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Background: Cognitive abilities tend to decline in advanced age. A novel protective factor of cognitive decline in advanced age is purpose-in-life (PiL), a trait-like tendency to derive life meanings and purpose. However, whether PiL protects against cognitive decline in late-middle-age is unclear. Hence, we examined the association between PiL and perceived cognitive decline, one of the earliest detectable cognitive symptoms before the onset of cognitive impairment. Furthermore, we used a machine learning approach to investigate whether PiL is a robust predictor of cognitive decline when considered with the known protective and risk factors for cognition.Methods: PiL was assessed with a 10-item questionnaire and perceived cognitive decline with the Cognitive Function Instrument among 5,441 Emory Healthy Aging Study participants, whose mean age was 63 and 51% were employed. Association between PiL and perceived cognitive decline was examined with linear regression adjusting for relevant confounding factors. Elastic Net was performed to identify the most robust predictors of cognitive decline.Results: Greater PiL was associated with less perceived cognitive decline after adjusting for the relevant factors. Furthermore, Elastic Net modeling suggested that PiL is a robust predictor of cognitive decline when considered simultaneously with known protective (education, exercise, enrichment activities) and risk factors for cognition (depression, anxiety, diagnosed medical, mental health problems, smoking, alcohol use, family history of dementia, and others).Limitation: This is a cross-sectional study.Conclusions: PiL is a robust protective factor of perceived cognitive decline observed as early as middle age. Thus, interventions to enhance PiL merit further investigation. [ABSTRACT FROM AUTHOR]

Background: Targeted resequencing offers a cost-effective alternative to whole-genome and whole-exome sequencing when investigating regions known to be associated with a trait or disease. There are a number of approaches to targeted resequencing, including microfluidic PCR amplification, which may be enhanced by multiplex PCR. Currently, there is no open-source software that can design next-generation multiplex PCR experiments that ensures primers are unique at a genome-level and efficiently pools compatible primers. Results: We present MPD, a software package that automates the design of multiplex PCR primers for next-generation sequencing. The core of MPD is implemented in C for speed and uses a hashed genome to ensure primer uniqueness, avoids placing primers over sites of known variation, and efficiently pools compatible primers. A JavaScript web application (http://multiplexprimer.io) utilizing the MPD Perl package provides a convenient platform for users to make designs. Using a realistic set of genes identified by genome-wide association studies (GWAS), we achieve 90% coverage of all exonic regions using stringent design criteria. Using the first 47 primer pools for wet-lab validation, we sequenced ~25Kb at 99.7% completeness with a mean coverage of 300X among 313 samples simultaneously and identified 224 variants. The number and nature of variants we observe are consistent with high quality sequencing. Conclusions: MPD can successfully design multiplex PCR experiments suitable for next-generation sequencing, and simplifies retooling targeted resequencing pipelines to focus on new targets as new genetic evidence emerges. [ABSTRACT FROM AUTHOR]

Background: The genetic basis of amyotrophic lateral sclerosis (ALS) is not entirely clear. While there are families with rare highly penetrant mutations in Cu/Zn superoxide dismutase 1 and several other genes that cause apparent Mendelian inheritance of the disease, most ALS occurs in families without another affected individual. However, twin studies suggest that all ALS has a substantial genetic basis. Herein, we estimate the genetic contribution to ALS in a clinically ascertained case series from the United States. Methodology/Principal Findings: We used the database of the Emory ALS Center to ascertain individuals with ALS along with their family histories to determine the concordance among parents and offspring for the disease. We found that concordance for all parent-offspring pairs was low (<2%). With this concordance we found that ALS heritability, or the proportion of the disease explained by genetic factors, is between 40 and 45% for all likely estimates of ALS lifetime prevalence. Conclusions/Significance: We found the lifetime risk of ALS is 1.1% in first-degree relatives of those with ALS. Environmental and genetic factors appear nearly equally important for the development of ALS. [ABSTRACT FROM AUTHOR]

