Journal Article

DZNE-2026-01042

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Thomassen, J. Q. ; Leonard, H. ; Ulms, B. ; Grenier-Boley, B. ; Heikkinen, S. ; Garcia-González, P. ; Castillo-Morales, A. ; Kikuchi, M. ; Gim, J. ; Cao, H. ; Küçükali, F. ; Amin, N. ; Yoon, D. ; de Rojas, I. ; Alvarez Jerez, P. ; Alvarez, V. ; Arosio, B. ; Bellenguez, C. ; Bergh, S. ; Billingsley, K. ; Blauwendraat, C. ; Boada, M. ; Borroni, B. ; Bossù, P. ; Bullido, M. J. ; Daniele, A. ; Carracedo, Á. ; de Mendonça, A. ; Cookson, M. ; Deckert, J. ; Dichgans, M.DZNE* ; Djurovic, S. ; Dols-Icardo, O. ; Dufouil, C. ; Düzel, E.DZNE* ; Escott-Price, V. ; Fladby, T. ; Fratiglioni, L. ; Fu, A. K. Y. ; Galimberti, D. ; García-Alberca, J. M. ; Giedraitis, V. ; Garcia-Ribas, G. ; Graff, C. ; Grimmer, T. ; Grünblatt, E. ; Hanon, O. ; Hausner, L. ; Heilmann-Heimbach, S. ; Hort, J. ; Jessen, F.DZNE* ; 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, K. Y. ; Molina Porcel, L. ; Moreno, F. ; Nacmias, B. ; Parnetti, L. ; Pastor, P. ; Pérez-Tur, J. ; Peters, O.DZNE* ; Pijnenburg, Y. A. L. ; Piñol-Ripoll, G. ; Popp, J. ; Rainero, I. ; Real, L. M. ; Riedel-Heller, S. ; Rodriguez-Rodriguez, E. ; Rongve, A. ; Rossi, G. ; Royo, J. L. ; Rujescu, D. ; Saltvedt, I. ; Sáez, M. E. ; Sánchez-Valle, R. ; Sanchez-Garcia, F. ; Sandau, N. ; Scarmeas, N. ; Scheffler, K. ; Scherbaum, N. ; Schneider, A.DZNE* ; Selbæk, G. ; Seripa, D. ; Solfrizzi, V. ; Spallazzi, M. ; Squassina, A. ; Stordal, E. ; Tesi, N. ; Tremolizzo, L. ; Tripathi, K. P. ; van der Flier, W. M. ; Williams, J. ; Wiltfang, J.DZNE* ; Aarsland, D. ; Singleton, A. B. ; Amouyel, P. ; Debette, S. ; Tsolaki, M. ; Nicolas, G. ; van der Lee, S. ; Holstege, H. ; Fernandez, M. V. ; Kehoe, P. G. ; Sleegers, K. ; Ingelsson, M. ; Ghidoni, R. ; Andreassen, O. A. ; Holmans, P. A. ; Sánchez-Juan, P. ; Sims, R. ; Ip, N. Y. ; Lee, K. H. ; Ikeuchi, T. ; Ramirez, A.DZNE* ; Ruiz, A. ; Hiltunen, M. ; Lambert, J.-C. ; van Duijn, C. ; Nalls, M. ; Frikke-Schmidt, R.

2026
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-026-02713-9

Abstract: 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.

Keyword(s): Genome-Wide Association Study (MeSH) ; Humans (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Quantitative Trait Loci (MeSH) ; Apolipoprotein E4: genetics (MeSH) ; Apolipoproteins E ; Apolipoprotein E4

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Contributing Institute(s):

1. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
2. Clinical Neurophysiology and Memory (AG Düzel)
3. Clinical Alzheimer’s Disease Research (AG Jessen)
4. Translational Dementia Research (Bonn) (AG Schneider)
5. Patient Studies (Bonn) (Patient Studies (Bonn))
6. Biomarker-Assisted Early Detection of Dementias (AG Peters)
7. Molecular biomarkers for predictive diagnostics of neurodegenerative diseases (AG Wiltfang)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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