Alzheimer's Disease Susceptibility Research Articles

Sex differences in gene expression patterns associated with the APOE4 allele.

Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain area*sex* genotype for PSEN2, a risk factor gene for AD. Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.

Association between rs10046, rs1143704, rs767199, rs727479, rs1065778, rs1062033, rs1008805, and rs700519 polymorphisms in aromatase (CYP19A1) gene and Alzheimer's disease risk: a systematic review and meta-analysis involving 11,051 subjects.

CYP19A1 enzyme (aromatase) encoded by CYP19A1 (cytochrome p450 family 19 subfamily a member 1) gene plays a key role in the biosynthesis of estrogen, which has been significantly associated with Alzheimer's disease (AD). To ascertain whether CYP19A1 gene polymorphisms are correlated with the susceptibility to AD, we performed this systematic review and meta-analysis of currently available studies. A comprehensive literature search was conducted by using PubMed, Embase, and Web of Science databases and the Cochrane Library. The association was evaluated by using odds ratios (ORs) and 95% confidence intervals (CIs) through Stata software (version 12.0). A total of eight articles including 39 case-control studies with 11,051 subjects including 3215 AD cases and 7836 controls were involved in this meta-analysis. By pooling all eligible studies, we detected that rs10046, rs1143704, rs767199, and rs727479 polymorphisms in CYP19A1 gene were significantly associated with AD risk. A significant association between rs10046 polymorphism and AD risk was found under allele contrast, homozygous (TT vs CC: OR = 1.17, 95%CI = 1.02-1.34, I2= 0.0%, P = 0.026), and dominant genetic models. In addition, we observed an association between with rs1143704 polymorphism under heterozygous and dominant genetic models (TT+TA vs AA: OR = 1.36, 95%CI = 1.03-1.79, I2= 0.0%, P = 0.033). Similar results were found in rs767199 and rs727479 polymorphisms, while null results were found for other polymorphisms. This systematic review and meta-analysis suggested that the rs10046, rs1143704, rs767199, and rs727479 polymorphisms in CYP19A1 gene significantly increase AD susceptibility. In addition, our results demonstrated that homozygous TT genotype in rs10046, dominant AA and AG genotypes in rs767199, homozygous TT genotype in rs727479, and dominant TT and TA genotypes in rs1143704 might be the susceptibility genotypes for AD, while no associations were observed between rs1065778, rs1062033, rs1008805, and rs700519 polymorphisms and AD susceptibility.

Does SCFD1 rs10139154 Polymorphism Decrease Alzheimer’s Disease Risk?

Α number of genetic variants have been associated with Alzheimer's disease (AD) susceptibility. Sec1 family domain-containing protein 1 (SCFD1) gene polymorphism rs10139154 has recently been implicated in the risk of developing amyotrophic lateral sclerosis (ALS). Similarities in the pathogenetic cascade of both diseases have also been described. The present study was designed to evaluate the possible contribution of SCFD1 rs10139154 to AD. A total of 327 patients with AD and an equal number of healthy controls were included in the study and genotyped for rs10139154. With logistic regression analyses, rs10139154 was examined for the association with the risk of developing AD. In the recessive mode, SCFD1 rs10139154 was associated with a decreased risk of developing AD (odds ratio (OR) (95% confidence interval (CI)) = 0.63 (0.40-0.97), p = 0.036). The current study provides preliminary evidence of the involvement of SCFD1 rs10139154 in the risk of developing AD.

Attitudes and completion of advance care planning: Assessing the contribution of health beliefs about Alzheimer's disease among Israeli laypersons.

