APOE-Stratified Genome-Wide Association Analyses Provide Insights into the Genetic Etiology of Alzheimers's Disease

@article{thomassen2026apoestratified,
  title = {{APOE-Stratified Genome-Wide Association Analyses Provide Insights into the Genetic Etiology of Alzheimers's Disease}},
  author = {Jesper Qvist Thomassen and Hampton Leonard and Brittany Ulms and Benjamin Grenier‐Boley and Sami Heikkinen and Pablo García‐González and Atahualapa Castillo-Morales and Masataka Kikuchi and Jungsoo Gim and Han Cao and Fahri Küçükali and Najaf Amin and Dabin Yoon and Itziar de Rojas and Pilar Álvarez Jerez and Victoria Álvarez and Beatrice Arosio and Céline Bellenguez and Sverre Bergh and Kimberley J. Billingsley and Cornelis Blauwendraat and Merçé Boada and Barbara Borroni and Paola Bossù and Maria Jesus Bullido and Antonio Daniele and Ángel Carracedo and Alexandre de Mendonça and Mark Cookson and Jürgen Deckert and Martin Dichgans and Srdjan Djurovic and Oriol Dols‐Icardo and Carole Dufouil and Emrah Düzel and Valentina Escott‐Price and Tormod Fladby and Laura Fratiglioni and Amy K.Y. Fu and Daniela Galimberti and José María García‐Alberca and Vilmantas Giedraitis and Guillermo García‐Ribas and Caroline Graff and Timo Grimmer and Edna Grünblatt and Olivier Hanon and Lucrezia Hausner and Stefanie Heilmann‐Heimbach and Jakub Hort and Frank Jessen and Kendall Jensen and Caroline Jonson and Y T Kim and Nicole Kuznetsov and Ville Leinonen and Anssi Lipponen and Jiao Luo and Mary B. Makarious and Henna Martiskainen},
  journal = {Nature Genetics},
  year = {2026},
  month = sep,
  doi = {10.1038/s41588-026-02713-9},
  url = {https://hal.science/hal-05784438v1},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - APOE-Stratified Genome-Wide Association Analyses Provide Insights into the Genetic Etiology of Alzheimers's Disease
AU  - Jesper Qvist Thomassen
AU  - Hampton Leonard
AU  - Brittany Ulms
AU  - Benjamin Grenier‐Boley
AU  - Sami Heikkinen
AU  - Pablo García‐González
AU  - Atahualapa Castillo-Morales
AU  - Masataka Kikuchi
AU  - Jungsoo Gim
AU  - Han Cao
AU  - Fahri Küçükali
AU  - Najaf Amin
AU  - Dabin Yoon
AU  - Itziar de Rojas
AU  - Pilar Álvarez Jerez
AU  - Victoria Álvarez
AU  - Beatrice Arosio
AU  - Céline Bellenguez
AU  - Sverre Bergh
AU  - Kimberley J. Billingsley
AU  - Cornelis Blauwendraat
AU  - Merçé Boada
AU  - Barbara Borroni
AU  - Paola Bossù
AU  - Maria Jesus Bullido
AU  - Antonio Daniele
AU  - Ángel Carracedo
AU  - Alexandre de Mendonça
AU  - Mark Cookson
AU  - Jürgen Deckert
AU  - Martin Dichgans
AU  - Srdjan Djurovic
AU  - Oriol Dols‐Icardo
AU  - Carole Dufouil
AU  - Emrah Düzel
AU  - Valentina Escott‐Price
AU  - Tormod Fladby
AU  - Laura Fratiglioni
AU  - Amy K.Y. Fu
AU  - Daniela Galimberti
AU  - José María García‐Alberca
AU  - Vilmantas Giedraitis
AU  - Guillermo García‐Ribas
AU  - Caroline Graff
AU  - Timo Grimmer
AU  - Edna Grünblatt
AU  - Olivier Hanon
AU  - Lucrezia Hausner
AU  - Stefanie Heilmann‐Heimbach
AU  - Jakub Hort
AU  - Frank Jessen
AU  - Kendall Jensen
AU  - Caroline Jonson
AU  - Y T Kim
AU  - Nicole Kuznetsov
AU  - Ville Leinonen
AU  - Anssi Lipponen
AU  - Jiao Luo
AU  - Mary B. Makarious
AU  - Henna Martiskainen
PY  - 2026
DA  - 2026/09/14
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02713-9
UR  - https://hal.science/hal-05784438v1
AB  - Among the more than 90 identified genetic risk loci for late-onset Alzheimer’s disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1–10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 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. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases. Genome-wide association analyses of Alzheimer’s disease stratified by APOE carrier status identify variants whose effects are attenuated or augmented by the ε4 risk allele.
SN  - 1061-4036
SN  - 1546-1718
ER  -