. 2024 Sep;20(9):6146-6160.

doi: 10.1002/alz.14096. Epub 2024 Jul 29.

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

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.

PMID: 39073684
PMCID: PMC11497686
DOI: 10.1002/alz.14096

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

Luigi Lorenzini et al. Alzheimers Dement. 2024 Sep.

. 2024 Sep;20(9):6146-6160.

doi: 10.1002/alz.14096. Epub 2024 Jul 29.

Authors

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.

PMID: 39073684
PMCID: PMC11497686
DOI: 10.1002/alz.14096

Erratum in

Correction to "Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals".
[No authors listed] [No authors listed] Alzheimers Dement. 2025 Feb;21(2):e14427. doi: 10.1002/alz.14427. Epub 2024 Dec 30. Alzheimers Dement. 2025. PMID: 39737543 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

EPAD is supported by the EU/EFPIA Innovative Medicines Initiative (IMI) grant agreement 115736.

The project leading to this paper has received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No 115952. This Joint Undertaking receives the support from the European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries Association (EFPIA). This communication reflects the views of the authors, and neither IMI nor the European Union (EU) and EFPIA are liable for any use that may be made of the information contained herein. A.M.W., H.M., L.E.C., and F.B. are supported by AMYPAD (IMI 115952). H.M. is supported by the Dutch Heart Foundation (2020T049), the Eurostars‐2 joint programme with co‐funding from the European Union Horizon 2020 research and innovation programme (ASPIRE E!113701), provided by the Netherlands Enterprise Agency (RvO), and by the EU Joint Program for Neurodegenerative Disease Research, provided by the Netherlands Organisation for Health Research and Development and Alzheimer Nederland (DEBBIE JPND2020‐568‐106). F.B. is supported by Engineering and Physical Sciences Research Council (EPSRC), EU‐JU (IMI), National Institute for Health and Care Research ‐ Biomedical Research Center (NIHR‐BRC), General Eletronic (GE) HealthCare, and Alzheimer's Disease Data Initiative (ADDI; paid to institution); is a consultant for Combinostics, IXICO, and Roche; participates on advisory boards of Biogen, Prothena, and Merck; and is a co‐founder of Queen Square Analytics. L.E.C. has received research support from GE HealthCare Ltd. (paid to institution). C.F. is an employee of GE HealthCare Ltd. P.H.S. is a full‐time employee of EQT Life Sciences (formerly LSP) and professor emeritus at Amsterdam University Medical Centers. He has received consultancy fees (paid to the university) from Alzheon, Brainstorm Cell, and Green Valley. Within his university affiliation, he is global principal investigator of the Phase 1b study of AC Immune, Phase 2b study with FUJI‐film/Toyama, and Phase 2 study of UCB. He is past chair of the EU steering committee of the Phase 2b program of Vivoryon and the Phase 2b study of Novartis Cardiology, and he is presently co‐chair of the Phase 3 study with NOVO‐Nordisk. R.W. is an employee of IXICO. C.R. has done paid consultancy work in the last 3 years for Eli Lilly, Biogen, Actinogen, Brain Health Scotland, Roche, Roche Diagnostics, Novo Nordisk, Eisai, Signant, Merck, Alchemab, Sygnature, and Abbvie. His group has received Research Income for his Research Unit from Biogen, AC Immune, and Roche. He has out‐licensed IP developed at the University of Edinburgh to Linus Health and is chief executive officer (CEO) and Founder of Scottish Brain Sciences. S.H. is a consultant for WYSS Center, Geneva, Switzerland, and a consultant for SPINEART, Geneva, Switzerland. G.C. has received research support from the European Union's Horizon 2020 research and innovation programme (grant agreement number 667696), Fondation d'entreprise MMA des Entrepreneurs du Futur, Fondation Alzheimer, Agence Nationale de la Recherche, Région Normandie, Association France Alzheimer et maladies apparentées, Fondation Vaincre Alzheimer, Fondation Recherche Alzheimer, and Fondation pour la Recherche Médicale (all to Inserm), and personal fees from Inserm and Fondation Alzheimer. A.J.S. is an employee and minor shareholder of Takeda Pharmaceutical Company Ltd. J.O.B. has acted as a consultant for TauRx, Novo Nordisk, Biogen, Roche, Lilly, and GE Healthcare; and received grant support from Avid/ Lilly, Merck, and Alliance Medical.

