SORL1 is genetically associated with Alzheimer disease in a Japanese population

A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-?4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.     

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese

Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid β (Aβ) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population.     

No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals

The leucine-rich repeat kinase–2 (LRRK2) gene has been regarded as 1 of the most common genetic causes of Parkinson's disease (PD). We hypothesized that LRRK2-susceptible allele(s) for PD might pose a risk for Alzheimer's disease (AD). In this study, we screened 12 LRRK2 gene variants in 2 independent cohorts from southwestern China (341 AD patients and 435 normal individuals) and eastern China (297 AD patients and 384 normal individuals), to discern the potential association between this gene and AD. No variant was identified to be associated with AD in either case-control sample. As both of the cohorts were of Han Chinese origin, we combined the LRRK2 variant data for the 2 sample sets together (a total of 638 AD patients and 819 normal individuals) and still found no association between the LRRK2 gene and AD, suggesting that LRRK2 gene variants may not affect the development of AD in Han Chinese individuals.     

Participation of the Cowpea mosaic virus protease in eliciting extreme resistance

Extreme resistance of Arlington line cowpea (Vigna unguiculata) to Cowpea mosaic virus (CPMV) is under control of a dominant locus designated Cpa. We transiently expressed, using Tomato bushy stunt virus (TBSV) vectors and Agrobacterium tumefaciens, in nearly isogenic Cpa/Cpa and cpa/cpa cowpea lines, sequences from RNA1, the larger of two CPMV genomic RNAs. Activation of a Cpa-specific response mapped to the CPMV 24K protease (24KPro). Mutational analysis of the 24KPro gene implicated protease activity, rather than 24KPro structure, in Cpa-mediated recognition of CPMV invasion. A 24KPro with alanine replacing the active site cysteine [24KPro(C-A)], but not wildtype 24KPro, accumulated after agroinfiltration of the corresponding binary vector constructions into Cpa/Cpa cowpea. In cpa/cpa cowpea, both protease versions accumulated, with 24KPro(C-A) in greater abundance. Thus, enzymically active 24KPro was recognized by both cowpea genotypes, but in Cpa/Cpa cowpea the suppression of 24KPro accumulation was very strong, consistent with extreme resistance to CPMV.     

No association between high temperature requirement 1 (HTRA1) gene polymorphisms and Alzheimer's disease

High temperature requirement 1 (HTRA1) gene is a plausible risk factor in Alzheimer's disease (AD) as it encodes a protease known to degrade amyloid-β peptide. Here we have studied whether single nucleotide polymorphisms (SNPs) in the HTRA1 gene or its nearby regions associated with AD in a large clinic-based case-control cohort originating from Finland. We did not observe significant association of the HTRA1 SNPs with AD among the whole case-control cohort or age-at-onset risk effect among AD patients.     

Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population

We performed case-control studies using 2 Canadian cohorts to examine the role of 10 promising Alzheimer's disease (AD) loci identified in recent genomewide association studies. Patients age 65 years and older diagnosed with AD at baseline (prevalent cases) or who developed AD during follow-up assessments (incident cases) were compared with control subjects with no cognitive impairment. Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype. The incident case study comparing patients who developed AD during longitudinal observation (n = 152) with participants with no cognitive impairment found that rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of developing AD in this population. In addition, pooled analysis of our AD patients confirmed that CR1, TOMM40, BIN1, and CD33 contribute to late-onset AD susceptibility, in addition to apolipoprotein E.     

microRNA-24a is required to repress apoptosis in the developing neural retina

Programmed cell death is important for the proper development of the retina, and microRNAs (miRNAs) may be critical for its regulation. Here, we report that miR-24a is expressed in the neural retina and is required for correct eye morphogenesis in Xenopus. Inhibition of miR-24a during development causes a reduction in eye size due to a significant increase in apoptosis in the retina, whereas overexpression of miR-24a is sufficient to prevent apoptosis. We show that miR-24a negatively regulates the proapoptotic factors caspase9 and apaf1, demonstrating a role for miRNAs in the regulation of apoptosis during normal development.     

Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes (P = 0.016) and allele frequency (P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ?4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ?4 allele in the risk of developing AD.     

Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African–American and Isreali–Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of β amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45–70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR = 0.26, 95% CI: 0.08–0.86; and HR = 0.40, 95% CI: 0.16–0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.     

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.     

Genetic variation in APOE cluster region and Alzheimer's disease risk

We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3′ to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.     

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain β-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TT-homozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between. Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TT-homozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences β-amyloid metabolism. CYP46 C-carriers are privileged both in terms of β-amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated.     

CAT53 and HFE alleles in Alzheimer's disease: A putative protective role of the C282Y HFE mutation

Alzheimer's disease (AD) is a complex disorder, resulting from an interaction between environmental and genetic factors. Several studies addressed the association of AD with MHC class-I polymorphisms without definite conclusions. Considering the remarkable linkage disequilibrium at the MHC region, it is not possible to assume if the reported associations result from a direct effect of the respective genes or result from associations with other closely linked genes transmitted in an extended conserved haplotype. Recent evidence pointed to CAT53, a newly described gene located at the MHC class-I region in the vicinity of HLA-C, as a candidate modifier gene in AD. CAT53 encodes a phosphatase 1 nuclear inhibitor protein and is strongly expressed in brain regions involved in memory and AD. Here we tested the potential association of CAT53 with the risk of developing AD and searched for potential haplotypic associations of CAT53 with two common mutations (H63D, C282Y) in the HFE gene, also located at chromosome 6p21.3. The allele frequencies of these mutations in AD patients were compared to the expected frequencies previously established in the normal Portuguese population. We detected only one polymorphism (G>A) in CAT53, at position 8232, in intron 17. Screening of this polymorphism in 113 AD patients and 82 controls did not show any evidence of association, therefore excluding the hypothetical role of the CAT53 polymorphism as modifier in AD. In contrast, we found a significant negative association of the C282Y HFE mutation with AD, thus supporting a putative protective role of this protein variant in neurodegeneration.     

