Apolipoprotein E ε4 Modulates Cognitive Profiles, Hippocampal Volume, and Resting-State Functional Connectivity in Alzheimer's Disease

Article type: Research Article

Authors: Wang, Xiao^{a; 1} | Wang, Jinhui^{b; c; d; 1} | He, Yi^a | Li, Huiying^a | Yuan, Huishu^e | Evans, Alan^f | Yu, Xin^a | He, Yong^{b; *} | Wang, Huali^{a; *}

Affiliations: [a] Dementia Care & Research Center, Peking University Institute of Mental Health; Key Laboratory for Mental Health, Ministry of Health (Peking University); Beijing Municipal Key Laboratory for Translational Research on Diagnosis and Treatment of Dementia, Beijing, China | [b] State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China | [c] Center for Cognition and Brain Disorders, Hangzhou Normal University, Hangzhou, China | [d] Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, China | [e] Department of Radiology, Peking University Third Hospital, Beijing, China | [f] McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada

Correspondence: [*] Correspondence to: Huali Wang, MD, Peking University Institute of Mental Health, Beijing 100191, China. Tel.: +86 10 82801983; E-mail: [email protected] and Yong He, PhD, State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, 100875, China. Tel.: +86 10 5880 2036; E-mail: [email protected].

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

Abstract: The apolipoprotein E ε4 (APOE ε4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). Numerous studies have suggested that the modulation of APOE ε4 affects cognition and brain structure and function in healthy populations, particularly in the hippocampus, a key area associated with AD pathology. However, the effect of APOE ε4 allele on cognitive performance, hippocampal structural morphology, and specifically on functional characteristics in patients with AD remains poorly understood. Here, we employed a neuropsychological battery test and multi-modal structural MRI and resting-state functional MRI dataset to systematically investigate cognitive performance, hippocampal structural volume, and functional properties (including local low-frequency oscillating amplitude, intra-regional functional synchrony, and inter-regional functional connectivity) in 16 APOE ε4-carriers and 26 non-carriers at early stages of AD. Compared to non-carriers, APOE ε4-carriers exhibited poorer performance on recognition performance, but performed better on the late item generation of the verbal fluency task (associated with executive function). Structural imaging analysis revealed that APOE ε4-carriers exhibited smaller left hippocampal volumes compared to non-carriers, and the result remains significant after correcting for effects of brain size. Functional imaging analysis revealed that APOE ε4-carriers exhibited decreased amplitude of low-frequency fluctuations in the left hippocampus, non-significant changes in intra-regional synchronization within the hippocampus and decreased hippocampal functional connectivity predominantly in components of the default-mode network including the medial frontal and parietal cortices and the lateral temporal cortical regions. Taken together, our results showed APOE genotypic effects on the cognitive profile and hippocampal structural and functional characteristics in patients at early stages of AD, thus providing empirical evidence for the modulation of the APOE genotype on disease phenotype.

Keywords: Apolipoprotein E, default-mode, functional connectivity, hippocampus, resting-state functional MRI

DOI: 10.3233/JAD-142556

Journal: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 781-795, 2015