Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals-Reference-Cited by-同舟云学术

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals

Published:2024-07-29 Issue: Volume: Page:
ISSN:1552-5260
Container-title:Alzheimer's & Dementia
language:en
Short-container-title:Alzheimer's & Dementia

Author:

Lorenzini Luigi¹²^ORCID,Collij Lyduine E.¹²³,Tesi Niccoló²⁴⁵,Vilor‐Tejedor Natàlia⁶⁷⁸⁹,Ingala Silvia¹⁰¹¹,Blennow Kaj¹²¹³,Foley Christopher¹⁴,Frisoni Giovanni B.¹⁵¹⁶,Haller Sven¹⁷¹⁸¹⁹,Holstege Henne⁴,van der van der Lee Sven⁴²⁰,Martinez‐Lage Pablo²¹,Marioni Riccardo E.²²,McCartney Daniel L.²²,O’ Brien John²³,Oliveira Tiago Gil²⁴²⁵,Payoux Pierre²⁶²⁷,Reinders Marcel⁵,Ritchie Craig²⁸²⁹,Scheltens Philip²⁰,Schwarz Adam J.³⁰,Sudre Carole H.³¹³²³³,Waldman Adam D.³⁴³⁵,Wolz Robin³⁶,Chatelat Gael³⁷,Ewers Michael³⁸,Wink Alle Meije¹²,Mutsaerts Henk J. M. M.²³⁹,Gispert Juan Domingo⁶⁷⁴⁰⁴¹,Visser Pieter Jelle²⁰⁴²⁴³⁴⁴,Tijms Betty M.²⁰⁴²,Altmann Andre⁴⁵,Barkhof Frederik¹⁴⁶

Affiliation:

1. Department of Radiology and Nuclear Medicine Amsterdam University Medical Centre, Vrije Universiteit Amsterdam The Netherlands

2. Amsterdam Neuroscience, Brain Imaging Amsterdam The Netherlands

3. Clinical Memory Research Unit Department of Clinical Sciences Malmö Lund University Lund Sweden

4. Genomics of Neurodegenerative Diseases and Aging, Human Genetics Vrije Universiteit Amsterdam Amsterdam The Netherlands

5. Delft Bioinformatics Lab Delft University of Technology Delft The Netherlands

6. Barcelonaβeta Brain Research Center (BBRC) Pasqual Maragall Foundation Barcelona Spain

7. Universitat Pompeu Fabra Barcelona Spain

8. Centre for Genomic Regulation (CRG) The Barcelona Institute for Science and Technology Barcelona Spain

9. Department of Clinical Genetics Erasmus University Medical Center Rotterdam The Netherlands

10. Department of Radiology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

11. Cerebriu A/S Copenhagen Denmark

12. Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology the Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden

13. Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

14. GE Healthcare Amersham UK

15. Laboratory Alzheimer's Neuroimaging & Epidemiology IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy

16. University Hospitals and University of Geneva Geneva Switzerland

17. CIMC ‐ Centre d'Imagerie Médicale de Cornavin Geneva Switzerland

18. Department of Surgical Sciences, Radiology Uppsala University Uppsala Sweden

19. Department of Radiology Beijing Tiantan Hospital Capital Medical University Beijing P. R. China

20. Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience, Vrije Universiteit Amsterdam Amsterdam The Netherlands

21. Centro de Investigación y Terapias Avanzadas, Neurología, CITA‐Alzheimer Foundation San Sebastián Spain

22. Centre for Genomic and Experimental Medicine Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

23. Department of Psychiatry School of Clinical Medicine University of Cambridge Cambridge UK

24. Life and Health Sciences Research Institute (ICVS) School of Medicine University of Minho Braga Portugal

25. ICVS/3B's ‐ PT Government Associate Laboratory Braga/Guimarães Portugal

26. Department of Nuclear Medicine Toulouse University Hospital Toulouse France

27. ToNIC, Toulouse NeuroImaging Center University of Toulouse, Inserm Toulouse France

28. Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, Outpatient Department 2 Western General Hospital University of Edinburgh Edinburgh UK

29. Brain Health Scotland Edinburgh UK

30. Takeda Pharmaceuticals Ltd. Cambridge Massachusetts USA

31. Department of Medical Physics and Biomedical Engineering Centre for Medical Image Computing (CMIC) University College London (UCL) London UK

32. MRC Unit for Lifelong Health & Ageing at UCL University College London London UK

33. School of Biomedical Engineering and Imaging Sciences King's College London London UK

34. Centre for Clinical Brain Sciences The University of Edinburgh Edinburgh UK

35. Department of Medicine Imperial College London London UK

36. IXICO London UK

37. Université de Normandie, Unicaen, Inserm, U1237, PhIND “Physiopathology and Imaging of Neurological Disorders”, institut Blood‐and‐Brain @ Caen‐Normandie, Cyceron Caen France

38. German Center for Neurodegenerative Diseases (DZNE) Munich Germany

39. Ghent Institute for Functional and Metabolic Imaging (GIfMI) Ghent University Ghent Belgium

40. CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBER‐BBN) Madrid Spain

41. IMIM (Hospital del Mar Medical Research Institute) Barcelona Spain

42. Amsterdam Neuroscience, Neurodegeneration Amsterdam The Netherlands

43. Alzheimer Center Limburg Department of Psychiatry & Neuropsychology School of Mental Health and Neuroscience Maastricht University Maastricht The Netherlands

44. Division of Neurogeriatrics Department of Neurobiology, Care Sciences and Society Karolinska Institutet Stockholm Sweden

45. Centre for Medical Image Computing Department of Medical Physics and Biomedical Engineering University College London London UK

46. Institutes of Neurology and Healthcare Engineering University College London London UK

Abstract

AbstractINTRODUCTIONUnraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine.METHODSWe computed pathway‐specific genetic risk scores (GRSs) in non‐demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity.RESULTSCSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication.DISCUSSIONThis study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD‐associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies.Highlights

Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway‐specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers.

Inflammatory pathways are mostly related to cerebrovascular burden.

White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Publisher

Wiley

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