Research Paper|Volume 14, Issue 24|pp 9782—9804

Associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer’s disease biomarkers

Alexander M. Kulminski¹, Ethan Jain-Washburn¹, Elena Loiko¹, Yury Loika¹, Fan Feng¹, Irina Culminskaya¹, for the Alzheimer’s Disease Neuroimaging Initiative²

¹Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27705, USA
²Center for Imaging of Neurodegenerative Disease, University of California, San Francisco, CA 94143, USA

* Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Received: August 4, 2022Accepted: October 31, 2022Published: November 17, 2022

https://doi.org/10.18632/aging.204384

Copyright: © 2022 Kulminski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Capturing the genetic architecture of Alzheimer’s disease (AD) is challenging because of the complex interplay of genetic and non-genetic factors in its etiology. It has been suggested that AD biomarkers may improve the characterization of AD pathology and its genetic architecture. Most studies have focused on connections of individual genetic variants with AD biomarkers, whereas the role of combinations of genetic variants is substantially underexplored. We examined the associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with cerebrospinal fluid (CSF) and plasma amyloid β (Aβ40 and Aβ42) and tau biomarkers. Our findings support associations of the ε4 alleles with both plasma and CSF Aβ42 and CSF tau, and the ε2 alleles with baseline, but not longitudinal, CSF Aβ42 measurements. We found that the ε4-bearing polygenic profiles conferring higher and lower AD risks are differentially associated with tau but not Aβ42. Modulation of the effect of the ε4 alleles by TOMM40 and APOC1 variants indicates the potential genetic mechanism of differential roles of Aβ and tau in AD pathogenesis.