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Tijms, Betty M. (author), Vromen, Ellen M. (author), Mjaavatten, Olav (author), Holstege, Henne (author), Reus, Lianne M. (author), van der Lee, Sven (author), Wesenhagen, Kirsten E.J. (author), Lorenzini, Luigi (author), Tesi, N. (author)Alzheimer’s disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187)....journal article 2024
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Zhang, M. (author), Bouland, G.A. (author), Holstege, H. (author), Reinders, M.J.T. (author)Background and Objectives - With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the...journal article 2023
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Baker, Emily (author), Leonenko, Ganna (author), Schmidt, Karl Michael (author), Hill, Matthew (author), Myers, Amanda J. (author), Shoai, Maryam (author), de Rojas, Itziar (author), Tesi, N. (author), Holstege, H. (author)Introduction Both late-onset Alzheimer’s disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability....journal article 2023
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Zhang, M. (author), Ganz, Andrea B. (author), Rohde, Susan (author), Lorenz, Linda (author), Rozemuller, Annemieke J.M. (author), Reinders, M.J.T. (author), Hulsman, M. (author), Hoozemans, Jeroen J.M. (author), Holstege, H. (author)INTRODUCTION: Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance?. METHODS: The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian...journal article 2023
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van der Lee, S.J. (author), De Rojas, I. (author), Holstege, H. (author), Hulsman, M. (author), Reinders, M.J.T. (author), Tesi, N. (author), van Rooij, Jeroen (author), Zhao, Y. (author), Zhang, X. (author)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<br/>genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found...journal article 2022
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Mol, Merel O. (author), van der Lee, S.J. (author), Hulsman, M. (author), Pijnenburg, Yolande A.L. (author), Scheltens, Phillip (author), Seelaar, Harro (author), van Swieten, John C. (author), Kaat, Laura Donker (author), Holstege, H. (author), van Rooij, Jeroen G.J. (author)Background: Many families with clinical early-onset Alzheimer’s disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be...journal article 2022
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Holstege, H. (author), Hulsman, M.J. (author), Charbonnier, Camille (author), Grenier-Boley, Banjamin (author), Quenez, Olivier (author), Grozeva, Detelina (author), van Rooij, Jeroen G.J. (author), Reinders, M.J.T. (author), van der Lee, S.J. (author)Alzheimer’s disease (AD), the leading cause of dementia, has an estimated<br/>heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome...journal article 2022
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van Bree, Elisabeth J. (author), Guimarães, Rita L.F.P. (author), Lundberg, Mischa (author), Blujdea, Elena R. (author), Rosenkrantz, Jimi L. (author), White, Fred T.G. (author), Reinders, M.J.T. (author), Holstege, H. (author), Jacobs, Frank M.J. (author)Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable...journal article 2022
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Zhang, M. (author), Ganz, Andrea B. (author), Rohde, Susan (author), Rozemuller, Annemieke J.M. (author), Bank, Netherlands Brain (author), Reinders, M.J.T. (author), Scheltens, Philip (author), Hulsman, M. (author), Hoozemans, Jeroen J.M. (author), Holstege, H. (author)Introduction: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals—are they resilient, or resistant to AD-associated neuropathologies?. Methods: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and...journal article 2022
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Holstege, H. (author), Reinders, M.J.T. (author)Genetic association studies are frequently used to study the genetic basis of numerous human phenotypes. However, the rapid interrogation of how well a certain genomic region associates across traits as well as the interpretation of genetic associations is often complex and requires the integration of multiple sources of annotation, which...journal article 2021
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author)Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with...journal article 2021
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Tesi, N. (author), Hulsman, M. (author), van der Lee, S.J. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, Natasja M. (author), Scheltens, Philip (author), Reinders, M.J.T. (author), Holstege, H. (author)Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in...journal article 2021
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Hung, Christy (author), Tuck, Eleanor (author), Stubbs, Victoria (author), van der Lee, S.J. (author), Aalfs, Cora (author), van Spaendonk, Resie (author), Scheltens, Philip (author), Hardy, John (author), Holstege, H. (author)Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis,...journal article 2021
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Tesi, N. (author), Stringa, N. (author), Hadjigeorgiou, Georgios (author), Hulsman, M. (author), van Schoor, Natasja M. (author), Ruiz, A. (author), Jansen, Iris E. (author), Holstege, H. (author), van der Lee, S.J. (author)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...journal article 2021
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Mokveld, T.O. (author), Linthorst, J. (author), Al-Ars, Z. (author), Holstege, H. (author), Reinders, M.J.T. (author)The practical use of graph-based reference genomes depends on the ability to align reads to them. Performing substring queries to paths through these graphs lies at the core of this task. The combination of increasing pattern length and encoded variations inevitably leads to a combinatorial explosion of the search space. Instead of heuristic...journal article 2020
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- van den Akker, E.B. (author), Makrodimitris, S. (author), Hulsman, M. (author), Brugman, Martijn H. (author), Nikolic, Tatjana (author), Bradley, Ted (author), Waisfisz, Quinten (author), Baas, Frank (author), Reinders, M.J.T. (author), Holstege, H. (author) journal article 2020
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Scheltens, Philip (author), van der Flier, Wiesje M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author)Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what...journal article 2020
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Rutten, Julie W. (author), Hack, Remco J. (author), Duering, Marco (author), Gravesteijn, Gido (author), Dauwerse, Johannes G. (author), Overzier, Maurice (author), van den Akker, E.B. (author), Slagboom, Eline (author), Holstege, H. (author)To determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants. The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy...journal article 2020
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Linthorst, J. (author), Meert, Wim (author), Hestand, Matthew S. (author), Korlach, Jonas (author), Vermeesch, Joris Robert (author), Reinders, M.J.T. (author), Holstege, H. (author)The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a...journal article 2020
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Wong, Tsz Hang (author), van der Lee, S.J. (author), van Rooij, Jeroen G.J. (author), Meeter, Lieke H.H. (author), Frick, Petra (author), Melhem, Shamiram (author), Seelaar, Harro (author), Ikram, M. Arfan (author), Holstege, H. (author), Hulsman, M. (author)Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum...journal article 2019
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