APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease

Jesper Qvist Thomassen; Leonard Hampton; Brittany Ulms; Benjamin Grenier-Boley; Sami Heikkinen; Pablo Garcia; Atahualapa Castillo-Morales; Masataka Kikuchi; Jungsoo Gim; Han Cao; Fahri Küçükali; Najaf Amin; Dabin Yoon; Itziar de Rojas; Pilar Alvarez Jerez; Victoria Alvarez; Beatrice Arosio; Celine Bellenguez; Sverre Bergh; Kimberly Billingsley; Cornelis Blauwendraat; Merce Boada; Barbara Borroni; Paola Bossù; María J Bullido; Antonio Daniele; Ángel Carracedo; Alexandre de Mendonça; Mark Cookson; Jürgen Deckert; Martin Dichgans; Srdjan Djurovic; Oriol Dols-Icardo; Carole Dufouil; Emrah Düzel; Valentina Escott-Price; Tormod Fladby; Laura Fratiglioni; Amy K Y Fu; Daniela Galimberti; Jose Maria García-Alberca; Vilmantas Giedraitis; Guillermo Garcia-Ribas; Caroline Graff; Timo Grimmer; Edna Grünblatt; OIivier Hanon; Lucrezia Hausner; Stefanie Heilmann-Hemibach; Jakub Hort; Frank Jessen; Kendall Jensen; Caroline Jonson; Yoontae Kim; Nicole Kuznetsov; Ville Leinonen; Anssi Lipponen; Jiao Luo; Mary Makarious; Henna Martiskainen; Carlo Masullo; Patrizia Mecocci; Shima Mehrabian; Pablo Mir; Akinori Miyashita; Susanne Moebus; Kin Y Mok; Laura Molina Porcel; Fermin Moreno; Benedetta Nacmias; Lucilla Parnetti; Pau Pastor; Jordi Pérez-Tur; Oliver Peters; Yolande A L Pijnenburg; Gerard Piñol-Ripoll; Julius Popp; Innocenzo Rainero; Luis M Real; Steffi Riedel-Heller; Eloy Rodriguez-Rodriguez; Arvid Rongve; Giacomina Rossi; Jose Luis Royo; Dan Rujescu; Ingvild Saltvedt; María Eugenia Sáez; Raquel Sánchez-Valle; Florentino Sanchez-Garcia; Nicolai Sandau; Nikolaos Scarmeas; Katja Scheffler; Norbert Scherbaum; Anja Schneider; Geir Selbæk; Davide Seripa; Vincenzo Solfrizzi; Marco Spallazzi; Alessio Squassina; Eystein Stordal; Niccoló Tesi; Lucio Tremolizzo; Kumar P Tripathi; Wiesje M van der Flier; Julie Williams; Jens Wiltfang; Dag Aarsland; Andrew B Singleton; Philippe Amouyel; Stéphanie Debette; Gael Nicolas; Sven van der Lee; Henne Holstege; Maria Victoria Fernandez; Patrick Gavin Kehoe; Kristel Sleegers; Martin Ingelsson; Roberta Ghidoni; Ole A Andreassen; Peter A Holmans; Pascual Sánchez-Juan; Rebecca Sims; Nancy Y Ip; Kun Ho Lee; Takeshi Ikeuchi; Alfredo Ramirez; Agustin Ruiz; Mikko Hiltunen; Jean-Charles Lambert; Cornelia van Duijn; Mike Nalls; Ruth Frikke-Schmidt

