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Sökning: WFRF:(Mecocci P) > (2020-2022)

  • Resultat 1-10 av 18
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  • 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 Science and Business Media LLC. - 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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  • Bellenguez, C, et al. (författare)
  • New insights into the genetic etiology of Alzheimer's disease and related dementias
  • 2022
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 ε4 allele.
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  • Elvsashagen, T, et al. (författare)
  • The genetic architecture of human brainstem structures and their involvement in common brain disorders
  • 2020
  • Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4016-
  • Tidskriftsartikel (refereegranskat)abstract
    • Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
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  • Boccardi, V, et al. (författare)
  • Metabolic Score for Insulin Resistance (METS-IR) and Circulating Cytokines in Older Persons: The Role of Gender and Body Mass Index
  • 2022
  • Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Inflammation, along with aging processes, contributes to the development of insulin resistance (IR), but the roles of different inflammatory and other cytokines in this process remain unclear. Thus, we aimed to analyze the association between several plasma cytokines with IR as evaluated by the metabolic score for insulin resistance, METS-IR. Methods: We measured the plasma concentrations of thirty cytokines from a cohort of older persons and analyzed their role as independent factors for IR. We used regression analyses adjusted for known IR-associated factors (including age, gender, cholesterol levels, and BMI) to find the determinants of IR. Results: The study evaluated 132 subjects, mostly women (82F/50M), slightly overweight, and with a mean age of 78.5 ± 6.5 years. In the overall population, IL-15 significantly and negatively correlates with METS-IR (r = −0.183, p = 0.036). A regression model showed that the association between IL-15 and METS-IR was significantly modulated by gender and BMI (R2: 0.831). Only in women, EGF, Eotaxin and MCP-1 significantly correlated with METS-IR even after controlling by age (EGF, r = 0.250 p = 0.025; Eotaxin, r = 0.276 p = 0.13; MCP-1, r = 0.237, p = 0.033). Furthermore, regression models showed that these molecules were associated with METS-IR and were strongly mediated by BMI. Conclusions: Our results indicate the association between cytokines and IR has to be interpreted in a gender-specific manner. In women, EGF, Eotaxin, and MCP-1 circulating levels are associated with METS-IR being BMI a significant mediator. Understanding the role of gender in the relationship between cytokines and IR will help to define individualized preventive and treatment interventions to reduce the risk of age-related metabolic disorders.
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  • Kurbatova, N., et al. (författare)
  • Urinary metabolic phenotyping for Alzheimer's disease
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer's Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer's Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer's Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer's Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer's pathology in previous studies.
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