Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

INSIGHT-preAD Study Group; Alzheimer Precision Medicine Initiative (APMI)

doi:10.1016/j.jalz.2019.03.006

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

INSIGHT-preAD Study Group, Alzheimer Precision Medicine Initiative (APMI)

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

18 Scopus citations

Abstract

Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

Original language	English
Pages (from-to)	940-950
Number of pages	11
Journal	Alzheimer's and Dementia
Volume	15
Issue number	7
DOIs	https://doi.org/10.1016/j.jalz.2019.03.006
State	Published - Jul 2019

Keywords

Alzheimer's disease
Brain functional dynamics
Precision medicine
Subjective memory complaints
fMRI

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@article{c94b7aa9d1b14b2798487e12aae0bb8f,

title = "Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease",

abstract = "Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.",

keywords = "Alzheimer's disease, Brain functional dynamics, Precision medicine, Subjective memory complaints, fMRI",

author = "{INSIGHT-preAD Study Group} and {Alzheimer Precision Medicine Initiative (APMI)} and Chiesa, {Patrizia A.} and Enrica Cavedo and Andrea Vergallo and Simone Lista and Potier, {Marie Claude} and Habert, {Marie Odile} and Bruno Dubois and {Thiebaut de Schotten}, Michel and Harald Hampel and Hovagim Bakardjian and Habib Benali and Hugo Bertin and Joel Bonheur and Laurie Boukadida and Nadia Boukerrou and Patrizia Chiesa and Olivier Colliot and Marion Dubois and St{\'e}phane Epelbaum and Geoffroy Gagliardi and Remy Genthon and Marion Houot and Aur{\'e}lie Kas and Foudil Lamari and Marcel Levy and Christiane Metzinger and Fanny Mochel and Francis Nyasse and Catherine Poisson and Marie Revillon and Antonio Santos and Andrade, {Katia Santos} and Marine Sole and Mohmed Surtee and {de Schotten}, {Michel Thiebaud} and Nadjia Younsi and Mohammad Afshar and Aguilar, {Lisi Flores} and Leyla Akman-Anderson and Joaqu{\'i}n Arenas and Jesus Avila and Claudio Babiloni and Filippo Baldacci and Richard Batrla and Norbert Benda and Black, {Keith L.} and Bokde, {Arun L.W.} and Ubaldo Bonuccelli and Karl Broich and O'Bryant, {Sid E.}",