The purpose of this study was to assess laypersons' attitudes and completion of advance care planning (ACP) and to examine associations with sociodemographic characteristics and health beliefs on Alzheimer's disease. A cross-sectional telephone survey was conducted during April and May 2017, with a sample of 514 Israeli adults, aged 18 years and above. A structured, pretested questionnaire assessing participants' awareness, attitudes, and completion of ACP, as well as health beliefs on Alzheimer's disease (subjective knowledge, susceptibility, and worry), and sociodemographic factors, was used. Two-fifths of the participants had heard of at least one of the terms: advance directives or durable power of attorney. Overall, participants expressed positive attitudes toward ACP. Results of regression models showed that gender, religiosity, and subjective knowledge of Alzheimer's disease were statistically significant correlates of attitudes toward ACP. Adding health beliefs on Alzheimer's disease doubled the amount of the variance explained, from 3% to 6%. Our results support the use of cognitive models of health behavior by assessing intra-personal beliefs and knowledge to understand ACP attitudes and completion. Specifically, we demonstrated the importance of knowledge of Alzheimer's disease for ACP attitudes, suggesting the importance of including a module on the topic to ACP interventions.

Apolipoprotein E associated with reconstituted high-density lipoprotein-like particles is protected from aggregation.

Apolipoprotein E (APOE) genotype determines Alzheimer's disease (AD) susceptibility, with the APOE ε4 allele being an established risk factor for late‐onset AD. The ApoE lipidation status has been reported to impact amyloid‐beta (Aβ) peptide metabolism. The details of how lipidation affects ApoE behavior remain to be elucidated. In this study, we prepared lipid‐free and lipid‐bound ApoE particles, mimicking the high‐density lipoprotein particles found in vivo, for all three isoforms (ApoE2, ApoE3, and ApoE4) and biophysically characterized them. We find that lipid‐free ApoE in solution has the tendency to aggregate in vitro in an isoform‐dependent manner under near‐physiological conditions and that aggregation is impeded by lipidation of ApoE.

Sex differences in gene expression patterns associated with the APOE4 allele

Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain area*sex* genotype for PSEN2, a risk factor gene for AD. Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment.

Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P-tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV-1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P-tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE-ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti-herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.

Sex differences in gene expression patterns associated with the APOE4 allele

Background:TheAPOEgene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of theAPOEgene:APOE2,APOE3, andAPOE4. TheAPOE4allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males.Methods:In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for theAPOE4allele in order to identify possible sex-related differences that may be relevant to AD.Results:Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that ofAPOEinAPOE4-positive individuals. The number of these genes was much higher inAPOE4-positive females than inAPOE4-positive males, who in turn had more of such genes thanAPOE4-negative control groups.Conclusions:Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role ofAPOEwith respect to sex differences and AD.

Sirtuins in Alzheimer's Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics.

Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.

Predicting Short-term MCI-to-AD Progression Using Imaging, CSF, Genetic Factors, Cognitive Resilience, and Demographics

In the Alzheimer’s disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical management. Our goal was to develop generalizable multivariate models that integrate high-dimensional data (multimodal neuroimaging and cerebrospinal fluid biomarkers, genetic factors, and measures of cognitive resilience) for identification of MCI individuals who progress to AD within 3 years. Our main findings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments.

Genetic Analyses of Alzheimer's Disease in China: Achievements and Perspectives.

Since 2010, the Chinese have become one of the most aged populations in the world, leading to a severe burden of neurodegenerative disorders. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and has a high genetic heritability. In the past two decades, numerous genetic analyses, from linkage analyses and candidate gene studies to genome-wide association studies (GWASs) and next-generation sequencing studies, have identified dozens of AD susceptibility or causal genes. These studies have provided a comprehensive genetic view and contributed to the understanding of the pathological and molecular mechanisms of the disease. However, most of the recognized AD genetic risk factors have been reported in studies based on European populations or populations of European ancestry, and data about the genetics of AD from other populations has been very limited. As China has the largest AD population in the world and because of the remarkable genetic differences between the East and the West, deciphering the genetic basis and molecular mechanism in Chinese patients with AD may add key points to the full characterization of AD. In this review, we present an overview of the current state of AD genetic research in China, with an emphasis on genome-level studies. We also describe the challenges and opportunities for future advances, especially for in-depth collaborations, brain bank construction, and primate animal modeling. There is an urgent need to promote public awareness and increase our collaborations and data sharing.

Genetic Analysis of PICK1 Gene in Alzheimer's Disease: A Study for Finding a New Gene Target.

