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

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene ( APOE ) ɛ2/ɛ3/ɛ4 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 ɛ4 increases and for how ɛ2 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 ε4 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.