Impact of Apolipoprotein E4 on the Locus Coeruleus Functional Connectivity in Preclinical Alzheimer’s Disease

Article type: Research Article

Authors: Um, Yoo Hyun^a | Wang, Sheng-Min^b | Kang, Dong Woo^c | Kim, Sunghwan^b | Lee, Chang Uk^c | Kim, Donghyeon^d | Choe, Yeong Sim^d | Kim, Regina E.Y.^d | Lee, Soyoung^{e; f} | Lee, Min-Kyung^g | Lim, Hyun Kook^{b; h; *}

Affiliations: [a] Department of Psychiatry, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea | [b] Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea | [c] Department of Psychiatry, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea | [d] Research Institute, Neurophet Inc., Seoul, Korea | [e] Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA | [f] Department of Psychiatry, Harvard Medical School, Boston, MA, USA | [g] Department of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea | [h] CMC Institute for Basic Medical Science, The Catholic Medical Center of The Catholic University of Korea, Seoul, Korea

Correspondence: [*] Correspondence to: Hyun Kook Lim, MD, PhD, Professor, Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10, 63-ro, Yeongdeungpo-gu, Seoul, 07345, Korea. Tel.: +82 2 3779 1048; Fax: +82 2 780 6577; E-mail: [email protected].

Abstract: Background:Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer’s disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4). Objective:This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition. Methods:A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values. Results:The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. Conclusions:These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies.

Keywords: Alzheimer’s disease, apolipoprotein E4, functional connectivity, locus coeruleus, preclinical

DOI: 10.3233/JAD-240065

Journal: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 705-714, 2024