Gerard D Schellenberg

..Others have shown that SNP6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk for Guam neuro-degenerative disorders by regulating MAPT expression...

..Identification of additional late-onset genes will require larger samples, more sophisticated analysis methods, and large-scale positional cloning efforts...

..Another critical lesson is that clinical, molecular, and statistical scientists need to work closely on disease projects to succeed in solving the complex problems of common genetic disorders...

..Diagnostic specificity and detailed analysis of the autism phenotype is critical for identifying autism loci...

..5, and approximately 8.5%, respectively. These results provide evidence that APOE and other loci modify onset in AD caused by PS2 mutation...

..Our data suggest that there is a significant physiological link between apoE and AbetaPP, as well as between apoE and tau in neurologically healthy, cognitively intact individuals...

..These observations diminish the possibility that loci in the TOMM40 gene may have a major effect on the risk for LOAD in Caucasians...

..These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration...

..To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) epsilon4 allele...

..We evaluated the effects of different methods of haplotype frequency estimation, and the use of marker phase information, on linkage analysis of a multi-SNP cluster in a candidate region for Alzheimer's disease (AD)...

..To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP)...

..However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations...

..Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis...

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..0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE epsilon4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia...

..Lewy body pathology (LBP) is a common finding in Alzheimer's disease (AD), but the pathophysiology for this coexistent pathology remains unclear...

..CONCLUSIONS: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD...

..Genetic influences on the development of late-onset Alzheimer disease (LOAD) are heterogeneous and ill defined...

..Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS...

..More generally, this study also demonstrates the value of searching for modifier loci in existing datasets previously used to identify primary causal variants for complex disease traits...

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..The location of the chromosome 16 signal suggests a candidate gene, CDH13, a T-cadherin expressed in the brain, which has been implicated in previous SNP studies of autism and ADHD...

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..The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood...

..Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease...

..These developmental and species-specific differences in the regulation and distribution of tau isoforms may be important to the understanding of normal and pathologic tau isoform expression...

..However, LRRK2 mutations appear to be rare among Japanese patients with PD...

..This work uncovers novel candidate genes that prevent tau toxicity, as well as genes previously implicated in tau-mediated neurodegeneration...

..Functional polymorphisms in tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) can affect immune response, inflammation, tissue injury, and possibly the susceptibility to Alzheimer disease (AD)...

..We demonstrate the feasibility of this molecular haplotyping procedure by generating apolipoprotein E (APOE) haplotypes from 100 unrelated subjects...

..The SUT-1/UNC-34 protein-protein interaction plays a role in both the normal function of UNC-34 and in the tau-induced phenotype. Thus, we have found a conserved molecular pathway participating in tau neurotoxicity in C. elegans...

..The identification of sut-2 as a gene required for tau neurotoxicity in C. elegans may suggest new neuroprotective strategies capable of arresting tau pathogenesis in tauopathy disorders...

..There is limited information regarding children's risk of Alzheimer disease (AD) if both parents are affected...

..We also obtained weak evidence of linkage to chromosome 10 at the same location as a previous report of linkage but found no evidence for linkage of LOFAD age-at-onset loci to chromosomes 9, 12, or 21...

..However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings...

..Incidence estimates for the United States are few and vary with the population sampled and study design; we present data that will contribute to a consensus of these rates...

..Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of tau-induced neurodegeneration and identification of genes and compounds that inhibit pathological tau formation...

..Apolipoprotein E is polymorphic in the human population. APOE4 has previously been reported to correlate with symptomatic oral and genital herpes disease...

..CONCLUSIONS: Ex vivo measures of oxidation improved the prediction of carotid artery disease status, suggesting that this is an important determinant of atherosclerotic risk in this older population...

..92). This finding suggests a shared genetic basis of these two traits and that they may be most promising for future gene mapping and for extending pedigrees by phenotyping additional relatives...

..Reduced task-associated MTL activation that does not correlate with either visuospatial perspective or task performance suggests that MTL dysregulation occurs prior to clinical symptoms of dementia in APOE*4 carriers...

..FTDP-17 highlights the association between splicing mutations and the pronounced variability in pathology as well as phenotype that is characteristic of inherited disorders...

..Thus, TDP-43 is essential for viability, and mild reduction in TDP-43 function is sufficient to cause motor deficits without degeneration of motor neurons...

..An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis...

..These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Abeta metabolism...

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..Vitamins C and E, dietary antioxidants, scavenge free-oxygen radical products that may depress PON1 activity. Therefore, we evaluated the relationship between dietary vitamin C and E intake and PON1 activity...

..The data suggest that SF2/ASF has both essential and regulatory roles, whereas Tra2beta has a supporting role in exon 10 splicing...

..The effects of paraoxonase (PON1) activity and of genetic variation in the PON1 promoter and coding region on carotid artery disease (CAAD) were investigated...

..A subset of familial PD exhibits anticipation, the cause of which is unknown. The aim of this study was to determine if anticipation was due to parkin mutation dosage...

..Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition...

..Thus, although it is unlikely that AUTS2 is an autism susceptibility gene for idiopathic autism, it may be the gene responsible for the disorder in the twins studied here...

..Substantially larger samples than are currently available would be required to resolve this question. G5460(A/T) variants were also investigated and found not to be associated with Alzheimer disease...

..Insoluble tau from cortical regions also contained 1N3R tau. Thus, the R5L mutation causes a progressive supranuclear palsy phenotype, presumably by a gain-of-function mechanism...

..A significant gender x APOE epsilon4 interaction was seen for change in performance on short delay cued recall. These results suggest that APOE epsilon4 is associated with cognitive decline differently in older adult men and women...

..Thus, risk variants on different H1 htSNP haplotypes and protective variants on H2 contribute to population risk for PSP...

..7-15.5; HR 3.3, 95% CI 1.4-8.1)). These findings indicate that clinical AD is a result of early life as well as later life risk factors, and that genetic predisposition to the disease may modify the constellation of predictors...

..Additionally, the 3' splice site of E10 is weak and requires exon splicing enhancer elements for efficient E10 inclusion. Thus far, tau FTDP-17 splicing mutations affect six predicted cis-regulatory sequences...

..We found that PON1 activity was correlated with HDL traits in controls and with LDL- and VLDL-related traits in cases. We hypothesize differences in the joint regulation of PON1 and lipoproteins in cases and controls...

..Neither is significantly associated with Reelin alleles. Our results are not consistent with a major role for Reelin alleles in liability to autism...

..This mutation sheds light on a novel mechanism by which over-expression of 4-repeat tau leads to disease. Based on our current findings, we propose a novel mechanism by which intronic mutations can lead to frontotemporal dementia...

..Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease...

..Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs...

..However, the strong association between heterozygosity and PPA raises new questions about its cause and the role of PrP in other neurodegenerative diseases...

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..Autism is a heritable neurodevelopmental disorder characterized biologically by enlargement of the head and brain and abnormalities of serotonin neurotransmission...

..We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD...

..The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders...

..Future studies investigating EN2 should consider how the association of variants in this gene with autism could be influenced by differences in phenotype and possible interactions with genotypes at other autism candidate genes...

..These findings may further our understanding of VLDLR function, its ligand APOE, and ultimately the pathogenesis of CAAD in the general population...

..Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA...

..Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1)...

..Therefore, although we cannot exclude the possibility that the samples in the two studies are intrinsically different, our data from our sample argue against a major role for HOXA1 (His)73(Arg) in liability to autism...

..We present a comprehensive sequence analysis of parkin in control subjects...

..Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates...

..Likewise, identification of trans-factors may lead to protein targets such as kinases that are also therapeutic targets. ..