note = "Funding Information: This publication is within the framework of the Program “MIDAS” led by the Sorbonne University Foundation and sponsored by MSDAVENIR. Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the ?Investissement d'Avenir? (ANR-10-AIHU-06). The study was promoted in collaboration with the ?CHU de Bordeaux? (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. The research leading to these results was supported by the Colam Initiatives and the ?Fondation pour la Recherchesur Alzheimer,? Paris, France. This publication benefited from the support of the Program ?PHOENIX? led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. Michel Thiebaut de Schotten is supported by the ?AgenceNationale de la Recherche? (grant number ANR-13- JSV4-0001-01) and a European Research Council Consolidator Investigator Award (ERC-2018-COG 818521). H.H. is supported by the AXA Research Fund, the ?Fondation partenariale Sorbonne Universit?? and the ?Fondation pour la Recherchesur Alzheimer,? Paris, France. Ce travail a b?n?fici? d'une aide de l'Etat ?Investissements d'avenir? ANR-10-IAIHU-06. The research leading to these results has received funding from the program ?Investissements d'avenir? ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Author contributions: P.A.C. E.C. B.D. H.H. and M.T.S. have contributed to the conception and design of the study. P.A.C. E.C. M.C.P. M.O.H. and M.T.S. have contributed to acquisition and analysis of data. P.A.C. A.V. E.C. S.L. M.T.S. and H.H. have contributed to drafting and revising a significant portion of the manuscript. Competing financial interests: H.H. serves as a Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics, Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is a coinventor in the following patents as a scientific expert and has received no royalties: ?In vitro multiparameter determination method for the diagnosis and early diagnosis of neurodegenerative disorders. Patent number: 8916388. ?In vitro procedure for diagnosis and early diagnosis of neurodegenerative diseases. Patent number: 8298784. ?Neurodegenerative markers for psychiatric conditions. Publication number: 20120196300. ?In vitro multiparameter determination method for the diagnosis and early diagnosis of neurodegenerative disorders. Publication number: 20100062463. ?In vitro method for the diagnosis and early diagnosis of neurodegenerative disorders. Publication number: 20100035286. ?In vitro procedure for diagnosis and early diagnosis of neurodegenerative diseases. Publication number: 20090263822. ?In vitro method for the diagnosis of neurodegenerative diseases. Patent number: 7547553. ?Cerebrospinal fluid diagnostic in vitro method for diagnosis of dementias and neuroinflammatory diseases. Publication number: 20080206797. ?In vitro method for the diagnosis of neurodegenerative diseases. Publication number: 20080199966. ?Neurodegenerative markers for psychiatric conditions. Publication number: 20080131921., INSIGHT-preAD Study Group: Hovagim Bakardjian, Habib Benali, Hugo Bertin, Joel Bonheur, Laurie Boukadida, Nadia Boukerrou, Enrica Cavedo, Patrizia Chiesa, Olivier Colliot, Bruno Dubois, Marion Dubois, St?phane Epelbaum, Geoffroy Gagliardi, Remy Genthon, Marie-Odile Habert, Harald Hampel, Marion Houot, Aur?lie Kas, Foudil Lamari, Marcel Levy, Simone Lista, Christiane Metzinger, Fanny Mochel, Francis Nyasse, Catherine Poisson, Marie-Claude Potier, Marie Revillon, Antonio Santos, Katia Santos Andrade, Marine Sole, Mohmed Surtee, Michel Thiebaud de Schotten, Andrea Vergallo, Nadjia Younsi. INSIGHT-preAD Scientific Committee Members: Dubois B, Hampel H, Bakardjian H, Colliot O, Habert MO, Lamari F, Mochel F, Potier MC, Thiebaut de Schotten M. Contributors to the Alzheimer precision medicine initiative?working group (APMI?WG): Mohammad Afshar (Paris), Lisi Flores Aguilar (Montr?al), Leyla Akman-Anderson (Sacramento), Joaqu?n Arenas (Madrid), Jesus Avila (Madrid), Claudio Babiloni (Rome), Filippo Baldacci (Pisa), Richard Batrla (Rotkreuz), Norbert Benda (Bonn), Keith L. Black (Los Angeles), Arun L.W. Bokde (Dublin), Ubaldo Bonuccelli (Pisa), Karl Broich (Bonn), Francesco Cacciola (Siena), Filippo Caraci (Catania), Juan Castrillo ? (Derio), Enrica Cavedo (Paris), Roberto Ceravolo (Pisa), Patrizia A. Chiesa (Paris), Jean-Christophe Corvol (Paris), Augusto Claudio Cuello (Montr?al), Jeffrey L. Cummings (Las Vegas), Herman Depypere (Gent), Bruno Dubois (Paris), Andrea Duggento (Rome), Enzo Emanuele (Robbio), Valentina Escott-Price (Cardiff), Howard Federoff (Irvine), Maria Teresa Ferretti (Z?rich), Massimo Fiandaca (Irvine), Richard A. Frank (Malvern), Francesco Garaci (Rome), Hugo Geerts (Berwyn), Filippo S. Giorgi (Pisa), Edward J. Goetzl (San Francisco), Manuela Graziani (Roma), Marion Haberkamp (Bonn), Marie-Odile Habert (Paris), Harald Hampel (Paris), Karl Herholz (Manchester), Felix Hernandez (Madrid), Dimitrios Kapogiannis (Baltimore), Eric Karran (Cambridge), Steven J. Kiddle (Cambridge), Seung H. Kim (Seoul), Yosef Koronyo (Los Angeles), Maya Koronyo-Hamaoui (Los Angeles), Todd Langevin (Minneapolis-Saint Paul), St?phane Leh?ricy (Paris), Alejandro Luc?a (Madrid), Simone Lista (Paris), Jean Lorenceau (Paris), Dalila Mango (Rome), Mark Mapstone (Irvine), Christian Neri (Paris), Robert Nistic? (Rome), Sid E. O'Bryant (Fort Worth), Giovanni Palermo (Pisa), George Perry (San Antonio), Craig Ritchie (Edinburgh), Simone Rossi (Siena), Amira Saidi (Rome), Emiliano Santarnecchi (Siena), Lon S. Schneider (Los Angeles), Olaf Sporns (Bloomington), Nicola Toschi (Rome), Steven R. Verdooner (Sacramento), Andrea Vergallo (Paris), Nicolas Villain (Paris), Lindsay A. Welikovitch (Montr?al), Janet Woodcock (Silver Spring), Erfan Younesi (Esch-sur-Alzette). Funding Information: H.H. is supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Universit{\'e}” and the “Fondation pour la Recherchesur Alzheimer,” Paris, France. Ce travail a b{\'e}n{\'e}fici{\'e} d'une aide de l'Etat “Investissements d'avenir” ANR-10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the “Investissement d'Avenir” (ANR-10-AIHU-06). The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/ Lilly . Funding Information: The research leading to these results was supported by the Colam Initiatives and the “Fondation pour la Recherchesur Alzheimer,” Paris, France. Funding Information: Competing financial interests: H.H. serves as a Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics, Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is a coinventor in the following patents as a scientific expert and has received no royalties: Funding Information: Michel Thiebaut de Schotten is supported by the “AgenceNationale de la Recherche” (grant number ANR-13- JSV4-0001-01) and a European Research Council Consolidator Investigator Award (ERC-2018-COG 818521). Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = jul,

doi = "10.1016/j.jalz.2019.03.006",

language = "English",

volume = "15",

pages = "940--950",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

number = "7",

}

TY - JOUR

T1 - Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

AU - INSIGHT-preAD Study Group

AU - Alzheimer Precision Medicine Initiative (APMI)

AU - Chiesa, Patrizia A.

AU - Cavedo, Enrica

AU - Vergallo, Andrea

AU - Lista, Simone

AU - Potier, Marie Claude

AU - Habert, Marie Odile

AU - Dubois, Bruno

AU - Thiebaut de Schotten, Michel

AU - Hampel, Harald

AU - Bakardjian, Hovagim

AU - Benali, Habib

AU - Bertin, Hugo

AU - Bonheur, Joel

AU - Boukadida, Laurie

AU - Boukerrou, Nadia

AU - Chiesa, Patrizia

AU - Colliot, Olivier

AU - Dubois, Marion

AU - Epelbaum, Stéphane

AU - Gagliardi, Geoffroy

AU - Genthon, Remy

AU - Houot, Marion

AU - Kas, Aurélie

AU - Lamari, Foudil

AU - Levy, Marcel

AU - Metzinger, Christiane

AU - Mochel, Fanny

AU - Nyasse, Francis

AU - Poisson, Catherine

AU - Revillon, Marie

AU - Santos, Antonio

AU - Andrade, Katia Santos

AU - Sole, Marine

AU - Surtee, Mohmed

AU - de Schotten, Michel Thiebaud

AU - Younsi, Nadjia

AU - Afshar, Mohammad

AU - Aguilar, Lisi Flores

AU - Akman-Anderson, Leyla

AU - Arenas, Joaquín

AU - Avila, Jesus

AU - Babiloni, Claudio

AU - Baldacci, Filippo

AU - Batrla, Richard

AU - Benda, Norbert

AU - Black, Keith L.

AU - Bokde, Arun L.W.

AU - Bonuccelli, Ubaldo

AU - Broich, Karl

AU - O'Bryant, Sid E.

N1 - Funding Information: This publication is within the framework of the Program “MIDAS” led by the Sorbonne University Foundation and sponsored by MSDAVENIR. Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the ?Investissement d'Avenir? (ANR-10-AIHU-06). The study was promoted in collaboration with the ?CHU de Bordeaux? (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. The research leading to these results was supported by the Colam Initiatives and the ?Fondation pour la Recherchesur Alzheimer,? Paris, France. This publication benefited from the support of the Program ?PHOENIX? led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. Michel Thiebaut de Schotten is supported by the ?AgenceNationale de la Recherche? (grant number ANR-13- JSV4-0001-01) and a European Research Council Consolidator Investigator Award (ERC-2018-COG 818521). H.H. is supported by the AXA Research Fund, the ?Fondation partenariale Sorbonne Universit?? and the ?Fondation pour la Recherchesur Alzheimer,? Paris, France. Ce travail a b?n?fici? d'une aide de l'Etat ?Investissements d'avenir? ANR-10-IAIHU-06. The research leading to these results has received funding from the program ?Investissements d'avenir? ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Author contributions: P.A.C. E.C. B.D. H.H. and M.T.S. have contributed to the conception and design of the study. P.A.C. E.C. M.C.P. M.O.H. and M.T.S. have contributed to acquisition and analysis of data. P.A.C. A.V. E.C. S.L. M.T.S. and H.H. have contributed to drafting and revising a significant portion of the manuscript. Competing financial interests: H.H. serves as a Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics, Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is a coinventor in the following patents as a scientific expert and has received no royalties: ?In vitro multiparameter determination method for the diagnosis and early diagnosis of neurodegenerative disorders. Patent number: 8916388. ?In vitro procedure for diagnosis and early diagnosis of neurodegenerative diseases. Patent number: 8298784. ?Neurodegenerative markers for psychiatric conditions. Publication number: 20120196300. ?In vitro multiparameter determination method for the diagnosis and early diagnosis of neurodegenerative disorders. Publication number: 20100062463. ?In vitro method for the diagnosis and early diagnosis of neurodegenerative disorders. Publication number: 20100035286. ?In vitro procedure for diagnosis and early diagnosis of neurodegenerative diseases. Publication number: 20090263822. ?In vitro method for the diagnosis of neurodegenerative diseases. Patent number: 7547553. ?Cerebrospinal fluid diagnostic in vitro method for diagnosis of dementias and neuroinflammatory diseases. Publication number: 20080206797. ?In vitro method for the diagnosis of neurodegenerative diseases. Publication number: 20080199966. ?Neurodegenerative markers for psychiatric conditions. Publication number: 20080131921., INSIGHT-preAD Study Group: Hovagim Bakardjian, Habib Benali, Hugo Bertin, Joel Bonheur, Laurie Boukadida, Nadia Boukerrou, Enrica Cavedo, Patrizia Chiesa, Olivier Colliot, Bruno Dubois, Marion Dubois, St?phane Epelbaum, Geoffroy Gagliardi, Remy Genthon, Marie-Odile Habert, Harald Hampel, Marion Houot, Aur?lie Kas, Foudil Lamari, Marcel Levy, Simone Lista, Christiane Metzinger, Fanny Mochel, Francis Nyasse, Catherine Poisson, Marie-Claude Potier, Marie Revillon, Antonio Santos, Katia Santos Andrade, Marine Sole, Mohmed Surtee, Michel Thiebaud de Schotten, Andrea Vergallo, Nadjia Younsi. INSIGHT-preAD Scientific Committee Members: Dubois B, Hampel H, Bakardjian H, Colliot O, Habert MO, Lamari F, Mochel F, Potier MC, Thiebaut de Schotten M. Contributors to the Alzheimer