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals.We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non‐AD cases, including 495 (16.5%) self‐identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data‐driven multivariate Gaussian mixture of regressions.Distinct effects of race were found in different groups. Total Tauand phospho181‐Tau were lower among AA individuals in all groups (p < 0.0001), and Aβ42 was markedly lower in AA controls compared with white controls (p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2‐decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker‐positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%).Although the risk of dementia is higher, data‐driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit). [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological evidence suggests air pollution adversely affects cognition and increases the risk of Alzheimer’s disease (AD), but little is known about the biological effects of fine particulate matter (PM2.5, particulate matter with aerodynamic diameter ≤2.5 μm) on early predictors of future disease risk. OBJECTIVES: We investigated the association between 1-, 3-, and 5-y exposure to ambient and traffic-related PM2.5 and cerebrospinal fluid (CSF) biomarkers of AD. METHODS: We conducted a cross-sectional analysis using data from 1,113 cognitively healthy adults (45-75 y of age) from the Emory Healthy Brain Study in Georgia in the United States. CSF biomarker concentrations of Aβ42, tTau, and pTau, were collected at enrollment (2016-2020) and analyzed with the Roche Elecsys system. Annual ambient and traffic-related residential PM2.5 concentrations were estimated at a 1-km and 250-m resolution, respectively, and computed for each participant's geocoded address, using three exposure time periods based on specimen collection date. Associations between PM2.5 and CSF biomarker concentrations, considering continuous and dichotomous (dichotomized at clinical cutoffs) outcomes, were estimated with multiple linear/logistic regression, respectively, controlling for potential confounders (age, gender, race, ethnicity, body mass index, and neighborhood socioeconomic status). RESULTS: Interquartile range (IQR; IQR=0.845) increases in 1-y [β:-0.101; 95% confidence interval (CI): -0.18, -0.02] and 3-y (β:-0.078; 95% CI: -0.15, -0.00) ambient PM2.5 exposures were negatively associated with Aβ42 CSF concentrations. Associations between ambient PM2.5 and Aβ42 were similar for 5- y estimates (β:-0.076; 95% CI: -0.160, 0.005). Dichotomized CSF variables revealed similar associations between ambient PM2.5 and Aβ42. Associations with traffic-related PM2.5 were similar but not significant. Associations between PM2.5 exposures and tTau, pTau tTau/Aβ42, or pTau/Aβ42 levels were mainly null. CONCLUSION: In our study, consistent trends were found between 1-y PM2.5 exposure and decreased CSF Aβ42, which suggests an accumulation of amyloid plaques in the brain and an increased risk of developing AD. [ABSTRACT FROM AUTHOR]

The analysis of human whole-genome sequencing data presents significant computational challenges. The sheer size of datasets places an enormous burden on computational, disk array, and network resources. Here, we present an integrated computational package, PEMapper/PECaller, that was designed specifically to minimize the burden on networks and disk arrays, create output files that are minimal in size, and run in a highly computationally efficient way, with the single goal of enabling whole-genome sequencing at scale. In addition to improved computational efficiency, we implement a statistical framework that allows for a base by base error model, allowing this package to perform as well or better than the widely used Genome Analysis Toolkit (GATK) in all key measures of performance on human whole-genome sequences. [ABSTRACT FROM AUTHOR]

Abstract: Paraoxonase-1 (PON1) is a serum arylsulfatase that metabolizes organophosphate pesticides and protects low-density lipoprotein from oxidation. Case-control studies of PON1 genetic variants in Alzheimer''s disease (AD) and Parkinson''s disease (PD) have revealed some positive albeit inconsistent associations with 2 PON1 coding polymorphisms: Q192R (rs662) and L55M (rs854560). Because AD and PD exist along a spectrum of disorders with shared epidemiologic, clinical, and pathologic features, here we evaluated PON1 variants in a cohort of 746 AD, 566 PD, 132 AD-PD, and 719 cognitively normal age-matched controls. In the combined AD and Caucasian PD cohorts we had 80% power to detect a relative risk of at least 1.25 and 1.35, respectively, for each polymorphism. We found no association between 2 PON1 coding polymorphisms and AD in African Americans or Caucasians, and no association with PD or AD-PD in Caucasians. There was also no evidence of an interaction between PON1 and apolipoprotein E for any of these diseases. Our results suggest that either these functional PON1 polymorphisms are not associated with AD and PD spectrum disorders, or that the relative risk conferred is small. [Copyright &y& Elsevier]

