Apolipoprotein E and α-1-antichymotrypsin allele polymorphism in sporadic and familial Alzheimer's disease

Alzheimer disease (AD) patients with both sporadic and familial forms of AD and non-demented controls were genotyped for common polymorphisms in the signal peptide for α-1-antichymotrypsin (ACT) gene and in two different regions of apolipoprotein E (APOE) gene. The ACT TT genotype was over-represented (P=0.025) in patients with early onset of sporadic AD. In this patient's group ACT TT genotype conferred a significant crude odds ratio for the disease (OR=2.09; 95% CI=1.09–4.00, P=0.025). After adjustment for the APOE ε4 and APOE −491 genotypes, logistic regression analysis confirmed that the ACT TT genotype resulted independently associated with early onset AD (adjusted OR=2.56; 85% C.I.=1.3–5.2, P=0.009). The frequency of APOE ε4 allele was increased in AD, as expected (OR=5.92, 95% CI=3.60–9.70, P=0.0001). On the contrary, the APOE −491 A/T genotypes were not associated with AD. No preferential association of the APOE ε4 allele or APOE −491 A/T genotypes with ACT A/T alleles was observed in AD. Present findings indicated that subjects with ACT TT genotype had an increased risk of developing AD and suggested that this genotype influenced the risk of an early onset of the disease by affecting the production of ACT molecules.     

Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease

The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the regulatory regions of the apolipoprotein E (APOE) gene modify the well-established epsilon4-associated risk for Alzheimer's disease (AD). Sequencing of the APOE gene regulatory regions revealed four previously reported promoter SNPs and one novel SNP in the previously described macrophage enhancer (ME.1). In addition, we also studied the two classic allelic missense SNPs that define epsilon2/epsilon3/epsilon4 status in a case-control association study. Analysis of pair-wise linkage disequilibrium (LD) of the five regulatory region SNPs with classic APOE SNPs revealed a previously unreported 7 kb LD block covering the entire APOE gene, part of the promoter and 3' enhancer region. We report here that in a case-control association study (N=719) of the seven SNPs, the genotype at codon 112 captures all the information required to assess disease risk. To explore correlations with quantitative traits, 169 patients were studied in whom rates of cognitive decline were available. In addition to the epsilon4 allele, two regulatory region SNPs were associated with the rate of cognitive decline in AD patients. This study highlights the effect of APOE gene variation on risk of AD and rate of cognitive decline and demonstrates that a single SNP, which confers epsilon4 status, captures all of the risk of developing AD but two SNPs in the regulatory region may affect the rate of cognitive decline in AD patients.     

No association between alpha-1-antichymotrypsin polymorphism and Alzheimer's disease in Koreans

To examine the possible involvement of the alpha-1-antichymotrypsin gene (ACT) polymorphism in the manifestation of Alzheimer's disease (AD), we analyzed genotypes of the ACT and apolipoprotein E gene (APOE) among 110 Korean patients with probable AD and 209 nondemented controls. No significant difference was obtained in genotypic (chi(2)=1.98, df=2, P>0.1) and allelic frequencies (chi(2)=1.61, df=1, P>0.1) of ACT between the AD and control groups. No overexpression of the ACT A/A genotype and ACT A allele was found when we analyzed the late-onset AD patients and the early-onset AD patients, separately. Then we stratified the ACT genotypes based on the presence or absence of the APOE epsilon4 allele to evaluate the possible interaction between them. In the APOE epsilon4-negative subjects, although the ACT A allele tended to be overexpressed in the AD group, the differences in the frequencies of the ACT A allele (chi(2)=2.79, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.16, df=1, P>0.1) were not statistically significant. No significant overrepresentations of the ACT A allele (chi(2)=0.02, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.17, df=1, P>0.1) were found in the APOE epsilon4-positive subjects, either. In addition, the status of the ACT genotype did not influence the age-at-onset of AD (F=0.03, df=2, P>0.1). Therefore, the ACT polymorphism does not contribute to the development of AD independently or interactively with the APOE epsilon4 allele in Koreans.     