doi:10.1101/2025.05.07.25327065

APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease

Jesper Qvist Thomassen, Leonard Hampton, Brittany Ulms, Benjamin Grenier-Boley, Sami Heikkinen, Pablo Garcia, Atahualapa Castillo-Morales, Masataka Kikuchi, Jungsoo Gim, Han Cao, Fahri Küçükali, Najaf Amin, Dabin Yoon, Itziar de Rojas, Pilar Alvarez Jerez, Victoria Alvarez, Beatrice Arosio, Celine Bellenguez, Sverre Bergh, Kimberly BillingsleyCornelis Blauwendraat, Merce Boada, Barbara Borroni, Paola Bossù, María J Bullido, Antonio Daniele, Ángel Carracedo, Alexandre de Mendonça, Mark Cookson, Jürgen Deckert, Martin Dichgans, Srdjan Djurovic, Oriol Dols-Icardo, Carole Dufouil, Emrah Düzel, Valentina Escott-Price, Tormod Fladby, Laura Fratiglioni, Amy K Y Fu, Daniela Galimberti, Jose Maria García-Alberca, Vilmantas Giedraitis, Guillermo Garcia-Ribas, Caroline Graff, Timo Grimmer, Edna Grünblatt, OIivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Hemibach, Jakub Hort, Frank Jessen, Kendall Jensen, Caroline Jonson, Yoontae Kim, Nicole Kuznetsov, Ville Leinonen, Anssi Lipponen, Jiao Luo, Mary Makarious, Henna Martiskainen, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Pablo Mir, Akinori Miyashita, Susanne Moebus, Kin Y Mok, Laura Molina Porcel, Fermin Moreno, Benedetta Nacmias, Lucilla Parnetti, Pau Pastor, Jordi Pérez-Tur, Oliver Peters, Yolande A L Pijnenburg, Gerard Piñol-Ripoll, Julius Popp, Innocenzo Rainero, Luis M Real, Steffi Riedel-Heller, Eloy Rodriguez-Rodriguez, Arvid Rongve, Giacomina Rossi, Jose Luis Royo, Dan Rujescu, Ingvild Saltvedt, María Eugenia Sáez, Raquel Sánchez-Valle, Florentino Sanchez-Garcia, Nicolai Sandau, Nikolaos Scarmeas, Katja Scheffler, Norbert Scherbaum, Anja Schneider, Geir Selbæk, Davide Seripa, Vincenzo Solfrizzi, Marco Spallazzi, Alessio Squassina, Eystein Stordal, Niccoló Tesi, Lucio Tremolizzo, Kumar P Tripathi, Wiesje M van der Flier, Julie Williams, Jens Wiltfang, Dag Aarsland, Andrew B Singleton, Philippe Amouyel, Stéphanie Debette, Gael Nicolas, Sven van der Lee, Henne Holstege, Maria Victoria Fernandez, Patrick Gavin Kehoe, Kristel Sleegers, Martin Ingelsson, Roberta Ghidoni, Ole A Andreassen, Peter A Holmans, Pascual Sánchez-Juan, Rebecca Sims, Nancy Y Ip, Kun Ho Lee, Takeshi Ikeuchi, Alfredo Ramirez, Agustin Ruiz, Mikko Hiltunen, Jean-Charles Lambert, Cornelia van Duijn, Mike Nalls, Ruth Frikke-Schmidt

Afdeling for Klinisk Biokemi DIA

Abstract

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (APOE) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. Such insights may help to understand and overcome side effects, to impact clinical trial enrolment strategies, and to create the scientific basis for targeted mechanism-driven therapies in neurodegenerative diseases.

Originalsprog	Engelsk
DOI	https://doi.org/10.1101/2025.05.07.25327065
Status	Udgivet - 9 maj 2025

Navn	medRxiv

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10.1101/2025.05.07.25327065Licens: CC BY-NC-ND

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Thomassen, J. Q., Hampton, L., Ulms, B., Grenier-Boley, B., Heikkinen, S., Garcia, P., Castillo-Morales, A., Kikuchi, M., Gim, J., Cao, H., Küçükali, F., Amin, N., Yoon, D., de Rojas, I., Jerez, P. A., Alvarez, V., Arosio, B., Bellenguez, C., Bergh, S., ... Frikke-Schmidt, R. (2025). APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease. medRxiv https://doi.org/10.1101/2025.05.07.25327065

