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

Jesper Qvist Thomassen; Hampton L. Leonard; Brittany Ulms; Benjamin Grenier‐Boley; Sami Heikkinen; Pablo García‐González; Atahualapa Castillo-Morales; Masataka Kikuchi; Jungsoo Gim; Han Cao; Fahri Küçükali; Najaf Amin; Dabin Yoon; Itziar de Rojas; Pilar Álvarez Jerez; Victoria Álvarez; Beatrice Arosio; Céline Bellenguez; Sverre Bergh; Kimberley J. Billingsley; Cornelis Blauwendraat; Merçé Boada; Barbara Borroni; Paola Bossù; Maria Jesus Bullido; Antonio Daniele; Ángel Carracedo; Alexandre de Mendonça; Mark Cookson; Jürgen Deckert

doi:10.1101/2025.05.07.25327065

Genetic & Genomic MedicinemedRxivMay 7, 2025

Preprint

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

Jesper Qvist Thomassen iD, Hampton L. Leonard iD, Brittany Ulms, Benjamin Grenier‐Boley iD, Sami Heikkinen iD, Pablo García‐González iD, Atahualapa Castillo-Morales, Masataka Kikuchi iD, Jungsoo Gim iD, Han Cao iD, Fahri Küçükali iD, Najaf Amin iD, Dabin Yoon, Itziar de Rojas iD, Pilar Álvarez Jerez iD, Victoria Álvarez iD, Beatrice Arosio iD, Céline Bellenguez iD, Sverre Bergh iD, Kimberley J. Billingsley iD, Cornelis Blauwendraat iD, Merçé Boada iD, Barbara Borroni iD, Paola Bossù iD, Maria Jesus Bullido iD, , Eystein Stordal iD

Abstract

Among the more than 90 identified genetic risk loci for late-onset Alzheimers disease (AD) and related dementias, the apolipoprotein E gene (APOE) {varepsilon}2/{varepsilon}3/{varepsilon}4 polymorphisms 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 {varepsilon}4 increases and for how {varepsilon}2 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 {varepsilon}4 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 {varepsilon}4 and {varepsilon}2 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.

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