Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.

'523 variant and cognitive decline in older persons with ε3/3 genotype.

Objective: To interrogate a poly-T variant (rs10524523, '523) in , a gene adjacent to the gene on chromosome 19, in older persons with ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).

Methods: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. and '523 genotypes were determined from DNA from blood or brain samples.

Selection of first-line therapy in multiple sclerosis using risk-benefit decision analysis.

Objective: To integrate long-term measures of disease-modifying drug efficacy and risk to guide selection of first-line treatment of multiple sclerosis.

Methods: We created a Markov decision model to evaluate disability worsening and progressive multifocal leukoencephalopathy (PML) risk in patients receiving natalizumab (NTZ), fingolimod (FGL), or glatiramer acetate (GA) over 30 years. Leveraging publicly available data, we integrated treatment utility, disability worsening, and risk of PML into quality-adjusted life-years (QALYs).

Genetic architecture of age-related cognitive decline in African Americans.

Objective: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs).

Methods: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS.

Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans.

The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S.

Neuropsychological characteristics of child and adolescent offspring of patients with schizophrenia or bipolar disorder.

Background: Schizophrenia (SZ) and bipolar disorder (BD) are considered neurobiological disorders which share some clinical, cognitive and neuroimaging characteristics. Studying child and adolescent offspring of patients diagnosed with bipolar disorder (BDoff) or schizophrenia (SZoff) is regarded as a reliable method for investigating early alterations and vulnerability factors for these disorders. This study compares the neuropsychological characteristics of SZoff, BDoff and a community control offspring group (CC) with the aim of examining shared and differential cognitive characteristics among groups.

A multi-step classifier addressing cohort heterogeneity improves performance of prognostic biomarkers in three cancer types.

Cancer research continues to highlight the extensive genetic diversity that exists both between and within tumors. This intrinsic heterogeneity poses one of the central challenges to predicting patient clinical outcome and the personalization of treatments. Despite progress in some individual tumor types, it is not yet possible to prospectively, accurately classify patients by expected survival.

A Child's HLA-DRB1 genotype increases maternal risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) disproportionately affects women of reproductive age. During pregnancy, women are exposed to various sources of fetal material possibly constituting a significant immunologic exposure relevant to the development of SLE. The objective of this study was to investigate whether having any children who carry DRB1 alleles associated with SLE increase the risk of maternal SLE.

Personality Polygenes, Positive Affect, and Life Satisfaction.

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures.

Trans-pQTL study identifies immune crosstalk between Parkinson and Alzheimer loci.

Objective: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes.

Methods: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study. Linear regression was used to identify associations between 24 PD risk variants and protein expression.

Polygenic risk of Alzheimer disease is associated with early- and late-life processes.

Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies.

Methods: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia.

Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.

Objective: To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies.

Methods: This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses.

Genetic variants in Alzheimer disease - molecular and brain network approaches.

Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care of AD. However, owing to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extraction of actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants.

NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is neuroprotective in numerous preclinical models of neurodegeneration. Here, we show that brain nmnat2 mRNA levels correlate positively with global cognitive function and negatively with AD pathology. In AD brains, NMNAT2 mRNA and protein levels are reduced.

Current State of Immune-Based Therapies for Glioblastoma.

Glioblastoma is one of the most aggressive solid tumors, and, despite treatment options such as surgery, radiation, and chemotherapy, its prognosis remains grim. Novel approaches are needed to improve survival. Immunotherapy has proven efficacy for melanoma, lung cancer, and kidney cancer and is now a focus for glioblastoma.

Genetic and environmental factors associated with delirium severity in older adults with dementia.

Objective: To determine (1) whether delirium severity was associated with Apolipoprotein E (APOE) genotype status and occupational complexity, a measure of cognitive reserve, in individuals with delirium superimposed on dementia; and (2) whether decline in delirium severity was associated with these same factors over a post-acute care (PAC) stay.

Methods: Control group data (n = 142) from a completed randomized clinical trial were used to address the aims of the study. Delirium severity was calculated by combining items from the Confusion Assessment Method and the Montreal Cognitive Assessment.

Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer's disease.

The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer's disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) phases GO/2 (n=678).

Higher brain BDNF gene expression is associated with slower cognitive decline in older adults.

Objectives: We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults.

Methods: Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex.

Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis.

Background: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS).

Objective: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk.

Methods: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS.

Fine mapping the region reveals a common intronic insertion associated to HDL-C.

Background: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein ( gene. In this study, we investigate the association of and HDL-C further to identify novel, independent variants associated with HDL-C in humans.

Methods: We performed a meta-analysis of HDL-C within the region using 59,432 individuals imputed with 1000 Genomes data.

Association of APOE with tau-tangle pathology with and without β-amyloid.

This study tested the hypothesis that the association of apolipoprotein E (APOE) with paired helical filament tau (PHF-tau) tangle pathology differs in brains with and without β-amyloid. Participants were 1056 autopsied individuals from 2 clinical-pathologic cohort studies of aging and Alzheimer's disease (AD), the Religious Orders Study, and the Rush Memory and Aging Project. Neuropathologic measures were obtained using immunohistochemistry targeting β-amyloid and PHF-tau tangles in 8 brain regions.

A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome.

Despite recent progress in the characterization of genetic loci associated with multiple sclerosis (MS) risk, the ubiquitous linkage disequilibrium operating across the genome has stalled efforts to distinguish causative variants from proxy single-nucleotide polymorphisms (SNPs). Here, we have identified through fine mapping and meta-analysis EVI5 as the most plausible disease risk gene within the 1p22.1 locus.