Genome-wide association study of brain arteriolosclerosis.

Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC.

Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes.

The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC).

Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role.

Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy.

To better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer's Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.

Genome-Wide Sensitivity Analysis of the Microsymbiont to Symbiotically Important, Defensin-Like Host Peptides.

The model legume species expresses more than 700 nodule-specific cysteine-rich (NCR) signaling peptides that mediate the differentiation of bacteria into nitrogen-fixing bacteroids. NCR peptides are essential for a successful symbiosis in legume plants of the inverted-repeat-lacking clade (IRLC) and show similarity to mammalian defensins. In addition to signaling functions, many NCR peptides exhibit antimicrobial activity and Bacterial resistance to these antimicrobial activities is likely to be important for symbiosis.

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study.

Background: Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD.

Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.

Introduction: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

Methods: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

Crowdsourced estimation of cognitive decline and resilience in Alzheimer's disease.

Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

Introduction: Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study.

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

Background: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).

Variant Tool Chest: an improved tool to analyze and manipulate variant call format (VCF) files.

Background: Since the advent of next-generation sequencing many previously untestable hypotheses have been realized. Next-generation sequencing has been used for a wide range of studies in diverse fields such as population and medical genetics, phylogenetics, microbiology, and others. However, this novel technology has created unanticipated challenges such as the large numbers of genetic variants.

Population substructure in Cache County, Utah: the Cache County study.

Background: Population stratification is a key concern for genetic association analyses. In addition, extreme homogeneity of ethnic origins of a population can make it difficult to interpret how genetic associations in that population may translate into other populations. Here we have evaluated the genetic substructure of samples from the Cache County study relative to the HapMap Reference populations and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).