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

Luigi Lorenzini; Lyduine E Collij; Niccoló Tesi; Natàlia Vilor-Tejedor; Silvia Ingala; Kaj Blennow; Christopher Foley; Giovanni B Frisoni; Sven Haller; Henne Holstege; Sven van der van der Lee; Pablo Martinez-Lage; Riccardo E Marioni; Daniel L McCartney; John O' Brien; Tiago Gil Oliveira; Pierre Payoux; Marcel Reinders; Craig Ritchie; Philip Scheltens; Adam J Schwarz; Carole H Sudre; Adam D Waldman; Robin Wolz; Gael Chatelat; Michael Ewers; Alle Meije Wink; Henk J M M Mutsaerts; Juan Domingo Gispert; Pieter Jelle Visser; Betty M Tijms; Andre Altmann; Frederik Barkhof

doi:10.1002/alz.14096

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

Alzheimers Dement. 2024 Sep;20(9):6146-6160. doi: 10.1002/alz.14096. Epub 2024 Jul 29.

Authors

Luigi Lorenzini^{1

2}, Lyduine E Collij^{1

2

3}, Niccoló Tesi^{2

4

5}, Natàlia Vilor-Tejedor^{6

7

8

9}, Silvia Ingala^{10

11}, Kaj Blennow^{12

13}, Christopher Foley¹⁴, Giovanni B Frisoni^{15

16}, Sven Haller^{17

18

19}, Henne Holstege⁴, Sven van der van der Lee^{4

20}, Pablo Martinez-Lage²¹, Riccardo E Marioni²², Daniel L McCartney²², John O' Brien²³, Tiago Gil Oliveira^{24

25}, Pierre Payoux^{26

27}, Marcel Reinders⁵, Craig Ritchie^{28

29}, Philip Scheltens²⁰, Adam J Schwarz³⁰, Carole H Sudre^{31

32

33}, Adam D Waldman^{34

35}, Robin Wolz³⁶, Gael Chatelat³⁷, Michael Ewers³⁸, Alle Meije Wink^{1

2}, Henk J M M Mutsaerts^{2

39}, Juan Domingo Gispert^{6

7

40

41}, Pieter Jelle Visser^{20

42

43

44}, Betty M Tijms^{20

42}, Andre Altmann⁴⁵, Frederik Barkhof^{1

46}

Affiliations

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

Introduction: Unraveling 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.

Methods: We 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.

Results: CSF 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.

Discussion: This 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.

Keywords: biological pathways; magnetic resonance imaging; polygenic risk; preclinical Alzheimer's disease.

MeSH terms

Aged
Alzheimer Disease* / cerebrospinal fluid
Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Amyloid beta-Peptides* / cerebrospinal fluid
Biomarkers* / cerebrospinal fluid
Brain / diagnostic imaging
Brain / pathology
Endophenotypes*
Female
Genetic Predisposition to Disease
Humans
Magnetic Resonance Imaging
Male
Middle Aged
White Matter / diagnostic imaging
White Matter / pathology
tau Proteins / cerebrospinal fluid

Substances

Biomarkers
Amyloid beta-Peptides
tau Proteins

Grants and funding

115736/EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD