GAB2 is not associated with late-onset Alzheimer’s disease in Chinese Han

It has recently been shown that GAB2 alleles modify the risk for late-onset Alzheimer disease (LOAD) in apolipoprotein E (ApoE)ε4 allele carriers in a genome-wide association study. Some studies subsequently in Caucasians population, though not all, have demonstrated that GAB2 polymorphisms might be associated with LOAD susceptibility. The aim of this study is to evaluate the reported polymorphisms (rs2373115 and rs1385600) and GAB2 haplotypes (rs2373115–rs1385600) for an interaction with the ApoEε4 allele in a cohort of Chinese LOAD. We conducted a case–control study in 292 LOAD and 227 non-demented controls from the Chinese Han population. Our study does not find any association between the two tested SNPs and GAB2 haplotypes and LOAD or any synergetic interaction between the SNPs and ApoE either. However, since the sample size required to show this point is large, our finding needs to be confirmed by a large independent sample of Chinese population.     

The neuronal sortilin-related receptor gene SORL1 and late-onset Alzheimer’s disease

Recent studies indicate that two clusters of single nucleotide polymorphisms in the neuronal sortilin-related receptor gene (SORL1) are causally associated with late-onset Alzheimer’s disease (AD). At the cellular level, SORL1 is thought to be involved in intracellular trafficking of amyloid precursor protein. When this gene is suppressed, toxic amyloid β production is increased, and high levels of amyloid β are associated with a higher AD risk. Extending the cellular findings, gene expression studies show that SORL1 is differentially expressed in AD patients compared with controls. Furthermore, several genetic studies have identified allelic and haplotypic SORL1 variants associated with late-onset AD, and these variants confer small to modest risk of AD. Taken together, the evidence for SORL1 as a causative gene is compelling. However, putative variants have not yet been identified. Further research is necessary to determine its utility as a diagnostic marker of AD or as a target for new therapeutic approaches.     

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

The aim of the study was to identify chromosomal regions that may harbor putative genetic variants influencing age at onset in familial late-onset Alzheimer’s disease (LOAD). Data from a genome-wide scan that included genotyping of APOE were analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age at onset of 73.3 years multiply affected by LOAD. Two-point and multipoint analyses were conducted using variance component methods using 376 microsatellite markers with an average intermarker distance of 9.3 cM. Family-based test of association was also conducted for the same set of markers. Age at onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ɛ4 lowered the age at onset by 3 years. Several candidate loci were identified. Using linkage analysis strategy, the highest logarithm of odds (LOD) scores were obtained using a conservative definition of LOAD at 5q15 (LOD = 3.1), 17q25.1 (LOD = 2.94), 14q32.12 (LOD = 2.36), and 7q36.3 (LOD = 2.29) in a model that adjusted for APOE-ɛ4 and other covariates. Both linkage and family-based association identified 17p13 as a candidate region. Family-based association analysis showed markers at 12q13 (p = 0.00002), 13q33 (p = 0.00043), and 14q23 (p = 0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age at onset of late onset Alzheimer’s disease. The novel loci at 5q15, 17q25.1, 13q33, and 17p13 and the previously reported loci at 7q36.3, 12q13, 14q23, and 14q32 need further investigation. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Joseph H. Lee, Sandra Barral, Rong Cheng, and Inara Chacon contributed equally to this work.     

Genetic association of BACE1 gene polymorphism C786G with late-onset Alzheimer’s disease in Chinese

β-Amyloid (Aβ) peptides are derived from the end oproteolytic processing of amyloid precursor protein (APP) and play a key role in the pathogenesis of Alzheimer’s disease (AD). β-Site APP-cleaving enzyme 1 ([BACE1] also known as β-secretase) is responsible for cleaving APP to generate neurotoxic Aβ peptides in patients with AD. The BACE1 gene is located on chromosome 11q23.3, near the recently identified region with increased lod scores for AD. The biological functional and genetic association studies indicated that the BACE1 gene might be a genetic risk factor for late-onset Alzheimer’s disease (LOAD). To investigate an association between the BACE1 C786G polymorphism and sporadic LOAD in Chinese, we examined 105 LOAD patients and 130 healthy controls. Our results showed higher frequency of the 786G-allele in LOAD patients (38.6%) than that in controls (28.5%), and a statistical significance was observed for an association of the G-allele with LOAD (odds ratio [OR]=1.58, 95% confidence interval [CI] 1.07–2.23, p=0.02). We also found a synergetic interaction between the G-allele and apolipoprotein E allele 4 (APOE ε4) status on the risk of LOAD (OR=1.91, 95% CI 1.23–2.95, p=0.003). These results suggest that BACE1 gene polymorphism C786G might act as an APOE ε4 allele-dependent risk factor for developing LOAD in Chinese.     

Point mutation in exon 4 of presenilin-1 gene and early-onset familial Alzheimer disease

INTRODUCTION Alzheimer disease can be classified into familial Alzheimer disease (FAD) and sporadic Alzheimer disease (SAD)[1]. Among FAD, ear- ly-onset FAD(EOFAD) is a familialform in which the onset ofsymptoms occurs before the age of 60 to 65 years, an…     

A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease

Journal of Neurology -     

A novel ARC gene polymorphism is associated with reduced risk of Alzheimer’s disease

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aβ application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aβ(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c)?=?0.005; OR?=?0.74; 95?% CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.     

APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer’s disease

Current evidence shows that apolipoprotein E(APOE), apolipoprotein CI(APOC1) and low density lipoprotein receptor-related protein(LRP) variations are related to late-onset Alzheimer's disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer's disease patients. We performed a 30-month longitudinal cohort study to investigate the relationship between Alzheimer's disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer's disease were recruited form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess patients' cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE ε4 carriers compared with non-carriers. In addition, the APOE ε4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive impairment progression group. In conclusion, APOE ε4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ε4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer's disease.     

Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer’s disease in Mexican families

The etiology of Alzheimer’s disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and β-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer’s disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.A summary of the results of this study was presented at the Congress of the Human Genome Organization (HUGO, April, 2003). Workshop Abstract No 11: pp 14.     

SLC26A4 gene polymorphism and late-onset Alzheimer’s disease in a Han Chinese population from Qingdao,China

In a recent genome-wide association study,the SLC26A4 gene rs2072064 polymorphism was found to be associated with late-onset Alzheimer’s disease in Caucasians.Here,we investigated this association in a large Northern Han Chinese cohort consisting of 599 sporadic late-onset Alzheimer’s disease patients and 598 healthy controls matched for sex and age in a Northern Han Chinese population from Qingdao,China.Genotyping by the polymerase chain reaction-ligase detection reaction revealed that there were significant differences in the genotype (P=0.017) and allele (P=0.007) frequencies of the rs2072064 polymorphism between late-onset Alzheimer’s disease patients and controls.The A allele of this polymorphism was significantly associated with a reduced risk of late-onset Alzheimer’s disease (odds ratio (OR)=0.792,95% confidence interval (CI)=0.670-0.937,P=0.007).When the data were stratified by the apolipoprotein E ε4 status,there was a significant difference only among apolipoprotein E ε4 non-carriers (genotypic P=0.001,allelic P=0.001).Furthermore,the association between rs2072064 and late-onset Alzheimer’s disease remained significant by logistic regression analysis after adjustment for age,gender,and the apolipoprotein E ε4 carrier status (dominant model:OR=0.787,95% CI=0.619-1.000,P=0.050;recessive model:OR=0.655,95% CI=0.448-0.959,P=0.030;additive model:OR=0.792,95% CI=0.661-0.950,P=0.012).These findings suggest that SLC26A4 is a susceptibility gene for late-onset Alzheimer’s disease in a Northern Han Chinese population from the Qingdao area.     

PEN–2 gene mutation in a familial Alzheimer’s disease case

Genetic evidence indicates a central role of cerebral accumulation of β–amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with γ–secretase activity, the enzymatic complex generating Aβ. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age–matched controls (n = 253), sporadic AD (SAD, n = 256) and familial AD (FAD, n = 140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele ε4 of apolipoprotein E than controls. The pathogenic role of the PEN–2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role.*These two authors contributed equally to the paper.     

The role of α-synuclein gene multiplications in early-onset Parkinson’s disease and dementia with Lewy bodies

Summary. Background: A triplication of the α-synuclein gene was found to cause autosomal dominant Lewy body disease in two distinct families. Method: We searched for alterations of α-synuclein gene dosage and analysed the entire coding region for point mutations in 54 dementia with Lewy body disease (DLB) and in 103 young onset Parkinson’s disease (PD) patients from Central Europe. Results: We could not detect any quantitative alterations in the gene dosage of α-synuclein. Mutational screening of the entire coding region of α-synuclein revealed only one silent mutation V3V (adenine9guanine) in one case. Conclusions: Thus, this phenomenon appears not to be a major cause in the pathogenesis of sporadic DLB and young onset PD in this European population.     

Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer’s disease in Chinese Han population

Abstract

Objective:

We conducted a case–control study to investigate whether TREM2 polymorphism (rs75932628-T) was associated with late onset Alzheimer’s disease in Chinese Southern Han population.

Methods:

PCR-restriction fragment length polymorphism assay was performed to genotype rs75932628 in 279 cases with late onset Alzheimer’s diseases patients and 346 control subjects in Shanghai and Nanjing.

Results:

There was no rs75932628-T variant detected in our sample. However, APOE?4 was shown closely associated with the risk of Alzheimer’s disease (Chi-square?=?60·288, P?=?0·000).

Conclusion:

Our study suggested that TREM2 (rs75932628-T) was rare in Chinese Han population. Further association studies with large samples are needed to further study the association of TREM2 with late-onset Alzheimer’s disease.     

Association of MTHFR gene polymorphism C677T with susceptibility to late-onset alzheimer’s disease

Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer's disease (AD). Because the methylenetetrahydrofolate reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy concentrations, the association between the C677T polymorphism and AD remains inconclusive. To determine whether the MTHFR gene C677T polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we have investigated 104 sporadic LOAD patients and 130 healthy controls. The strong associations of the TT genotype and T-allele with LOAD (p 0.001, OR 5.73 95% CI 1.85-17.72, and p 0.002, OR 1.89 95% CI 1.25-2.86) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the TT genotype only in the APOE epsilon4 noncarriers (chi2=8.92, df=1, p=0.003) and with the T-allele in either group (chi2=5.18, df=1, p=0.023 and chi2=5.53, df=1, p=0.019) were seen. These results suggest that as an APOE epsilon4 allele-dependent risk factor, the MTHFR gene C677T polymorphism is involved in developing LOAD in Chinese.     

Environmental factors in the development and progression of late-onset Alzheimer’s disease

Late-onset Alzheimer’s disease (LOAD) is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.     

TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism

Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer’s disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV–VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features.