R.E.M. has received a speaker fee from Illumina; is an advisor to the Epigenetic Clock Development Foundation; and has received consultant fees from Optima partners. Author disclosures are available in the supporting information.

Figures

**FIGURE 2**
Association of global and pathway‐specific genetic risk scores (pathway‐GRSs) with cerebrospinal fluid (CSF) biomarkers. Forest plot reporting illustrating the association (standardized β coefficients, confidence intervals and p‐values) of GRS (with and without apolipoprotein E [*APOE*]) and the six pathway‐GRSs with CSF amyloid beta 1‐42 (Aβ_1‐42) phosphorylated tau (p‐tau₁₈₁). * = p < 0.05; ** = p < 0.005; *** = p < 0.001.

**FIGURE 3**
Association of global and pathway‐specific genetic risk scores (pathway‐GRSs) with radiological visual scores of cerebral small vessel disease (cSVD). Boxplots represent the association of GRS (with and without apolipoprotein E) and the six pathway‐GRSs with Fazekas deep white matter hyperintensities (DWMHs; upper‐row), microbleeds (middle‐row), perivascular spaces (PVSs) in the basal ganglia (lower‐row). APOE, apolipoprotein E.

**FIGURE 4**
Association (n = 1334) of global and pathway‐GRSs with FLAIR and T1w MRI‐derived phenotypes. Upper‐left: shows FLAIR‐derived phenotypes as computed using BaMoS. From left to right, first WMH segmentation was performed, followed by grouping WMH volumes into the four major lobes, and finally in periventricular (blue and green) and deep (yellow and red) regions, effectively providing eight regions of interest. Lower‐left: T1w‐derived phenotypes are obtained from the LEAP pipeline. Right: β coefficients (colors) and p‐values (circles) of linear models with global (GRS_noAPOE) and pathway‐GRSs predicting MRI‐derived phenotypes. APOE, apolipoprotein E; FLAIR, fluid‐attenuated inversion recovery; T1w, T1‐weighted; HCV, hippocampal volume; PeriVent, global periventricular; PV, periventricular; D, deep; Front, frontal; Temp, temporal; Parie, parietal; Occ, occipital; uncorr, uncorrected; FDR, false discovery rate; GRS, genetic risk score; MRI, magnetic resonance imaging; BaMoS, Bayesian model selection; LEAP, learning embeddings for atlas propagation.

**FIGURE 5**
Association (n = 776) of global and pathway GRSs with rs‐fMRI derived phenotypes. Top panel: rs‐fMRI–derived phenotypes are computed as the mean within network functional connectivity in three subsystems of the DMN defined as dorsal DMN (yellow), medial DMN (orange), and ventral DMN (red). Bottom panel: the heatmap shows β coefficients (colors) and p‐values (circles) of linear models with global (GRS_noAPOE) and pathway‐GRSs predicting rs‐fMRI–derived phenotypes. *DMN, default mode network; GRS, genetic risk score; Uncorr, uncorrected; FDR, false discovery rate; rs‐fMRI, resting‐state functional magnetic resonance imaging*.

**FIGURE 6**
Association (n = 790) of global and pathway‐GRSs with DWI‐derived phenotypes. Left panel: DWI‐derived phenotypes are computed through TBSS pipeline as mean FA and MD within 10 regions of interest including commissural (genu, body, and splenium of CC), limbic (fornix and cingulum), associative (superior longitudinal, fronto‐occipital and inferior longitudinal fasciculi), and projection (corona radiata and internal capsule) white matter tracts. Right panel: the heatmap shows β coefficients (colors) and p values (circles) of linear models with global (GRS_noAPOE) and pathway‐GRSs predicting DWI‐derived phenotypes. CC, corpus callosum; Sup‐Long(SL), superior longitudinal; Front‐Occ(SFO), fronto‐occipital; Inf‐Long(IL), inferior longitudinal; Fasc, fasciculus; Uncorr, uncorrected; FDR, false discovery rate; DWI, diffusion‐weighted imaging; TBSS, tract‐based spatial statistics; FA, fractional anisotropy; MD, mean diffusivity; GRS, genetic risk score.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical