Youjie Zeng, Noah Cook, Chenyu Yang, Sathesh K. Sivasankaran, Masashi Fujita, Zachary A. Gardell, Yann Le Guen, Daichi Shigemizu, Kouichi Ozaki, Takashi Morizono, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Cyril Pottier, Carlos Cruchaga, Valerio Napolioni, M. Ryan Corces, Vilas Menon, Michael D. Greicius, Michaël E. Belloy
Abstract INTRODUCTION Genetics studies can identify drug targets that counteract the effects of the apolipoprotein E ε4 allele ( APOE *4) on Alzheimer's disease (AD) but have remained limited in power and crucially did not assess genetic findings with regard to APOE *4's cell‐type‐specific impact on pathobiology. METHODS We conducted a novel APOE *4‐stratified genome‐wide association study (GWAS) of AD ( N = 447,669) and integrated results with brain cell‐type‐specific multi‐omics data to identify APOE *4 and cell‐type‐specific AD genes, followed by compound and drug repurposing. RESULTS In APOE *4 non‐carriers ( APOE *4−) and carriers ( APOE *4+), we respectively identified 33 and 11 cell type–gene pairs with strong prioritization support. Oligodendrocytes displayed the largest proportion of APOE *4+ genes. Several genes were druggable and pinpointed APOE *4‐stratified drugs or compounds. DISCUSSION We identified a set of APOE *4‐stratified genes that may be causal for AD through brain cell‐type‐specific mechanisms. We additionally identified compounds that may shed light on therapeutic avenues for treating AD based on an individual's APOE *4 status.