Background: Alzheimer's disease (AD) is a neurodegenerative disease with no effective treatment. Researchers have focused on exploring biomarkers for its early diagnosis, especially on finding a new gene target. Recent studies have shown that protein interacting with C-kinase-1(PICK1) is related to AD through regulating hippocampal synaptic plasticity. PICK1 gene polymorphisms have been identified in psychological and other related disorders.Methods: This study included 133 sporadic AD patients and 173 healthy controls. All coding exons and intron-exon boundaries of the PICK1 gene were amplified by polymerase chain reaction (PCR), which were subsequently sequenced and analyzed.Results: This is the first genetic association study to investigate the association between PICK1 gene and AD risk in Chinese Han population. Seven single nucleotide polymorphisms (SNPs) were found in our research (rs397780637, rs713729, rs2076369, rs58230476, rs7289911, rs149474436; and rs146770324 for patient M1659 only). Frequencies of the T allele (p = 0.002; OR, 0.083; 95%CI, 0.011–0.634) and TT/TC genotypes (p = 0.001) of rs149474436 were lower in AD patients than in the controls. The GG homozygotes of rs397780637 were found to be associated with an increased risk of AD (p = 0.018) in APOEε4 allele carriers, while the frequency of the T allele of rs149474436 was significantly lower among AD patients in APOEε4 non-carriers (p = 0.005).Conclusions: Our results suggest that PICK1 gene SNPs are associated with AD susceptibility in East Asian population, T allele of rs149474436 may play as a protective factor while the rs397780637 GG homozygotes may be associated with an increased risk of AD. Further studies should be considered in a larger cohort of patients with diverse demographics.

Alzheimer's disease susceptibility genes in low-grade glioma

Background and Aim: Cognitive deficits in low-grade glioma are well documented. Patients with glioma who are carriers of the apolipoprotein E (APOE) e4 allele may have increased memory problems and executive dysfunction. While APOE is ranked the number one Alzheimer's disease (AD) susceptibility gene, many other susceptibility genes have been identified in genome-wide association studies. This study aimed to analyze the expression of APOE and the next 23 ranked AD susceptibility genes in malignant gliomas to identify significantly co-occurrent genes. Materials and Methods: To identify the most important AD susceptibility genes, the AlzGene database ( http://www.alzgene.org/ ) was consulted, which displays this information and regularly updates it. To analyze AD susceptibility genes in glioma, The Cancer Genome Atlas, a project begun in 2005, was used to catalog genetic mutations responsible for cancer, employing genome sequencing and bioinformatics. The cBioPortal for cancer genomics and the UCSC Xena browser were used to analyze the data in The Cancer Genome Atlas. Results: APOE and CD33 were the only significantly co-occurrent genes in 514 low-grade glioma tumor samples. APOE was altered in 1.8% of cases and CD33 in 3%. Heatmap indicates that the two genes tend to coexpress. The most common alteration was deep deletion. The cBioPortal and the Xena browser cannot distinguish or identify the alleles of APOE or CD33. Conclusions: AD patients with one or more APOE e4 alleles, having one or more copies of the CD33 risk allele (rs3865444 C), are at increased risk of cognitive decline compared to APOE E4 carriers, no doubt reflected by the co-occurrence of APOE and CD33 alterations in the gliomas. Better understanding of the interaction of genes and cognition in glioma patients may lead to new opportunities to personalize cancer therapy.

