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Sökning: WFRF:(Alcolea D)

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1.
  • de Rojas, I., et al. (författare)
  • Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
  • 2021
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic discoveries of Alzheimer’s 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 n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s 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 Alzheimer’s disease patients in APOE ɛ4 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 Alzheimer’s disease. © 2021, The Author(s).
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3.
  • Mattsson, Niklas, et al. (författare)
  • Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease
  • 2018
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P <.05) but not in Aβ+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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  • Hong, S. J., et al. (författare)
  • TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
  • 2021
  • Ingår i: Alzheimers & Dementia. - 1552-5260. ; 17:10, s. 1628-1640
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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6.
  • Lleó, A., et al. (författare)
  • Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study
  • 2019
  • Ingår i: Alzheimer's and Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 742-753
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Within-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined. Methods: We included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years. Results: CSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period. Discussion: All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau. © 2019 the Alzheimer's Association
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7.
  • van der Lee, S. J., et al. (författare)
  • A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
  • 2019
  • Ingår i: Acta Neuropathologica. - 0001-6322. ; 138:2, s. 237-250
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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8.
  • Bos, Isabelle, et al. (författare)
  • The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
  • 2017
  • Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 56, s. 33-40
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
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9.
  • Bujarrabal, V., et al. (författare)
  • Herschel/HIFI observations of high-J CO transitions in the protoplanetary nebula CRL 618
  • 2010
  • Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L3-
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims. We aim to study the physical conditions, particularly the excitation state, of the intermediate-temperature gas components in the protoplanetary nebula CRL 618. These components are particularly important for understanding the evolution of the nebula. Methods. We performed Herschel/HIFI observations of several CO lines in the far-infrared/sub-mm in the protoplanetary nebula CRL 618. The high spectral resolution provided by HIFI allows measurement of the line profiles. Since the dynamics and structure of the nebula is well known from mm-wave interferometric maps, it is possible to identify the contributions of the different nebular components (fast bipolar outflows, double shells, compact slow shell) to the line profiles. The observation of these relatively high-energy transitions allows an accurate study of the excitation conditions in these components, particularly in the warm ones, which cannot be properly studied from the low-energy lines. Results. The (CO)-C-12 J = 16-15, 10-9, and 6-5 lines are easily detected in this source. Both (CO)-C-13 J = 10-9 and 6-5 are also detected. Wide profiles showing spectacular line wings have been found, particularly in (CO)-C-12 J = 16-15. Other lines observed simultaneously with CO are also shown. Our analysis of the CO high-J transitions, when compared with the existing models, confirms the very low expansion velocity of the central, dense component, which probably indicates that the shells ejected during the last AGB phases were driven by radiation pressure under a regime of maximum transfer of momentum. No contribution of the diffuse halo found from mm-wave data is identified in our spectra, because of its low temperature. We find that the fast bipolar outflow is quite hot, much hotter than previously estimated; for instance, gas flowing at 100 km s(-1) must have a temperature higher than similar to 200 K. Probably, this very fast outflow, with a kinematic age
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10.
  • Decin, L., et al. (författare)
  • Water content and wind acceleration in the envelope around the oxygen-rich AGB star IK Tauri as seen by Herschel/HIFI
  • 2010
  • Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L4-
  • Tidskriftsartikel (refereegranskat)abstract
    • During their asymptotic giant branch evolution, low-mass stars lose a significant fraction of their mass through an intense wind, enriching the interstellar medium with products of nucleosynthesis. We observed the nearby oxygen-rich asymptotic giant branch star IK Tau using the high-resolution HIFI spectrometer onboard Herschel. We report on the first detection of (H2O)-O-16 and the rarer isotopologues (H2O)-O-17 and (H2O)-O-18 in both the ortho and para states. We deduce a total water content (relative to molecular hydrogen) of 6.6 x 10(-5), and an ortho-to-para ratio of 3:1. These results are consistent with the formation of H2O in thermodynamical chemical equilibrium at photospheric temperatures, and does not require pulsationally induced non-equilibrium chemistry, vaporization of icy bodies or grain surface reactions. High-excitation lines of (CO)-C-12, (CO)-C-13, (SiO)-Si-28, (SiO)-Si-29, (SiO)-Si-30, HCN, and SO have also been detected. From the observed line widths, the acceleration region in the inner wind zone can be characterized, and we show that the wind acceleration is slower than hitherto anticipated.
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