MAPT haplotype-stratified GWAS reveals differential association for AD risk variants.

Introduction: MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD).

Methods: Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci.

Results: We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance.

African American exome sequencing identifies potential risk variants at Alzheimer disease loci.

Objective: In African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes.

Methods: We identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants.

Results: Two missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk.

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria.

Human cerebral malaria (HCM) is a serious complication of infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM.

Comprehensive Screening for Disease Risk Variants in Early-Onset Alzheimer's Disease Genes in African Americans Identifies Novel PSEN Variants.

We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer's disease (EOAD) genes (APP, PSEN1, and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2:NM_000447:exon5:c.

LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways.

Background: Neuroinflammation is characterized by microglial activation and the increased levels of cytokines and chemokines in the central nervous system (CNS). Recent evidence has implicated both beneficial and toxic roles of microglia when over-activated upon nerve injury or in neurodegenerative diseases, including Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for apolipoprotein E (apoE) and amyloid-β (Aβ), which play critical roles in AD pathogenesis.