precision medicine initiative?working group (APMI?WG): Mohammad Afshar (Paris), Lisi Flores Aguilar (Montr?al), Leyla Akman-Anderson (Sacramento), Joaqu?n Arenas (Madrid), Jesus Avila (Madrid), Claudio Babiloni (Rome), Filippo Baldacci (Pisa), Richard Batrla (Rotkreuz), Norbert Benda (Bonn), Keith L. Black (Los Angeles), Arun L.W. Bokde (Dublin), Ubaldo Bonuccelli (Pisa), Karl Broich (Bonn), Francesco Cacciola (Siena), Filippo Caraci (Catania), Juan Castrillo ? (Derio), Enrica Cavedo (Paris), Roberto Ceravolo (Pisa), Patrizia A. Chiesa (Paris), Jean-Christophe Corvol (Paris), Augusto Claudio Cuello (Montr?al), Jeffrey L. Cummings (Las Vegas), Herman Depypere (Gent), Bruno Dubois (Paris), Andrea Duggento (Rome), Enzo Emanuele (Robbio), Valentina Escott-Price (Cardiff), Howard Federoff (Irvine), Maria Teresa Ferretti (Z?rich), Massimo Fiandaca (Irvine), Richard A. Frank (Malvern), Francesco Garaci (Rome), Hugo Geerts (Berwyn), Filippo S. Giorgi (Pisa), Edward J. Goetzl (San Francisco), Manuela Graziani (Roma), Marion Haberkamp (Bonn), Marie-Odile Habert (Paris), Harald Hampel (Paris), Karl Herholz (Manchester), Felix Hernandez (Madrid), Dimitrios Kapogiannis (Baltimore), Eric Karran (Cambridge), Steven J. Kiddle (Cambridge), Seung H. Kim (Seoul), Yosef Koronyo (Los Angeles), Maya Koronyo-Hamaoui (Los Angeles), Todd Langevin (Minneapolis-Saint Paul), St?phane Leh?ricy (Paris), Alejandro Luc?a (Madrid), Simone Lista (Paris), Jean Lorenceau (Paris), Dalila Mango (Rome), Mark Mapstone (Irvine), Christian Neri (Paris), Robert Nistic? (Rome), Sid E. O'Bryant (Fort Worth), Giovanni Palermo (Pisa), George Perry (San Antonio), Craig Ritchie (Edinburgh), Simone Rossi (Siena), Amira Saidi (Rome), Emiliano Santarnecchi (Siena), Lon S. Schneider (Los Angeles), Olaf Sporns (Bloomington), Nicola Toschi (Rome), Steven R. Verdooner (Sacramento), Andrea Vergallo (Paris), Nicolas Villain (Paris), Lindsay A. Welikovitch (Montr?al), Janet Woodcock (Silver Spring), Erfan Younesi (Esch-sur-Alzette). Funding Information: H.H. is supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherchesur Alzheimer,” Paris, France. Ce travail a bénéficié d'une aide de l'Etat “Investissements d'avenir” ANR-10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the “Investissement d'Avenir” (ANR-10-AIHU-06). The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/ Lilly . Funding Information: The research leading to these results was supported by the Colam Initiatives and the “Fondation pour la Recherchesur Alzheimer,” Paris, France. Funding Information: Competing financial interests: H.H. serves as a Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics, Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is a coinventor in the following patents as a scientific expert and has received no royalties: Funding Information: Michel Thiebaut de Schotten is supported by the “AgenceNationale de la Recherche” (grant number ANR-13- JSV4-0001-01) and a European Research Council Consolidator Investigator Award (ERC-2018-COG 818521). Publisher Copyright: © 2019

PY - 2019/7

Y1 - 2019/7

N2 - Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

AB - Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

KW - Alzheimer's disease

KW - Brain functional dynamics

KW - Precision medicine

KW - Subjective memory complaints

KW - fMRI

UR - http://www.scopus.com/inward/record.url?scp=85065804629&partnerID=8YFLogxK

U2 - 10.1016/j.jalz.2019.03.006

DO - 10.1016/j.jalz.2019.03.006

M3 - Article

C2 - 31113760

AN - SCOPUS:85065804629

VL - 15

SP - 940

EP - 950

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

SN - 1552-5260

IS - 7

ER -

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

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