Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer’s Disease: A Longitudinal Study

Article type: Research Article

Authors: Chi, Hao-Chen^{a; 1} | Ma, Ling-Zhi^{a; 1} | Wang, Zhi-Bo^a | Sheng, Ze-Hu^a | Liu, Jia-Yao^a | Mi, Yin-Chu^b | Fu, Yan^a | Huang, Yi-Ming^a | Han, Shuang-Ling^a | Gao, Pei-Yang^a | for the Alzheimer’s Disease Neuroimaging Initiative² | Tan, Lan^{a; *} | Yu, Jin-Tai^{c; *}

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China | [b] Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China | [c] Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence: [*] Correspondence to: Jin-Tai Yu, MD, PhD, National Center for Neurological Diseases in China, Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China. Tel.: +86 21 52888160; Fax: +86 21 62483421; E-mail: jintai_yu@fudan.edu.cn and Lan Tan, MD, PhD, Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. E-mail: dr.tanlan@163.com.

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

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://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 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.

Abstract: Background:Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective:To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer’s disease (AD), especially in its different clinical stages. Methods:We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results:Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions:Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative database, frailty, modified frailty index, neuropsychiatric symptoms

DOI: 10.3233/JAD-231111

Journal: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 629-642, 2024