice. The performance of homozygous H1R-KO mice in the ELM task was primarily driven by familiarity-based memory processes. While the homozygous H1R-KO mice performed similar to the heterozygous H1R-KO and WT mice during the acquisition of a PM, as measured with an accelerating rotarod, after a retention interval of 7 days their performance was impaired relative to the heterozygous H1R-KO and WT mice. These findings suggest that, both, ELM and long-term PM are impaired in the homozygous H1R-KO mice. Neurochemical assays revealed that the H1R-KO mice had significantly lower levels of AChE activity in the dentate gyrus (DG) and CA1 subregions of the hippocampus as compared with the WT mice. The homozygous H1R-KO mice also displayed significantly reduced dihydroxyphenylacetic acid (DOPAC) levels and a reduced DOPAC/DA ratio in the cerebellum, suggesting that the DA turnover in the cerebellum is decelerated in homozygous H1R-KO mice. In conclusion, homozygous H1R-KO mice display severe long-term memory deficits in, both, ELM and PM, which coincide with changes in AChE activity in the hippocampus as well as DA turnover in the cerebellum. The importance of these findings for Alzheimer's (AD) and Parkinson's disease (PD) is discussed.     

Cognitive phenotypes in Alzheimer's disease and genetic variants in ACE and IDE

Alzheimer's disease (AD) is generally considered to be a disorder primarily affecting memory. It is increasingly recognized that the clinical presentation or "cognitive phenotype" is variable. The apolipoprotein E ε4 (APOE ε4) allele has been associated with an amnestic presentation, but does not appear to fully explain the high prevalence of family history within this group. We examined polymorphisms in the genes ACE and IDE in relation to cognitive phenotype. In this study 276 participants with AD were categorized into 1 of 4 cognitive phenotype classifications: typical, amnestic, language, and posterior. Family history and possession of the APOE ε4 allele were most prevalent in the amnestic group. Of the 10 genetic variants of IDE, and the 3 genetic variants of ACE studied, only ACErs4291 and ACErs1800764 were nominally associated with the amnestic presentation.