The Effect of Cholinesterase Inhibitors on Neurodegeneration in Individuals with Amnestic Mild Cognitive Impairment
Gihwan Byeon1, Min Soo Byun2,3, Dahyun Yi4, Hyejin Ahn4,5, Gijung Jung4, Bo Kyung Sohn6, Joon Hyung Jung7, Yoon Young Chang6, Kyungtae Kim2, Hyeji Choi2, Yoon Hee Kim2, Yu Kyeong Kim8, Koung Mi Kang9, Chul-Ho Sohn9, Dong Young Lee2,3,4,5; for the KBASE Research Group
1Department of Psychiatry, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea
2Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea
3Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
4Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, Korea
5Interdisciplinary Program of Cognitive Science, College of Humanities, Seoul National University, Seoul, Korea
6Department of Psychiatry, Sanggye Paik Hospital, College of Medicine, Inje University, Seoul, Korea
7Department of Neuropsychiatry, Chungbuk National University Hospital, Cheongju, Korea
8Department of Nuclear Medicine, SMG‑SNU Boramae Medical Center, Seoul, Korea
9Department of Radiology, Seoul National University Hospital, Seoul, Korea
Correspondence to: Dong Young Lee
Department of Neuropsychiatry, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: selfpsy@snu.ac.kr
ORCID: https://orcid.org/0000-0001-8976-8320
Received: September 2, 2024; Revised: November 27, 2024; Accepted: December 31, 2024; Published online: February 11, 2025.
© The Korean College of Neuropsychopharmacology. All rights reserved.

Abstract
Objective: Cholinesterase inhibitors (ChEIs) are effective in treating mild to moderate Alzheimer’s disease (AD) dementia by compensating for acetylcholine deficiency. While their use in mild cognitive impairment (MCI) lacks strong trial support, some studies suggest they may delay neurodegeneration. This study aims to investigate ChEIs’ neuroprotective effects in individuals with amnestic MCI (aMCI) using multi-modal neuroimaging, and to determine if amyloid-beta (Av) deposition influences these effects.
Methods: Longitudinal data from a cohort study were retrospectively analyzed. A total of 118 aMCI patients (ages 55− 90), who underwent baseline evaluations encompassing the assessment of ChEI use and [11C] Pittsburgh compound B-positron emission tomography (PET), were included in the analyses. All participants also received baseline and 2-year follow-up magnetic resonance imaging and [18F] fluorodeoxyglucose-PET imaging.
Results: The ChEI use group exhibited a significantly lesser decline in AD-signature region cerebral metabolism (AD-CM) over a 2-year period than the ChEI non-use group (B = 0.089, 95% CI: 0.030−0.149). However, there was no significant difference in the 2-year change of AD-signature region cortical thickness (AD-CT) (B = 0.032, 95% CI: −0.075 to 0.138) and hippocampal volume (B = −88.013, 95% CI: −323.900 to 147.874) between the ChEI use and non-use groups. The presence of Aβ pathology did not moderate the effect of ChEI use on AD-CM, AD-CT, or hippocampal volume.
Conclusion: The findings suggest that ChEIs may delay functional neurodegeneration in aMCI individuals, irrespective of the presence of amyloid pathology.
Keywords: Alzheimer’s disease; Biomarkers; Cholinesterase inhibitors; Neuroimaging


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