TY - JOUR
T1 - APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease
AU - EADB
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 - Kehoe, Patrick Gavin
PY - 2025/12/19
Y1 - 2025/12/19
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 studies 1-10. 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 carriers 11-13, 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 studies 1-10. 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 carriers 11-13, 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 - Article (Academic Journal)
C2 - 40385391
JO - medRxiv
JF - medRxiv
ER -