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Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans.

ABSTRACT: BACKGROUND:Less is known about the genetic basis of Alzheimer's disease (AD) in African Americans (AAs) than in non-Hispanic whites. METHODS:Whole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD-related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1037 cases and 1869 controls from the Alzheimer Disease Genetics Consortium (ADGC). RESULTS:Forty-four single nucleotide polymorphisms (SNPs) from WES passed filtering criteria and were successfully genotyped. Nominally significant (P < .05) association to AD was observed with two African-descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (P = .014) and rs149979685 (P = .037). These associations were replicated in the ADGC sample (rs144662445: P = .0022, odds ratio [OR] = 2.75; rs149979685: P = .0022, OR = 3.61). CONCLUSIONS:Because AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism.

SUBMITTER: Logue MW

PROVIDER: S-EPMC4253055 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Tau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans.

Project description:We studied the effect of two rare mutations (rs144662445 and rs149979685) in the A-kinase anchoring protein 9 (AKAP9) gene, previously associated with Alzheimer disease (AD) in African Americans (AA), on post-translational modifications of AD-related pathogenic molecules, amyloid precursor protein (APP) and microtubule-associated protein Tau using lymphoblastoid cell lines (LCLs) from 11 AA subjects with at least one AKAP9 mutation and 17 AA subjects lacking these mutations. LCLs were transduced by viral vectors expressing causative AD mutations in APP or human full-length wild type Tau. Cell lysates were analyzed for total APP, A?40, and total and T181 phospho-Tau (pTau). AKAP9 mutations had no effect on A?40/APP, but significantly increased pTau/Tau ratio in LCLs treated with phosphodiesterase-4 inhibitor rolipram, which activates protein kinase A. Proteomic analysis of Tau interactome revealed enrichment of RNA binding proteins and decrease of proteasomal molecules in rolipram-treated cells with AKAP9 mutations. This study shows the impact of rare functional AKAP9 mutations on Tau, a central mechanism of AD pathogenesis, in LCLs derived from AD and control subjects.

| S-EPMC5928172 | biostudies-literature

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

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TREM2 is associated with increased risk for Alzheimer's disease in African Americans.

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| S-EPMC4426167 | biostudies-literature

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

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Plasma Biomarkers of Alzheimer's Disease in African Americans.

Project description:Background/objectiveThe aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans.MethodsWe evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (A?42, tau, IL6, IL10, TNF?) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations.ResultsPlasma tau levels were higher in AD when adjusted for biological and technical covariates. APOE?4 was associated with lower plasma A?42 and tau levels. Older age was associated with higher plasma A?42, tau, and TNF?. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with A?42.ConclusionWe identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and A?42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

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Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.

Project description:Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression.

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Identification of Alzheimer's disease-associated rare coding variants in the ECE2 gene.

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Identification of rare variants in Alzheimer's disease.

Project description:Much progress has been made in recent years in identifying genes involved in the risk of developing Alzheimer's disease (AD), the most common form of dementia. Yet despite the identification of over 20 disease associated loci, mainly through genome wide association studies (GWAS), a large proportion of the genetic component of the disorder remains unexplained. Recent evidence from the AD field, as with other complex diseases, suggests a large proportion of this "missing heritability" may be due to rare variants of moderate to large effect size, but the methodologies to detect such variants are still in their infancy. The latest studies in the field have been focused on the identification of coding variation associated with AD risk, through whole-exome or whole-genome sequencing. Such variants are expected to have larger effect sizes than GWAS loci, and are easier to functionally characterize, and develop cellular and animal models for. This review explores the issues involved in detecting rare variant associations in the context of AD, highlighting some successful approaches utilized to date.

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Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility.

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| S-EPMC5725144 | biostudies-literature

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