Depression has been associated with a higher risk of Alzheimer's disease (AD) in several prospective studies; however, mechanisms underlying this association remain unclear. We examined genetic correlation between depression and AD using linkage disequilibrium score regression. We then tested for evidence of causality between depression and AD using Mendelian randomization and genome-wide association study results. Subsequently, cis and trans quantitative trait locus analyses for the depression genome-wide association study signals were performed to resolve the genetic signals to specific DNA methylation sites, brain transcripts, and proteins. These transcripts and proteins were then examined for associations with AD and its endophenotypes. Finally, the associations between depression polygenic risk score and AD endophenotypes were examined. We detected a significant genetic correlation between depression and AD, suggesting that they have a shared genetic basis. Furthermore, we found that depression had a causal role in AD through Mendelian randomization but did not find evidence for a causal role of AD on depression. Moreover, we identified 75 brain transcripts and 28 brain proteins regulated by the depression genome-wide association study signals through quantitative trait locus analyses. Of these, 46 transcripts and seven proteins were associated with rates of cognitive decline over time, AD pathologies, and AD diagnosis in two separate cohorts, thus implicating them in AD. In addition, we found that a higher depression polygenic risk score was associated with a faster decline of episodic memory over time. Depression appears to have a causal role in AD, and this causal relationship is likely driven, in part, by the 53 brain transcripts and proteins identified in this study. [ABSTRACT FROM AUTHOR]

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression. [ABSTRACT FROM AUTHOR]

Fragile X--associated tremor/ataxia syndrome (FXTAS) is a debilitating late-onset neurodegenerative disease in premutation carriers of the expanded CGG repeat in FMR1 that presents with a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism [P. J. Hagerman, R. J. Hagerman, Ann. N. Y. Acad. Sci. 1338, 58-70 (2015); S. Jacquemont et al., JAMA 291, 460-469 (2004)]. Here, we performed whole-genome sequencing (WGS) on male premutation carriers (CGG55-200) and prioritized candidate variants to screen for candidate genetic modifiers using a Drosophila model of FXTAS. We found 18 genes that genetically modulate CGG-associated neurotoxicity in Drosophila,suchas Prosbeta5 (PSMB5), pAbp (PABPC1L), e(y)1 (TAF9), and CG14231 (OSGEPL1). Among them, knockdown of Prosbeta5 (PSMB5) suppressed CGG-associated neurodegeneration in the flyaswellasinN2A cells. Interestingly, an expression quantitative trait locus variant in PSMB5, PSMB5rs11543947-A, was found to be associated with decreased expression of PSMB5 and delayed onset of FXTAS in human FMR1 premutation carriers. Finally, we demonstrate evidence that PSMB5 knockdown results in suppression of CGG neurotoxicity via both the RAN translation and RNA-mediated toxicity mechanisms, thereby presenting a therapeutic strategy for FXTAS. [ABSTRACT FROM AUTHOR]

Cognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain. We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously. We found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10−7) that was robust to adjustment for cell type proportions (p = 8.52 × 10−7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10−6) and working (p = 2.54 × 10−7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology. Differential methylation of CLDN5 , a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer's disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option. • A large cohort was searched for carriers of APOE LoF variants • Seven APOE LoF variant carriers, including five controls, were identified • Two ε3/ε4 controls with LoF variants on ε4 had normal amyloid at ages 76 and 90 years • ε4 appears to act via the gain of function; ε4 loss may protect against Alzheimer's disease The apolipoprotein E (APOE) ε4 allele strongly increases the risk for Alzheimer's disease. Chemparathy et al. identified seven carriers of APOE loss-of-function (LoF) variants, including two controls with LoF variants on ε4 and normal amyloid at ages 76 and 90 years. The knockdown of ε4 may protect against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral β-amyloid (Aβ) in patients with Alzheimer’s disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer’s disease with heavy Aβ deposition yet substantially diminished high-affinity binding of 3H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro 3H-PIB binding and 3H-PIB autoradiography. The PIB-refractory subject met the histopathological criteria for AD. However, cortical tissue from this case contained more vascular β-amyloidosis, higher levels of insoluble Aβ40 and Aβ42, and a higher ratio of Aβ40:Aβ42 than did tissue from the nine comparison AD cases. Furthermore, cerebral Aβ from the PIB-refractory subject displayed an unusual distribution of low- and high-molecular weight Aβ oligomers, as well as a distinct pattern of N- and C-terminally truncated Aβ peptides in both the soluble and insoluble cortical extracts. Genetically, the patient was apolipoprotein-E3/4 heterozygous, and exhibited no known AD-associated mutations in the genes for the β-amyloid precursor protein, presenilin1 or presenilin2. Our findings suggest that PIB may differentially recognize polymorphic forms of multimeric Aβ in humans with Alzheimer’s disease. In addition, while the prevalence of PIB-refractory cases in the general AD population remains to be determined, the paucity of high-affinity binding sites in this AD case cautions that minimal PIB retention in positron-emission tomography scans of demented patients may not always rule out the presence of Alzheimer-type Aβ pathology. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions. Methods: A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene's surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues. Results: Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1. Conclusions: We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes. [ABSTRACT FROM AUTHOR]

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease. [ABSTRACT FROM AUTHOR]

The transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis -acting expression quantitative trait loci (cis -eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we employ a nonparametric Bayesian method that was originally proposed for genetic prediction of complex traits, which assumes a data-driven nonparametric prior for cis -eQTL effect sizes. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R 2 for transcriptomic data and the TWAS power over PrediXcan when ≥1% cis -SNPs co-regulate gene expression and gene expression heritability ≤0.2. In real applications, the nonparametric Bayesian method fitted transcriptomic imputation models for 57.8% more genes over PrediXcan, thus improving the power of follow-up TWASs. We implement both parametric PrediXcan and nonparametric Bayesian methods in a convenient software tool "TIGAR" (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWASs using individual-level or summary-level GWAS data. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder influenced by a complex interplay of environmental, epigenetic, and genetic factors. DNA methylation (5mC) and hydroxymethylation (5hmC) are DNA modifications that serve as tissue-specific and temporal regulators of gene expression. TET family enzymes dynamically regulate these epigenetic modifications in response to environmental conditions, connecting environmental factors with gene expression. Previous epigenetic studies have identified 5mC and 5hmC changes associated with AD. In this study, we performed targeted resequencing of TET1 on a cohort of early-onset AD (EOAD) and control samples. Through gene-wise burden analysis, we observed significant enrichment of rare TET1 variants associated with AD (p = 0.04). We also profiled 5hmC in human postmortem brain tissues from AD and control groups. Our analysis identified differentially hydroxymethylated regions (DhMRs) in key genes responsible for regulating the methylome: TET3, DNMT3L, DNMT3A, and MECP2. To further investigate the role of Tet1 in AD pathogenesis, we used the 5xFAD mouse model with a Tet1 KO allele to examine how Tet1 loss influences AD pathogenesis. We observed significant changes in neuropathology, 5hmC, and RNA expression associated with Tet1 loss, while the behavioral alterations were not significant. The loss of Tet1 significantly increased amyloid plaque burden in the 5xFAD mouse (p = 0.044) and lead to a non-significant trend towards exacerbated AD-associated stress response in 5xFAD mice. At the molecular level, we found significant DhMRs enriched in genes involved in pathways responsible for neuronal projection organization, dendritic spine development and organization, and myelin assembly. RNA-Seq analysis revealed a significant increase in the expression of AD-associated genes such as Mpeg1, Ctsd, and Trem2. In conclusion, our results suggest that TET enzymes, particularly TET1, which regulate the methylome, may contribute to AD pathogenesis, as the loss of TET function increases AD-associated pathology. [Display omitted] • Variants in Tet1 are associated with human early-onset Alzheimer's disease. • 5hmC profiles and gene expression dysregulation are associated with AD in mice and human. • Heterozygous knockout of Tet1 in 5xFAD mice increases AD-associated pathology. • Increased expression of Trem2 and Fcer1g are observed in sporadic AD and 5xFAD/Tet1(+/−) mice. [ABSTRACT FROM AUTHOR]

