23 research outputs found
PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease
Increasing evidence suggests that inflammation is one pathophysio-logical mechanism in Alzheimer's disease (AD). Recent studies have identified an association between the poly (ADP-ribose) polymerase 1 (PARP1) gene and AD. This gene encodes a protein that is involved in many biological functions, including DNA repair and chromatin remodeling, and is a mediator of inflammation. Therefore, we performed a targeted genetic association analysis to investigate the relationship between the PARP1 polymorphisms and brain micro-glial activity as indexed by [11C]PBR28 positron emission tomography (PET). Participants were 26 non-Hispanic Caucasians in the Indiana Memory and Aging Study (IMAS). PET data were intensity-normalized by injected dose/total body weight. Average PBR standardized uptake values (SUV) from 6 bilateral regions of interest (thalamus, frontal, parietal, temporal, and cingulate cortices, and whole brain gray matter) were used as endophenotypes. Single nucleotide polymorphisms (SNPs) with 20% minor allele frequency that were within +/â 20 kb of the PARP1 gene were included in the analyses. Gene-level association analyses were performed using a dominant genetic model with translocator protein (18-kDa) (TSPO) genotype, age at PET scan, and gender as covariates. Analyses were performed with and without APOE Δ4 status as a covariate. Associations with PBR SUVs from thalamus and cingulate were significant at corrected p<0.014 and <0.065, respectively. Subsequent multi-marker analysis with cingulate PBR SUV showed that individuals with the âCâ allele at rs6677172 and âAâ allele at rs61835377 had higher PBR SUV than individuals without these alleles (corrected P<0.03), and individuals with the âGâ allele at rs6677172 and âGâ allele at rs61835377 displayed the opposite trend (corrected P<0.065). A previous study with the same cohort showed an inverse relationship between PBR SUV and brain atrophy at a follow-up visit, suggesting possible protective effect of microglial activity against cortical atrophy. Interestingly, all 6 AD and 2 of 3 LMCI participants in the current analysis had one or more copies of the âGGâ allele combination, associated with lower cingulate PBR SUV, suggesting that this gene variant warrants further investigation
New insights into the genetic etiology of Alzheimer's disease and related dementias.
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease
âąSequencing of the Alzheimer disease risk locus ABCA7 is performed.âąSeveral Alzheimerâs disease risk variants are identified in the gene ABCA7.âąThree previously associated ABCA7 variants are confirmed.âąA 3âČ-UTR splice variant in ABCA7 is identified as a potential risk variant.
Several variants in the gene ABCA7 have been identified as potential causal variants for late-onset Alzheimerâs disease (LOAD). In order to replicate these findings, and search for novel causal variants, we performed targeted sequencing of this gene in cohorts of non-Hispanic White (NHW) and African-American (AA) LOAD cases and controls. We sequenced the gene ABCA7 in 291 NHW LOAD cases and 103 controls. Variants were prioritized for rare, damaging variants and previously reported variants associated with LOAD, and were follow-up genotyped in 4076 NHW and 1157 AA cases and controls. We confirm three previously associated ABCA7 risk variants and extend two of these associations to other populations, an intronic variant in NHW (P=3.0Ă10â3) (originally reported in a Belgian population), and a splice variant originally associated in the Icelandic population, which was significantly associated in the NHW cohort (P=1.2Ă10â6) and nominally associated in the AA cohort (P=0.017). We also identify a 3âČ-UTR splice variant that segregates in four siblings of one family and is nominally associated with LOAD (P=0.040). Multiple variants in ABCA7 contribute to LOAD risk
SUCLG2 identified as both a determinator of CSF AÎČ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.
Cerebrospinal fluid amyloid-beta 1-42 (AÎČ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on AÎČ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between AÎČ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5Ă10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 Ă 10(-5)), with the strongest effect being observed in APOE-Δ4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 Ă 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of AÎČ1-42
Common variants in Alzheimerâs disease and risk stratification by polygenic risk scores
Genetic discoveries of Alzheimerâs disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery nâ=â409,435 and validation size nâ=â58,190). Here, we add six variants associated with Alzheimerâs disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimerâs disease patients in APOE É4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimerâs disease