S.-Y. He¹, W.-M. Su¹, X.-J. Wen², S.-J. Lu³, B. Cao¹, B. Yan¹, Y.-P. Chen¹

Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; 2. West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; 3. Department of Respiratory, The Fourth People’s Hospital of Chengdu, Mental Health Center of Chengdu, Chengdu, 610036, Sichuan, China.

Corresponding Author: Yong-Ping Chen, Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Tel: (86)-189-8060-6964. Email: Yongping Chen (yongping.chen@wchscu.edu.cn). Alternate corresponding author: Bo Yan, Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Tel: (86)-189-8060-1689. Email: yanbo96@163.com

Abstract

BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by intricate genetic and environmental etiology. The objective of this study was to identify robust non-genetic risk factors for AD through an updated umbrella review.

METHODS: We conducted a comprehensive search of meta-analyses and systematic reviews on non-genetic risk factors associated with AD in PubMed, Cochrane, Embase, and Ovid Medline up to June 30, 2023. After collecting data, we estimated the summary effect size and their 95% confidence intervals. The degree of heterogeneity between studies was assessed using I² statistics and a 95% prediction interval was determined. Additionally, we evaluated potential excess significant bias and small study effects within the selected candidate studies.

RESULTS: The umbrella review encompassed a total of 53 eligible papers, which included 84 meta-analyses covering various factors such as lifestyle, diet, environmental exposures, comorbidity or infections, drugs, and biomarkers. Based on the evidence classification criteria employed in this study, two factors as convincing evidence (Class I), including rheumatoid arthritis (RA), potentially reduced the risk of AD, but diabetes significantly increased the risk of AD. Furthermore, three factors as highly suggestive evidence (Class II), namely depression, high homocysteine, and low folic acid level, potentially increased the risk of AD.

CONCLUSION: Our findings highlight several risk factors associated with AD that warrant consideration as potential targets for intervention. However, it is crucial to prioritize the identified modifiable risk factors, namely rheumatoid arthritis, diabetes, depression, elevated homocysteine levels, and low folic acid levels to effectively address this complex neurodegenerative disorder.

Key words: Alzheimer’s disease, modifiable risk factors, meta-analysis, umbrella review.

GKB-NON-2024-00617