A review of the article "The strength of PEMapper/PECaller lies in unbiased calling using large sample sizes" by H. Richard Johnston which appeared in the periodical " Proceedings of the National Academy of Sciences of the United States of America (PNAS), on September 15, 2017 is presented.

Background: African Americans have been reported to have a higher prevalence of Alzheimer's disease (AD) than Caucasians, but etiology-specific AD biomarkers have not been systematically analyzed in older African Americans. Coexisting cerebrovascular disease may also contribute to this increased prevalence. We hypothesized that cerebrospinal fluid (CSF) biomarkers of amyloid, neurodegeneration, and endothelial dysfunction would differ between older African Americans and Caucasians with normal cognition and cognitive impairment associated with AD. Methods: We prospectively recruited 135 older Americans to undergo detailed clinical, neuropsychological, genetic, magnetic resonance imaging (MRI), and CSF analysis from 2013 to 2015 at Emory University (Atlanta, GA, USA). We compared levels of CSF markers for β-amyloid (Aβ42, Aβ40), total and phosphorylated tau (t-tau and p-tau181, respectively), endothelial dysfunction (soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1), α-synuclein, and neurodegeneration (neurofilament light chain [NfL]), as well as MRI markers, for hippocampal atrophy and cerebrovascular disease (white matter hyperintensity [WMH] volume). Results: Sixty-five older African Americans (average age, 69.1 years) and 70 older Caucasians (average age, 70.8 years) were included. After adjusting for demographic variables, AD risk alleles, and cognitive function, older African Americans had lower CSF levels of p-tau181 (difference of 7.4 pg/ml; 95% CI, 3.7-11.2 pg/ml; p < 0.001), t-tau (difference of 23.6 pg/ml; 95% CI, 9.5-37.7; p = 0.001), and Aβ40 (difference of 1.35 ng/ml; 95% CI, 0.29-2.42 ng/ml; p = 0.013) despite similar levels of Aβ42, NfL, WMH volume, and hippocampal volume. Cognitively impaired African Americans also had lower CSF t-tau/Aβ42 (difference of 0.255 per 1-SD change in composite cognition; 95% CI, 0.100-0.409; p = 0. 001) and p-tau181/Aβ42 (difference of 0.076 per 1-SD change in composite cognition; 95% CI, 0.031-0.122; p = 0.001). These could not be explained by measured biomarkers of non-AD processes, but African Americans may be more susceptible than Caucasians to the cognitive effects of WMH. Conclusions: Despite comparable levels of CSF Aβ42 and Aβ42/Aβ40, cognitive impairment in African Americans is associated with smaller changes in CSF tau markers but greater impact from similar WMH burden than Caucasians. Race-associated differences in CSF tau markers and ratios may lead to underdiagnosis of AD in African Americans. [ABSTRACT FROM AUTHOR]

Background: TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer's disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case-control analyses in a total of 906 LOAD cases vs. 2,487 controls. Results: We identified significant LOAD risk association with p.L211P (p = 0.01, OR = 1.27, 95%CI = 1.05-1.54) and suggestive association with p.W191X (p = 0.08, OR = 1.35, 95%CI = 0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk. Conclusions: Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur a and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur a in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur a forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Abstract: The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1−/− animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally motivated learning. [Copyright &y& Elsevier]

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in NTNG1. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (β = −0.27, 95% CI = (−0.35, −0.19), p = 1.29 × 10−10) and rs10881463 (β = −0.20, 95% CI = (−0.27, −0.13), p = 3.40 × 10−8). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4−NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis. [ABSTRACT FROM AUTHOR]