Clinical Psychopharmacology and Neuroscience  
Associations between Education Years and Resting-state Functional Connectivity Modulated by APOE ε4 Carrier Status in Cognitively Normal Older Adults
Jiwon Kim1, Sunghwan Kim2, Yoo Hyun Um3, Sheng-Min Wang2, Regina EY Kim4, Yeong Sim Choe4, Jiyeon Lee4, Donghyeon Kim4, Hyun Kook Lim2,4, Chang Uk Lee1, Dong Woo Kang1
1Department of Psychiatry, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
2Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
3Department of Psychiatry, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
4Research Institute, NEUROPHET Inc., Seoul, Korea
Correspondence to: Dong Woo Kang
Department of Psychiatry, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: kato7@hanmail.net
ORCID: https://orcid.org/0000-0003-3289-075X
Received: July 12, 2023; Revised: September 13, 2023; Accepted: September 26, 2023; Published online: November 20, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Objective: Cognitive reserve has emerged as a concept to explain the variable expression of clinical symptoms in the pathology of Alzheimer’s disease (AD). The association between years of education, a proxy of cognitive reserve, and resting-state functional connectivity (rFC), a representative intermediate phenotype, has not been explored in the preclinical phase, considering risk factors for AD. We aimed to evaluate whether the relationship between years of education and rFC in cognitively preserved older adults differs depending on amyloid-beta deposition and APOE ε4 carrier status as effect modifiers.
Methods: A total of 121 participants underwent functional magnetic resonance imaging, [18F] flutemetamol positron emission tomography-computed tomography, APOE genotyping, and a neuropsychological battery. Potential interactions between years of education and AD risk factors for rFC of AD-vulnerable neural networks were assessed with wholebrain voxel-wise analysis.
Results: We found a significant education years-by-APOE ε4 carrier status interaction for the rFC from the seed region of the central executive (CEN) and dorsal attention networks. Moreover, there was a significant interaction of rFC between right superior occipital gyrus and the CEN seed region by APOE ε4 carrier status for memory performances and overall cognitive function.
Conclusion: In preclinical APOE ε4 carriers, higher years of education were associated with higher rFC of the AD vulnerable network, but this contributed to lower cognitive function. These results contribute to a deeper understanding of the impact of cognitive reserve on sensitive functional intermediate phenotypic markers in the preclinical phase of AD.
Keywords: Apolipoproteins E; fMRI; Education; Cognitive function; Aged

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