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  • Jones, Lesley, et al. (författare)
  • Convergent genetic and expression data implicate immunity in Alzheimer's disease
  • 2015
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
  • Escott-Price, Valentina, et al. (författare)
  • Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
  • 2014
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 9:6, s. e94661-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
  • Lambert, J-C, et al. (författare)
  • Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
  • 2013
  • Ingår i: Molecular Psychiatry. - 1359-4184 .- 1476-5578. ; 18:4, s. 461-470
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 x 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A beta plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma A beta 42/A beta 40 ratio (best signal, P=5.4 x 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
  • Wang, R., et al. (författare)
  • Do cardiovascular risk factors explain the link between white matter hyperintensities and brain volumes in old age? : A population-based study
  • 2014
  • Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 21:8, s. 1076-1082
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: White matter hyperintensities (WMHs) and brain atrophy frequently coexist in older people. However, it is unclear whether the association between these two brain lesions is dependent on the aging process, a vascular mechanism or genetic susceptibility. It was therefore investigated whether the association between load of WMHs and brain atrophy measures is related to age, vascular risk factors (VRFs) or the APOE-epsilon 4 allele. Methods: This population-based study included 492 participants (age >= 60 years, 59.6% women) free of dementia and stroke. Data on demographics, VRFs and APOE genotypes were collected through interviews, clinical examination and laboratory tests. WMHs on magnetic resonance images were assessed using manual visual rating and automatic volumetric segmentation. Hippocampal and ventricular volumes were manually delineated, whereas total gray matter (GM) volume was measured by automatic segmentation. Data were analyzed with multivariate linear regression models. Results: More global WMHs, assessed using either a visual rating scale or a volumetric approach, were significantly associated with lower GM volume and higher ventricular volume; the associations remained significant after adjusting for age, VRFs and the APOE-epsilon 4 allele. In contrast, the association between global WMHs and hippocampal volume was no longer significant after adjusting for age, whereas adjustment for VRFs and APOE-epsilon 4 had no influential effect. Conclusion: The association of global WMHs with lower GM volume and higher ventricular volume is independent of age, VRFs and APOE-epsilon 4 allele, suggesting that the process of cerebral microvascular disease and neurodegeneration are associated independently of the normal aging process, vascular mechanisms or genetic susceptibility.
  • Qiu, C., et al. (författare)
  • Medial temporal lobe is vulnerable to vascular risk factors in men : a population based study
  • 2012
  • Ingår i: European Journal of Neurology. - 1351-5101 .- 1468-1331. ; 19:6, s. 876-883
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: Vascular risk factors (VRFs) are known to cause cerebral microvascular disease, but evidence supporting an effect of VRFs on regional brain atrophy is mixed. We investigate whether an aggregation of VRFs is associated with volume of hippocampus and entorhinal cortex in elderly people living in the community. Methods: This cross-sectional study consists of 523 participants (age =60 years, 59.3% women) of the SNAC-K Study in central Stockholm, Sweden, who were free of clinical stroke and cognitive impairment. We collected data on VRFs through interviews, clinical examination and inpatient register system. Hippocampal and entorhinal cortex volume was manually measured on magnetic resonance images. Data were analysed with general linear regression models controlling for demographics and total intracranial volume. Results: In men, high total cholesterol and diabetes were significantly or marginally associated with smaller hippocampus and entorhinal cortex; when current smoking, binge alcohol drinking, high cholesterol and diabetes were aggregated, an increasing number of VRFs were significantly associated with decreasing volume of hippocampus and entorhinal cortex (P for linear trend <0.01). In women, none of individual VRFs or their aggregation was significantly associated with the volume of these brain regions, except former smoking that was significantly associated with a larger volume of these regions. Conclusions: Aggregation of VRFs is associated with reduced hippocampal and entorhinal cortex volume in apparently healthy elderly men, but not in women. This implies that in men, the medial temporal lobe is vulnerable to cardiovascular risk factors.
  • Sindi, S., et al. (författare)
  • Sleep disturbances and later cognitive status: a multi-centre study
  • 2018
  • Ingår i: Sleep Medicine. - : Elsevier. - 1389-9457 .- 1878-5506. ; 52:December, s. 26-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To investigate the associations between sleep disturbances in mid-life and late-life and late-life cognitive status. Methods: In four population-based studies (three Swedish studies: H70 study, Kungsholmen Project (KP) and The Swedish Panel Study of Living Conditions of the Oldest Old (SWEOLD); and one Finnish study: Cardiovascular Risk Factors, Aging and Dementia (CAIDE)), participants provided self-reports on insomnia, nightmares and general sleep problems. Late-life cognitive status was measured by the Mini Mental State Exam (MMSE). The associations between late-life sleep disturbances and cognition 3-11 years later were investigated across all studies (n = 3210). Mean baseline ages were 70 (CAIDE, H70 and SWEOLD), and 84 years (KP). Additional analyses examined the association between midlife sleep and late-life cognition using CAIDE (21 and 31 years follow-up, n = 1306, mean age 50 years), and SWEOLD (20-24 years follow-up, n = 2068, mean age 58 years). Ordered logistic regressions, adjusted for potential baseline confounders, were used in the analyses. Results: Late-life sleep disturbances were associated with poorer cognition after 3-11 years (fully adjusted beta = -0.12, 95% CI = -0.24 to -0.01). Midlife nightmares and insomnia were also associated with lower MMSE scores (fully adjusted beta = -0.28, 95% CI = -0.49 to -0.07 and beta = -0.20, 95% CI = -0.39 to -0.01), although the latter association was attenuated after adjusting for lifestyle/health-related confounders. Midlife general sleep problems were not associated with late-life MMSE performance. Conclusions: Sleep disturbances and midlife nightmares were associated with lower MMSE scores, which suggests that sleep disturbances in earlier life stages can be associated with worse late-life cognition. (c) 2017 Published by Elsevier B.V.
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