Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jan 15, 2021; 12(1): 69-83
Published online Jan 15, 2021. doi: 10.4239/wjd.v12.i1.69
Impact of diabetes mellitus and cardiometabolic syndrome on the risk of Alzheimer’s disease among postmenopausal women
Longjian Liu, Edward J Gracely, Xiaoyan Yin, Howard J Eisen
Longjian Liu, Edward J Gracely, Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA 19104, United States
Edward J Gracely, Department of Family, Community and Preventive Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, United States
Xiaoyan Yin, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
Howard J Eisen, Heart and Vascular Institute, Pennsylvania State University, Hershey, PA 17033, United States
Author contributions: Liu L formulated the research questions and analysis designs, performed data analysis and drafted the manuscript; Gracely EJ critically reviewed and carefully edited this manuscript; Yin X and Eisen HJ critically reviewed and gave comments; all authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by Drexel University Institutional Review Board (Approval No. 1910007425).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors report no potential conflicts of interest relevant to this article.
Data sharing statement: Researchers who are interested in using the data should directly apply to the U.S. National Heart, Lung and Blood Institute through a standard application process. The authors are unable to share with the data.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Longjian Liu, MD, MSc, PhD, Doctor, Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Office 515, Nesbitt Hall, 3215 Market Street, Philadelphia, PA 19104, United States. longjian.liu@drexel.edu
Received: May 18, 2020
Peer-review started: May 18, 2020
First decision: September 24, 2020
Revised: November 13, 2020
Accepted: December 22, 2020
Article in press: December 22, 2020
Published online: January 15, 2021

In spite of an increase in the incidence and prevalence of diabetes mellitus (DM) and Alzheimer’s disease (AD) in the aging population worldwide, limited attention has been paid to their potential association.


To investigate the association of DM and cardiometabolic syndrome (CMS, a precursor to DM) with risk of incident AD among postmenopausal women.


Postmenopausal women aged 50-79 (n = 63117) who participated in the U.S. Women’s Health Initiative Observational Study (WHIOS), recruited in 1993-1998, without baseline AD and followed up through March 1, 2019, were analyzed. AD was classified by participant-reported history of doctor-diagnosis of incident AD in the WHIOS. DM was defined by participant-report or treated because of diabetes or serum glucose concentrations ≥ 126 mg/dL. CMS was defined as having ≥ 3 of five CMS components: large waist circumference, high blood pressure, elevated triglycerides, elevated glucose, and low high-density lipoprotein cholesterol. The associations of DM and CMS with AD were analyzed using Cox’s proportional hazards regression analysis.


During a median follow-up of 20 years (range: 3.36 to 23.36 years), of 63117 participants, 8340 developed incident AD. Women with DM had significantly higher incidence of AD [8.5, 95% confidence interval (CI): 8.0-9.0 per 1000 person-years (PY)] than those without DM (7.1, 95%CI: 6.9-7.2 per 1000 PY). Multivariate Cox’s regression analysis indicated that women with DM or CMS had a significantly higher risk of AD than those without DM or CMS. The corresponding hazard ratios [HR (95%CI)] were 1.22 (1.13-1.31, P < 0.001) in subjects with DM, and 1.18 (1.09-1.27, P < 0.001) in subjects with CMS. The HRs diminished with age and became non-significant in the oldest age group.


During a median follow-up of 20 years, DM and CMS were significantly associated with the risk of AD among postmenopausal women. More specifically, women aged 50-69 with DM or CMS vs those without these conditions had significantly higher relative risks of AD than the relative risks of AD in those aged 70-79 with DM or CMS vs those without DM or CMS.

Keywords: Epidemiology, Diabetes mellitus, Cardiometabolic disorders, Alzheimer’s disease, Aging population

Core Tip: Data from population-based studies on the association of diabetes and cardiometabolic syndrome (CMS) with risk of Alzheimer’s disease (AD) was limited. This study, using data from one of the largest population-based cohort studies in the United States women aged 50-79 at baseline to test a hypothesis that diabetes and CMS are significantly associated with the risk of AD. This analysis is one of the first studies to prospectively test this hypothesis using a large-scale longitudinal cohort data. Findings from the study add new evidence to the body of research literature and provide new insights into the prevention of AD through control of diabetes and CMS.