Genetic variation in GOLM1 and prefrontal cortical volume in Alzheimer's disease

Replications of the association between APOE-ε4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD.     

Lack of association between CALHM1 p.P86L variation and Alzheimer's disease in the Han Chinese population

In recent years, several studies have reported calcium homeostasis modulator 1 (CALHM1) was a potential gene related to Alzheimer's disease (AD) susceptibility. However, whether CALHM1 p.P86L variation (rs2986017), a risk factor for AD is still controversial. Two independent studies have been performed in the Chinese population and the conclusions have not reached an agreement. In the present study, we performed a replication case–control study in 1301 Chinese subjects including 452 sporadic AD patients and 849 unrelated age and gender-matched controls, to determine whether this variation is a risk factor for AD in the Han Chinese population. We failed to replicate the positive association between the CALHM1 p.P86L variation and AD. In addition, we also examined p.P86L variation in a meta-analysis of 5 independent studies performed in Chinese and other Asian populations and negative association was found in total 2328 AD patients and 2865 controls. Our study suggests that CALHM1 p.P86L variation may not be an AD susceptibility factor in the Han Chinese population.     

Deletion of AcMNPV AC16 and AC17 results in delayed viral gene expression in budded virus infected cells but not transfected cells

This study investigated the combined function of the Autographa californica multiple nucleopolyhedrovirus overlapping genes ac16 (BV/ODV-E26, DA26) and ac17. Ac17 is a late gene and the promoter is within the ac16 open reading frame. A double ac16-ac17 knockout virus was generated to assess the function of each gene independently or together. Loss of ac17 did not affect viral DNA synthesis but budded virus (BV) production was reduced. Deletion of both ac16-ac17 resulted in reduced viral DNA synthesis and a further reduction in BV production. In BV infected Sf9 cells, viral gene expression was delayed up to 12 h in the absence of both AC16 and AC17 but not if either gene was present. Cells infected by transfecting viral DNA, by-passing the BV particle, exhibited no delay in gene expression from the double knockout virus. AC16 and AC17 are therefore required for rapid viral gene expression in cells infected by BV.     

Exome array study did not identify novel variants in Alzheimer's disease

Genetic variants so far identified explain a small fraction of the overall inherited risk of Alzheimer's disease (AD). We aimed to identify novel genetic variants in AD using exome array that contains comprehensive panel. We genotyped 295,988 variants in 1005 subjects (400 AD cases and 605 controls) using Axiom Exome Genotyping Array that contains a pool of variants discovered in over 16 major human exome sequencing initiatives. Logistic regression analysis and the sequence kernel association optimal test were performed. The APOE, APOC1, and TOMM40 showed significant associations with AD in the single variant analysis. However, no significant association of other variants with AD was observed. This exome array study failed to identify novel genetic variants in AD.     

Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract

Alzheimer's disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (p_c = 0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p_c = 0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p_c = 0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset.     

TREM2 is associated with the risk of Alzheimer's disease in Spanish population

Two recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD). Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ?4 allele. However, this association has not been replicated in any independent studies to date. The allelic frequency of rs75932628 varies according to the population from 0.02% to 0.63% among healthy controls. In an attempt to replicate the association between rs75932628-T and AD risk, we genotyped rs75932628 in a cohort of 504 AD subjects and 550 healthy controls from a Spanish population. Rs75932628-T showed a minor allele frequency of 0.3% among this cohort. Interestingly, in our study, rs75932628-T was found exclusively in 1.4% of AD cases (7/504), including 4 early-onset AD cases, and in none of the controls (n = 0/550). Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD.     

Is KIF24 a genetic risk factor for Frontotemporal Lobar Degeneration?

Linkage analysis identified a region on chromosome 9p associated with Frontotemporal Lobar Degeneration (FTLD). A detailed analysis of candidate genes lying in this region demonstrated an association with Ubiquitin Associated Protein (UBAP)1. The distribution of five Single Nucleotide Polymorphisms (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083, has been determined in a population of 284 patients diagnosed with FTLD, including 245 with behavioural variant Frontotemporal Dementia (bvFTD), 23 with Progressive Aphasia and 16 with Semantic Dementia, compared with 318 age-matched controls. A statistically significant increased frequency of the KIF24 rs17350674 AA genotype was observed in patients compared with controls (7.4 versus 2.5%; P = 0.0068, OR: 3.63, CI: 1.58–8.35). Considering each syndrome separately, similar results where obtained in bvFTD versus controls (7.7 versus 2.5%, P = 0.005, OR: 3.26, CI: 1.40–7.57). Stratifying for gender, a statistically significant increased genotypic frequency was observed in female patients as compared with female controls (8.9 versus 2.5%, P = 0.008, OR: 3.85, CI: 1.36–10.93). In silico analysis predicted that the substitution from W to L caused by the rs17350674 affects protein function (P < 0.05). The KIF24 rs17350674 polymorphism likely acts as a risk factor for sporadic FTLD, but a replication study would be needed to confirm these preliminary findings.