Thomassen, JQ, Hampton, L, Ulms, B, Grenier-Boley, B, Heikkinen, S, Garcia, P, Castillo-Morales, A, Kikuchi, M, Gim, J, Cao, H, Küçükali, F, Amin, N, Yoon, D, de Rojas, I, Jerez, PA, Alvarez, V, Arosio, B, Bellenguez, C, Bergh, S, Billingsley, K, Blauwendraat, C, Boada, M, Borroni, B, Bossù, P, Bullido, MJ, Daniele, A, Carracedo, Á, de Mendonça, A, Cookson, M, Deckert, J, Dichgans, M, Djurovic, S, Dols-Icardo, O, Dufouil, C, Düzel, E, Escott-Price, V, Fladby, T, Fratiglioni, L, Fu, AKY, Galimberti, D, García-Alberca, JM, Giedraitis, V, Garcia-Ribas, G, Graff, C, Grimmer, T, Grünblatt, E, Hanon, OI, Hausner, L, Heilmann-Hemibach, S, Hort, J, Jessen, F, Jensen, K, Jonson, C, Kim, Y, Kuznetsov, N, Leinonen, V, Lipponen, A, Luo, J, Makarious, M, Martiskainen, H, Masullo, C, Mecocci, P, Mehrabian, S, Mir, P, Miyashita, A, Moebus, S, Mok, KY, Porcel, LM, Moreno, F, Nacmias, B, Parnetti, L, Pastor, P, Pérez-Tur, J, Peters, O, Pijnenburg, YAL, Piñol-Ripoll, G, Popp, J, Rainero, I, Real, LM, Riedel-Heller, S, Rodriguez-Rodriguez, E, Rongve, A, Rossi, G, Royo, JL, Rujescu, D, Saltvedt, I, Sáez, ME, Sánchez-Valle, R, Sanchez-Garcia, F, Sandau, N, Scarmeas, N, Scheffler, K, Scherbaum, N, Schneider, A, Selbæk, G, Seripa, D, Solfrizzi, V, Spallazzi, M, Squassina, A, Stordal, E, Tesi, N, Tremolizzo, L, Tripathi, KP, van der Flier, WM, Williams, J, Wiltfang, J, Aarsland, D, Singleton, AB, Amouyel, P, Debette, S, Nicolas, G, van der Lee, S, Holstege, H, Fernandez, MV, Kehoe, PG, Sleegers, K, Ingelsson, M, Ghidoni, R, Andreassen, OA, Holmans, PA, Sánchez-Juan, P, Sims, R, Ip, NY, Lee, KH, Ikeuchi, T, Ramirez, A, Ruiz, A, Hiltunen, M, Lambert, J-C, van Duijn, C, Nalls, M & Frikke-Schmidt, R 2025 'APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease' medRxiv. https://doi.org/10.1101/2025.05.07.25327065

@misc{0c9a71502f6e41029e0d095be19d235e,

title = "APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease",

abstract = "Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (APOE) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. Such insights may help to understand and overcome side effects, to impact clinical trial enrolment strategies, and to create the scientific basis for targeted mechanism-driven therapies in neurodegenerative diseases.",