A polymorphism of the interleukin-1 beta gene at position +3953 influences progression and neuro-pathological hallmarks of Alzheimer's disease

Interleukin-1 (IL-1) gene polymorphisms are associated with an increased risk of Alzheimer's disease (AD) and it has been suggested that altered immune responses of the brain may play a role in the pathogenesis of the disease. Here we investigated whether IL-1beta polymorphisms affected neuro-pathological features and clinical status of AD patients with autopsy confirmed diagnosis of the disease. AD patients (n=133) were genotyped for the polymorphic regions in the apolipoprotein E epsilon (APOE epsilon) and interleukin-1beta (IL-1beta) genes. APOE epsilon4 carriers showed increased neuritic amyloid plaques (NP) and neurofibrillary tangles (NFT). The IL-1beta +3953 polymorphism influenced survival in AD patients and those with the TT genotype and without the APOE epsilon4 allele showed the shortest cumulative survival. Patients with the +3953 IL-1beta T and without the APOE epsilon4 alleles had reduced NP and NFT, a delayed ages at onset and death, but a decreased duration of the disease. On the other hand a different polymorphism of the IL-1beta gene at position -511 did not influence any AD features. Our findings suggest that IL-1beta gene by affecting brain immune responses may influence the age at onset of the disease, survival and AD progression.     

The --491 TT apolipoprotein E promoter polymorphism is associated with reduced risk for sporadic Alzheimer's disease

Homozygosity for the A allele of the -491 A/T apolipoprotein E (APOE) promoter polymorphism has recently been reported to be associated with sporadic Alzheimer's disease (AD). Two hundred and fifty one patients with AD and an equal number of controls derived from the same region in a Spanish population, were genotyped for -491 A/T and epsilon2/epsilon3/epsilon4 APOE polymorphisms. We did not detect an elevated -491 AA genotype frequency when comparing AD cases to controls. In contrast, persons homozygous for the T allele were at a significantly reduced risk of AD (odds ratio of 0.10, P=0.006). Multiple logistic regression analysis indicated that the -491 TT polymorphism added information on the risk of AD which was independent of that of the APOE epsilon4 allele.     

APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease

We have investigated whether the -86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the alpha1-antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimer's disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n=90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76-3.23; p<0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR=2.03; 95% CI: 1-4.6; p=0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD.     

Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease

We examined polymorphisms in reduced folate carrier gene (RFC1) and methylenetetrahydrofolate reductase gene (MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD (p=0.008, OR=1.312, 95%CI=1.072-1.605, and p=0.042, OR=1.383, 95%CI=1.012-1.890) were found. Further stratification of total samples by APOE epsilon4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE epsilon4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD (p=0.031, OR=1.586, 95%CI=1.042-2.414, and p=0.028, OR=2.250, 95%CI=1.074-4.712) were identified in APOE epsilon4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE epsilon4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected.     

Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease

In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer's disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the alpha1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon -17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p = 0.019) and this difference was confined to male AD patients (p = 0.002). Among male AD patients, the ACT/AA genotype was also associated with shorter disease duration before death as compared to the ACT/AT+TT genotypes (p = 0.012). These data suggest that the ACT gene may affect AAO and disease duration of AD.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Cognitive frailty: Predementia syndrome and vascular risk factors

With increasing emphasis on early diagnosis of Alzheimer disease (AD), clinical research has focused on the identification of risk factors that may be modified at a preclinical and early clinical stage of dementing disorders. Prevalence and incidence of different predementia syndromes vary as a result of different diagnostic criteria, as well as different sampling and assessment procedures. Particular interest in mild cognitive impairment (MCI) arises from the fact that MCI is thought to be a prodromal phase and therefore highly predictive of subsequent AD. Furthermore, many of the risk factors for cerebrovascular disease (CVD) and vascular dementia (VaD), including serum total cholesterol, hypertension, atherosclerosis, and apolipoprotein E (APOE) genotype have also been shown to increase the risk of AD. Both vascular factors and APOE epsilon4 allele have been associated with higher risk of AD. Some recent studies suggested further that CVD or vascular factors increased the risk of conversion of MCI to dementia. This review will focus on the possible role of vascular risk factors in modulating the risk of age-related cognitive decline, and the progression of predementia syndrome such as MCI to dementia.     

Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study

The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this -491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the -491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the -491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the -491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk.     

Effect of the APOE‐491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study

The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this ?491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population‐based case‐control study. We found that there was a modest but statistically significant effect of the ?491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the ?491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the ?491A/T polymorphism has an APOE genotype‐independent effect on plasma apolipoprotein E levels but no APOE‐independent effect on AD risk. © 2002 Wiley‐Liss, Inc.     

Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer's disease

The Apolipoprotein E (APOE) epsilon 4 allele is an important risk factor for Alzheimer's disease (AD). Given the interest in early identification of at-risk individuals, we examined memory decline as a function of APOE status and age in cognitively intact participants aged 48-77 years old (yo). Participants were grouped by age (<60 versus > or =60) and APOE (epsilon4+/-). Longitudinal analysis of several components of memory over a 2-year interval showed a significant Age-by-APOE interaction reflecting a decline in new learning for the > or =60 epsilon4+ group only. Among epsilon4+, 76% of the > or =60 participants showed a decline versus 32% of the <60, but the amount of decline in new learning over the 2-year interval within the > or =60 group was not further influenced by age. That is, the size of the 2-year change was the same for 60 and 70 year old participants. This suggests that longitudinal study of new learning is a sensitive measure for detecting early cognitive changes in at-risk individuals that precede the symptomatic onset of mild cognitive impairment and AD.     

Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease

Possession of the apolipoprotein E (APOE) epsilon4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's disease (AD). Recently, new polymorphisms in the regulatory region of the APOE gene have been described. We analysed the effects of three of these mutations (-491 AT, -427 CT and Th1/E47cs) on disease risk in a large case-control study, and tested their impacts on APOE allelic expression in brain tissues. The Th1/E47cs T allele was associated with an increased risk of occurrence of AD, while the -491 T allele was associated with a decreased risk, independently of the APOE epsilon2/epsilon3/epsilon4 polymorphism effect. However, the impact of the Th1/E47cs mutation was the strongest. The -427 CT polymorphism was not associated with the disease. In AD subjects heterozygous for the epsilon4 allele, analysis of allelic expression showed that the relative expression levels of the epsilon4 allele were higher than those of the corresponding controls. Consistent with epidemiological data, the relative level of expression of the epsilon4 allele was modified accordingly to the presence or absence of the two main promoter polymorphisms, indicating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population. These data indicate that in addition to the qualitative effect of the APOE epsilon2/epsilon3/epsilon4 polymorphisms on the AD occurrence, the quantitative variation of expression of these alleles due to functional APOE promoter mutations, is a key determinant of AD development.      

Genotype-related differences of hippocampal apolipoprotein E levels only in early stages of neuropathological changes in Alzheimer's disease

Inheritance of the epsilon4 allele of apolipoprotein E (APOE, gene; apoE, protein) represents the most common genetic risk factor for developing Alzheimer's disease (AD), but the role of apoE in AD pathogenesis is yet to be clarified. A number of studies investigating apoE expression and protein levels in AD brain in correlation to its genetic polymorphism has yielded controversial results. We designed our approach based on neuropathological characteristics of AD to investigate apoE levels in relation to the APOE genotype and AD-related neurofibrillary changes, and amyloid deposits. We determined hippocampal apoE levels by reducing sodium dodecylsulfate-polyacrylamide gel electrophoresis and immunoblotting in 70 Braak-staged and APOE-genotyped autopsy brains. In our stage-, age- and gender-matched case sample, we found a significant increase of hippocampal apoE in the APOE epsilon3 homozygotes with beginning AD-related pathology (Braak stages I and II) compared with brain samples free of neurofibrillary changes and amyloid deposits. In the APOE epsilon4 allele carriers no such increase was found. In both genotype groups, severely affected brain samples with widespread neurofibrillary changes (Braak stages V and VI) and amyloid deposits (Braak stage C) showed low apoE levels comparable to those found in unaffected brain samples (Braak stage 0).Our data suggests that the isoform-specific impact of apoE on the development of AD may be of crucial importance only in the early stages of the disease. These stages are believed to represent phases of the disease in which the beginning neurodegeneration can be compensated by plastic reorganization.     

Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus

Besides apolipoprotein E (APOE) polymorphism, whose association with Alzheimer's disease (AD) has been confirmed in most of the numerous population samples studied, other markers have been investigated. In most cases the association firstly described was not confirmed in subsequent works. Since it is important to examine these associations in as many populations as possible, we investigated APOE, APOC1, APOC2, alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) polymorphisms in a series of elderly patients with late-onset sporadic AD from Northern Italy and in a sex and age-matched control group. We could not confirm the significantly higher frequency of the ACT*A allele among carriers of APOE e*4 allele described elsewhere, although a similar trend was observed. The APOC2 and the PS-1 distributions were similar between patients and controls. However, we observed a significant difference in the genotype and allele frequencies of APOE and APOC1: patients had higher e*4 and C1*2 allele frequencies. This finding confirms the important role for APOE in AD occurrence. In addition, APOC1 seems to be an interesting marker because, though in strict linkage disequilibrium with APOE, it seems to play an independent role in AD risk. In contrast to previously reported data, plasma apoE concentrations were similar in patients and in controls. An interaction between APOE and APOC1 polymorphisms and apoE levels was observed in patients: subjects carrying the APOE E3/E2 or the APOC1 2-2 genotype have higher apoE concentrations than those who do not.     

Alzheimer病中载脂蛋白E基因与α1—抗糜蛋白酶基因的相互 …

目的 探讨中国汉族Ａｌｚｈｅｉｍｅｒ病患者中载脂蛋白Ｅ基因多态性与α１抗糜蛋白酶基因多态性之间的关系。方法 应用聚合酶链式反应（ＰＣＲ）－限制性片段长度多态性（ＲＦＬＰ）方法,在１２５例ＡＤ患者和１４０便正常人中观察发ＡＡＣＴ信号肽基因和ＡｐｏＥ基因多态性的分布,并对ＡＡＣＰ信号肽基因多态性与ＡｐｏＥ基因ε４等位基因进行关联分析。结果 （１）ＡＡＣＴ信号肽基因多态性与ＡＤ之间不存在任何关联;（２）     

Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder with possible involvement of several genetic and environmental factors. For late-onset AD (LOAD), the epsilon4 allele of apolipoprotein E (APOE) has been identified as a major susceptible gene. However, the observation that APOE epsilon4 accounted for approximately one half of the genetic variance of LOAD prompted many researchers to undertake genome surveys to identify other susceptible genes. Recently, several candidate genes such as alpha-1 antichymotrypsin (ACT) and alpha-2 macroglobulin (A2M) were reported to be associated with LOAD. To evaluate the possible association between these genes and LOAD in Korean population, we genotyped ACT A/T and A2M 5-bp deletion (exon 18) polymorphisms in 89 LOAD cases and 50 age-matched healthy controls. The frequencies of ACT A and A2M 5-bp deletion alleles in LOAD and controls were 0.39 vs. 0.37, and 0.05 vs. 0.05, respectively. Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status. Our results do not support previously reported association of ACT and A2M with LOAD, at least in Korean population.     

Short arm of chromosome 11 and sporadic Alzheimer's disease: catalase and cathepsin D gene polymorphisms

Catalase (CAT) -262 C/T promoter (rs1001179), cathepsin D (CTSD) exon 2 (rs17571), and apolipoprotein E (APOE) gene polymorphisms were studied in 242 patients with sporadic Alzheimer's disease (AD) and 421 unrelated age-, sex-, and ethnically matched control subjects from Apulia (Southern Italy). No statistically significant differences in CAT rs1001179 and CTSD rs17571 genotype and allele distribution between AD cases and healthy controls were observed for the whole AD sample, and when AD group was categorized by age at onset in early- and late-onset AD subsets. Furthermore, we did not find any statistically significant differences in rates between CAT rs1001179 and CTSD rs17571 genotypes and AD controlling for APOE e4 allele status. Our data, at present, do not support a role of two gene polymorphisms of the short arm of the chromosome 11, the CAT rs1001179 and CTSD rs17571, as a possible susceptibility factors for sporadic AD.