Refining Risk for Alzheimer’s Disease Among Heterozygous APOEɛ4 Carriers

Article type: Short Communication

Authors: Patel, Smita^{a; 1} | Wei, Jun^{b; 1} | Shi, Zhuqing^b | Rifkin, Andrew S.^b | Zheng, S. Lilly^b | Gelfman, Elizabeth^c | Duggan, David^d | Helfand, Brian T.^{b; e} | Hulick, Peter J.^f | Xu, Jianfeng^{b; e; *}

Affiliations: [a] Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA | [b] Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA | [c] Northwestern Feinberg School of Medicine, Chicago, IL, USA | [d] Translational Genomics Research Institute, Part of City of Hope, Phoenix, AZ, USA | [e] University of Chicago Pritzker School of Medicine, Chicago, IL, USA | [f] Neaman Center for Personalized Medicine, NorthShore University HealthSystem, Evanston, IL, USA

Correspondence: [*] Correspondence to: Jianfeng Xu, 1001 University Place, Evanston, IL 60201, USA. Tel.: +1 224 364 7501; Fax: +1 224 364 7675; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: In a large population-based cohort, we show not all heterozygous APOE ɛ4 carriers are at increased risk for Alzheimer’s disease (AD); a significantly higher AD proportion was only found for ɛ3/ɛ4, not ɛ2/ɛ4. Among ɛ3/ɛ4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ɛ4 carriers for subjects at the top 5th-percentile PRS. Family history was no longer a significant predictor of AD risk after adjusting APOE and PRS.

Keywords: Alzheimer’s disease, APOE , genetic counseling, polygenic risk score, UK Biobank

DOI: 10.3233/JAD-230156

Journal: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 483-489, 2023