author = "Thomassen, \{Jesper Qvist\} and Leonard Hampton and Brittany Ulms and Benjamin Grenier-Boley and Sami Heikkinen and Pablo Garcia and Atahualapa Castillo-Morales and Masataka Kikuchi and Jungsoo Gim and Han Cao and Fahri K{\"u}{\c c}{\"u}kali and Najaf Amin and Dabin Yoon and \{de Rojas\}, Itziar and Jerez, \{Pilar Alvarez\} and Victoria Alvarez and Beatrice Arosio and Celine Bellenguez and Sverre Bergh and Kimberly Billingsley and Cornelis Blauwendraat and Merce Boada and Barbara Borroni and Paola Boss{\`u} and Bullido, \{Mar{\'i}a J\} and Antonio Daniele and {\'A}ngel Carracedo and \{de Mendon{\c c}a\}, Alexandre and Mark Cookson and J{\"u}rgen Deckert and Martin Dichgans and Srdjan Djurovic and Oriol Dols-Icardo and Carole Dufouil and Emrah D{\"u}zel and Valentina Escott-Price and Tormod Fladby and Laura Fratiglioni and Fu, \{Amy K Y\} and Daniela Galimberti and Garc{\'i}a-Alberca, \{Jose Maria\} and Vilmantas Giedraitis and Guillermo Garcia-Ribas and Caroline Graff and Timo Grimmer and Edna Gr{\"u}nblatt and OIivier Hanon and Lucrezia Hausner and Stefanie Heilmann-Hemibach and Jakub Hort and Frank Jessen and Kendall Jensen and Caroline Jonson and Yoontae Kim and Nicole Kuznetsov and Ville Leinonen and Anssi Lipponen and Jiao Luo and Mary Makarious and Henna Martiskainen and Carlo Masullo and Patrizia Mecocci and Shima Mehrabian and Pablo Mir and Akinori Miyashita and Susanne Moebus and Mok, \{Kin Y\} and Porcel, \{Laura Molina\} and Fermin Moreno and Benedetta Nacmias and Lucilla Parnetti and Pau Pastor and Jordi P{\'e}rez-Tur and Oliver Peters and Pijnenburg, \{Yolande A L\} and Gerard Pi{\~n}ol-Ripoll and Julius Popp and Innocenzo Rainero and Real, \{Luis M\} and Steffi Riedel-Heller and Eloy Rodriguez-Rodriguez and Arvid Rongve and Giacomina Rossi and Royo, \{Jose Luis\} and Dan Rujescu and Ingvild Saltvedt and S{\'a}ez, \{Mar{\'i}a Eugenia\} and Raquel S{\'a}nchez-Valle and Florentino Sanchez-Garcia and Nicolai Sandau and Nikolaos Scarmeas and Katja Scheffler and Norbert Scherbaum and Anja Schneider and Geir Selb{\ae}k and Davide Seripa and Vincenzo Solfrizzi and Marco Spallazzi and Alessio Squassina and Eystein Stordal and Niccol{\'o} Tesi and Lucio Tremolizzo and Tripathi, \{Kumar P\} and \{van der Flier\}, \{Wiesje M\} and Julie Williams and Jens Wiltfang and Dag Aarsland and Singleton, \{Andrew B\} and Philippe Amouyel and St{\'e}phanie Debette and Gael Nicolas and \{van der Lee\}, Sven and Henne Holstege and Fernandez, \{Maria Victoria\} and Kehoe, \{Patrick Gavin\} and Kristel Sleegers and Martin Ingelsson and Roberta Ghidoni and Andreassen, \{Ole A\} and Holmans, \{Peter A\} and Pascual S{\'a}nchez-Juan and Rebecca Sims and Ip, \{Nancy Y\} and Lee, \{Kun Ho\} and Takeshi Ikeuchi and Alfredo Ramirez and Agustin Ruiz and Mikko Hiltunen and Jean-Charles Lambert and \{van Duijn\}, Cornelia and Mike Nalls and Ruth Frikke-Schmidt",

year = "2025",

month = may,

day = "9",

doi = "10.1101/2025.05.07.25327065",

language = "English",

series = "medRxiv",

type = "WorkingPaper",

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T1 - APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease

AU - Thomassen, Jesper Qvist

AU - Hampton, Leonard

AU - Ulms, Brittany

AU - Grenier-Boley, Benjamin

AU - Heikkinen, Sami

AU - Garcia, Pablo

AU - Castillo-Morales, Atahualapa

AU - Kikuchi, Masataka

AU - Gim, Jungsoo

AU - Cao, Han

AU - Küçükali, Fahri

AU - Amin, Najaf

AU - Yoon, Dabin

AU - de Rojas, Itziar

AU - Jerez, Pilar Alvarez

AU - Alvarez, Victoria

AU - Arosio, Beatrice

AU - Bellenguez, Celine

AU - Bergh, Sverre

AU - Billingsley, Kimberly

AU - Blauwendraat, Cornelis

AU - Boada, Merce

AU - Borroni, Barbara

AU - Bossù, Paola

AU - Bullido, María J

AU - Daniele, Antonio

AU - Carracedo, Ángel

AU - de Mendonça, Alexandre

AU - Cookson, Mark

AU - Deckert, Jürgen

AU - Dichgans, Martin

AU - Djurovic, Srdjan

AU - Dols-Icardo, Oriol

AU - Dufouil, Carole

AU - Düzel, Emrah

AU - Escott-Price, Valentina

AU - Fladby, Tormod

AU - Fratiglioni, Laura

AU - Fu, Amy K Y

AU - Galimberti, Daniela

AU - García-Alberca, Jose Maria

AU - Giedraitis, Vilmantas

AU - Garcia-Ribas, Guillermo

AU - Graff, Caroline

AU - Grimmer, Timo

AU - Grünblatt, Edna

AU - Hanon, OIivier

AU - Hausner, Lucrezia

AU - Heilmann-Hemibach, Stefanie

AU - Hort, Jakub

AU - Jessen, Frank

AU - Jensen, Kendall

AU - Jonson, Caroline

AU - Kim, Yoontae

AU - Kuznetsov, Nicole

AU - Leinonen, Ville

AU - Lipponen, Anssi

AU - Luo, Jiao

AU - Makarious, Mary

AU - Martiskainen, Henna

AU - Masullo, Carlo

AU - Mecocci, Patrizia

AU - Mehrabian, Shima

AU - Mir, Pablo

AU - Miyashita, Akinori

AU - Moebus, Susanne

AU - Mok, Kin Y

AU - Porcel, Laura Molina

AU - Moreno, Fermin

AU - Nacmias, Benedetta

AU - Parnetti, Lucilla

AU - Pastor, Pau

AU - Pérez-Tur, Jordi

AU - Peters, Oliver

AU - Pijnenburg, Yolande A L

AU - Piñol-Ripoll, Gerard

AU - Popp, Julius

AU - Rainero, Innocenzo

AU - Real, Luis M

AU - Riedel-Heller, Steffi

AU - Rodriguez-Rodriguez, Eloy

AU - Rongve, Arvid

AU - Rossi, Giacomina

AU - Royo, Jose Luis

AU - Rujescu, Dan

AU - Saltvedt, Ingvild

AU - Sáez, María Eugenia

AU - Sánchez-Valle, Raquel

AU - Sanchez-Garcia, Florentino

AU - Sandau, Nicolai

AU - Scarmeas, Nikolaos

AU - Scheffler, Katja

AU - Scherbaum, Norbert

AU - Schneider, Anja

AU - Selbæk, Geir

AU - Seripa, Davide

AU - Solfrizzi, Vincenzo

AU - Spallazzi, Marco

AU - Squassina, Alessio

AU - Stordal, Eystein

AU - Tesi, Niccoló

AU - Tremolizzo, Lucio

AU - Tripathi, Kumar P

AU - van der Flier, Wiesje M

AU - Williams, Julie

AU - Wiltfang, Jens

AU - Aarsland, Dag

AU - Singleton, Andrew B

AU - Amouyel, Philippe

AU - Debette, Stéphanie

AU - Nicolas, Gael

AU - van der Lee, Sven

AU - Holstege, Henne

AU - Fernandez, Maria Victoria

AU - Kehoe, Patrick Gavin

AU - Sleegers, Kristel

AU - Ingelsson, Martin

AU - Ghidoni, Roberta

AU - Andreassen, Ole A

AU - Holmans, Peter A

AU - Sánchez-Juan, Pascual

AU - Sims, Rebecca

AU - Ip, Nancy Y

AU - Lee, Kun Ho

AU - Ikeuchi, Takeshi

AU - Ramirez, Alfredo

AU - Ruiz, Agustin

AU - Hiltunen, Mikko

AU - Lambert, Jean-Charles

AU - van Duijn, Cornelia

AU - Nalls, Mike

AU - Frikke-Schmidt, Ruth

PY - 2025/5/9

Y1 - 2025/5/9

N2 - Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (APOE) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. Such insights may help to understand and overcome side effects, to impact clinical trial enrolment strategies, and to create the scientific basis for targeted mechanism-driven therapies in neurodegenerative diseases.

AB - Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (APOE) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. Such insights may help to understand and overcome side effects, to impact clinical trial enrolment strategies, and to create the scientific basis for targeted mechanism-driven therapies in neurodegenerative diseases.

U2 - 10.1101/2025.05.07.25327065

DO - 10.1101/2025.05.07.25327065

M3 - Preprint

C2 - 40385391

T3 - medRxiv

BT - APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease

ER -

APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease

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