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

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

^*Corresponding author for this work

Radiology & Nuclear Medicine

Amsterdam UMC
Lund University (Malmö)
Vrije Universiteit Amsterdam
Delft University of Technology
Rigshospitalet
Cerebriu A/S
University of Gothenburg
Sahlgrenska University Hospital
GE Healthcare
IRCCS Centro San Giovanni di Dio Fatebenefratelli - Brescia
University of Geneva
CIMC - Centre d'Imagerie Médicale de Cornavin
Uppsala University
Capital Medical University
CITA-Alzheimer Foundation
University of Edinburgh
University of Cambridge
University of Minho
CHU de Toulouse
Toulouse Neuro Imaging Center
Brain Health Scotland
Takeda Pharmaceuticals Ltd.
Imperial College London
IXICO plc
Université de Caen Normandie
German Center for Neurodegenerative Diseases
Ghent University Hospital
Pasqual Maragall Foundation
Pompeu Fabra University
Centro de Investigación Biomédica en Red (CIBER)
Hospital del Mar
University College London

Research output: Contribution to journal › Article › Academic › peer-review

12 Citations (Scopus)

88 Downloads (Pure)

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.

Original language	English
Pages (from-to)	6146-6160
Number of pages	15
Journal	Alzheimer's and Dementia
Volume	20
Issue number	9
DOIs	https://doi.org/10.1002/alz.14096
Publication status	Published - Sept 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

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Alzheimer s Dementia - 2024 - Lorenzini - Alzheimer s disease genetic pathways impact cerebrospinal fluid biomarkers andFinal published version, 3.01 MBLicence: CC BY-NC-ND

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Lorenzini, L., Collij, L. E., Tesi, N., Vilor-Tejedor, N., Ingala, S., Blennow, K., Foley, C., Frisoni, G. B., Haller, S., Holstege, H., van der van der Lee, S., Martinez-Lage, P., Marioni, R. E., McCartney, D. L., O’ Brien, J., Oliveira, T. G., Payoux, P., Reinders, M., Ritchie, C., ... Barkhof, F. (2024). Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals. Alzheimer's and Dementia, 20(9), 6146-6160. https://doi.org/10.1002/alz.14096

@article{72a60ee9c06d401a9c22f47627537cc1,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = sep,

doi = "10.1002/alz.14096",

language = "English",

volume = "20",

pages = "6146--6160",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley \& Sons Inc.",

number = "9",

}

Lorenzini, L, Collij, LE, Tesi, N, Vilor-Tejedor, N, Ingala, S, Blennow, K, Foley, C, Frisoni, GB, Haller, S, Holstege, H, van der van der Lee, S, Martinez-Lage, P, Marioni, RE, McCartney, DL, O’ Brien, J, Oliveira, TG, Payoux, P, Reinders, M, Ritchie, C, Scheltens, P, Schwarz, AJ, Sudre, CH, Waldman, AD, Wolz, R, Chatelat, G, Ewers, M, Wink, AM, Mutsaerts, HJMM, Gispert, JD, Visser, PJ, Tijms, BM, Altmann, A & Barkhof, F 2024, 'Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals', Alzheimer's and Dementia, vol. 20, no. 9, pp. 6146-6160. https://doi.org/10.1002/alz.14096

TY - JOUR

T1 - Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals

AU - Lorenzini, Luigi

AU - Collij, Lyduine E.

AU - Tesi, Niccoló

AU - Vilor-Tejedor, Natàlia

AU - Ingala, Silvia

AU - Blennow, Kaj

AU - Foley, Christopher

AU - Frisoni, Giovanni B.

AU - Haller, Sven

AU - Holstege, Henne

AU - van der van der Lee, Sven

AU - Martinez-Lage, Pablo

AU - Marioni, Riccardo E.

AU - McCartney, Daniel L.

AU - O’ Brien, John

AU - Oliveira, Tiago Gil

AU - Payoux, Pierre

AU - Reinders, Marcel

AU - Ritchie, Craig

AU - Scheltens, Philip

AU - Schwarz, Adam J.

AU - Sudre, Carole H.

AU - Waldman, Adam D.

AU - Wolz, Robin

AU - Chatelat, Gael

AU - Ewers, Michael

AU - Wink, Alle Meije

AU - Mutsaerts, Henk J.M.M.

AU - Gispert, Juan Domingo

AU - Visser, Pieter Jelle

AU - Tijms, Betty M.

AU - Altmann, Andre

AU - Barkhof, Frederik

PY - 2024/9

Y1 - 2024/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85199976205

U2 - 10.1002/alz.14096

DO - 10.1002/alz.14096

M3 - Article

C2 - 39073684

AN - SCOPUS:85199976205

SN - 1552-5260

VL - 20

SP - 6146

EP - 6160

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 9

ER -

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

Abstract

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