Alzheimer's disease susceptibility genes in malignant breast tumors

Background:Cognitive problems have been reported in breast cancer patients after chemotherapy. A small group of older breast cancer survivors carrying the APOE4 gene, receiving chemotherapy, was at increased risk of long-term impairment of brain function. We have analyzed the expression of APOE and the next 23-ranked Alzheimer’s disease (AD) susceptibility genes in malignant breast tumors. We wished to determine if these 24 genes might be related to breast cancer.Methods:To identify the most important AD susceptibility genes, we consulted the ALZGENE database (www.alzgene.org/) which displays this information and regularly updates it. To analyze the effect of AD susceptibility genes on breast cancer, we used The Cancer Genome Atlas (TCGA). We analyzed TCGA data with cBioPortal for Cancer Genomics. cBioPortal provides visualization, analysis, and download of large-scale cancer genomic data sets. cBioPortal can analyze APOE in breast tumors but cannot distinguish its three alleles: E2, E3, and E4.Results:About 1.6% of the tumors had APOE amplification (copy number alteration). Two percent of the tumors had CD33 alterations. None of the tumors had APOE mutations. Two tumors had CD33 missense mutations of unknown significance. Expression heatmap shows that over- or underexpression of APOE and CD33 was correlated in most of the tumors. APOE alteration significantly co-occurred with CD33 and CD2AP.Conclusion:Alterations of certain cancer genes tend to co-occur, indicating that they may work in tandem to drive tumor formation and development. This may be the case with the co-occurring alterations of APOE, CD33, and CD2AP. It would be important to know which APOE allele(s) were co-occurrent with CD33 and CD2AP and whether co-occurrence in the tumor predicted increased risk of AD. This information could help in identification of specific risk factors for breast cancer-related cognitive decline in older women, which has important implications for oncology care.

SU32 - PATIENT-SPECIFIC AD IN VITRO MODELS FOR THE ANALYSIS OF LATE-ONSET ALZHEIMER'S DISEASE

Background Alzheimer´s Disease (AD) is the most common form of dementia. Environmental and genetic factors contribute to the risk for AD, but the underlying disease mechanisms are poorly understood. AD is genetically complex and shows heritability of up to 80%. Glia cells including astrocytes and microglia are affected in AD patients contributing to the tau pathology and the accumulation of neurotoxic amyloid as well. In recent years, Genome-Wide Association Studies (GWAS) allowed the identification of DNA variations associated with an elevated risk for AD. Together with other groups, we identified a number of AD susceptibility genes including CD33, SORL1, ABCA7 and TREM2, which highly recommends that the immune system plays a major role in onset, progression and treatment of AD. Reprogramming of EBV-transformed patient specific cell lines for the generation of induced pluripotent stem cells (iPS) enables the patient-specific differentiation into neurons, astrocytes, and microglia. Patient-specific cells can be used as a model to functionally characterize disease associated variants. Methods Blood was collected from AD patients carrying risk variants in AD susceptibility genes for the generation of iPS cells. SNP variants in those genes were genotyped based on their potential function according to literature and genomic localization (exonic non-synonymous, binding domain, or promoter affecting SNPs). Reprogrammed iPS cells carried the genetic background of a certain AD patient. Pluripotency was characterized by alkaline phosphatase staining, the expression of pluripotency markers, and the differentiation into the three germ layers. Crucial pluripotency markers are OCT4, SOX2, NANOG, KLF4, MYC, and LIN28. AD iPS cells were differentiated into astrocytes and microglia and the differentiation status was characterized by the expression of crucial glia cell markers. Further, AD susceptibility genes recently published in GWAS were analysed. Results The protein expression was successfully induced shown by immunofluorescence and western-blot analysis. Cells were also screened for the most efficient induction of the three germ layers and the induction of neural cell fates including glia cell fates. The established AD-specific iPS cell lines from AD patients represent a powerful tool for the analysis of molecular and cellular disease mechanisms. We established 4-step protocol for the generation of AD-specific microglia enabling the focused analysis of AD-associated risk variants. The protocol was verified by morphology, FACS analysis, immunofluorescence and RNA expression of crucial microglia marker, including hematopoetic lineage markers and the induction of well-described microglia markers including IBA1. The disease-specific analysis of the genetic background of AD patients represents a completely new approach for the understanding of AD genetics and AD-associated risk variants. Discussion Together, combining molecular genetics of AD for the investigation of risk variants and iPS cell technology for the generation of patient- and disease-specific stem cells provides a promising approach to characterize known disease mechanisms, to deepen the understanding of known disease mechanisms, and to discover unknown disease aspects.

<i>Cindr</i>, the <i>Drosophila</i> Homolog of the <i>CD2AP</i> Alzheimer's Disease Susceptibility Gene, is Required for Synaptic Transmission and Proteostasis

The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin-binding, adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog, cindr, enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. Here, we show that Cindr is expressed in Drosophila neurons and present at presynaptic terminals. Flies lacking cindr show impairments in synaptic maturation, as well as synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin protein and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and triggers reduction of cytosolic calcium. Studies of CD2AP mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are also inversely related to Synapsin abundance in human postmortem brains. Our results reveal novel CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure/function.

Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates with Tau pathology. In contrast, the loss of BIN1 expression in cultured cells elevates Aβ production and Tau propagation by insfluencing endocytosis and recycling. Here, we show that BIN1 accumulates adjacent to amyloid deposits in vivo. We found an increase in insoluble BIN1 and a striking accrual of BIN1 within and near amyloid deposits in the brains of multiple transgenic models of AD. The peri-deposit aberrant BIN1 localization was conspicuously different from the accumulation of APP and BACE1 within dystrophic neurites. Although BIN1 is highly expressed in mature oligodendrocytes, BIN1 association with amyloid deposits occurred in the absence of the accretion of other oligodendrocyte or myelin proteins. Finally, super-resolution microscopy and immunogold electron microscopy analyses highlight the presence of BIN1 in proximity to amyloid fibrils at the edges of amyloid deposits. These results reveal the aberrant accumulation of BIN1 is a feature associated with AD amyloid pathology. Our findings suggest a potential role for BIN1 in extracellular Aβ deposition in vivo that is distinct from its well-characterized function as an adaptor protein in endocytosis and membrane remodeling.

Association of PSEN1 rs165932 polymorphism with Alzheimer's disease susceptibility: An extensive meta-analysis

BackgroundMutations in the PSEN1 gene were found to be a causative factor with familial EOAD and PSEN1 genetic variations have the ability to alter APP metabolism. Numerous epidemiological, case-control studies have been conducted to identify the risk association between PSEN1 gene polymorphisms and Alzheimer's disease susceptibility. However, these results remain controversial. MethodsA systematic meta-analysis was performed based on previously published (Thirty seven) studies involving 12,059 participants to determine the association of rs165932 polymorphism with AD by calculating their pooled odds ratio and 95% confidence intervals under allelic, homozygote, heterozygote, dominant and recessive genetic models. Further, the publication bias was assessed by Begg's funnel plot, Egger's linear regression test and to measure the robustness of our meta-analysis, sensitivity test based on Leave one out method was also performed. Results: The analysis of rs165932 (G/T) polymorphism showed no significant association with AD risk in Caucasian, Asian and mixed ethnic populations under five genetic models. Overall, the meta-analysis demonstrated that rs165932 intronic polymorphism do not contribute to Alzheimer's disease susceptibility. ConclusionsLarge-scale case-control studies from multiple ethnic populations are needed for better understanding of PSEN1 gene polymorphisms in disease pathogenesis.

Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor.

Synapse dysfunction and loss represent critical early events in the pathophysiology of Alzheimer’s disease (AD). While extensive research has elucidated the direct synaptotoxic effects of Amyloid-β (Aβ) oligomers, less is known about how signaling pathways at the synapse are affected by Aβ. A better understanding of the cellular and molecular mechanisms underlying synaptic vulnerability in AD is key to illuminating the determinants of AD susceptibility and will unveil novel therapeutic avenues. Canonical Wnt signaling through the Wnt co-receptor LRP6 has a critical role in maintaining the structural and functional integrity of synaptic connections in the adult brain. Accumulating evidence suggests that deficient Wnt signaling may contribute to AD pathology. In particular, LRP6 deficiency compromises synaptic function and stability, and contributes to Aß production and plaque formation. Here, we review the role of Wnt signaling for synaptic maintenance in the adult brain and the contribution of aberrant Wnt signaling to synaptic degeneration in AD. We place a focus on emerging evidence implicating the LRP6 receptor as an important modulator of AD risk and pathology.

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.