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. 2025 Sep;12(8):100222.
doi: 10.1016/j.tjpad.2025.100222. Epub 2025 Jun 9.

Trajectories of Cardiorespiratory Fitness Measured by Metabolic Equivalents and the Risk of Alzheimer's and Related Dementias

Edward Zamrini  1 , Yan Cheng  2 , Peter Kokkinos  2 , Charity J Morgan  3 , Charles Faselis  2 , Helen M Sheriff  2 , Yijun Shao  2 , Xuemei Sui  4 , Ali Ahmed  2 , Qing Zeng  5
Affiliations

Trajectories of Cardiorespiratory Fitness Measured by Metabolic Equivalents and the Risk of Alzheimer's and Related Dementias

Edward Zamrini et al. J Prev Alzheimers Dis. 2025 Sep.

Abstract

Background: Higher fitness levels have been reported to protect against Alzheimer's Disease and Related Dementias (ADRD). However, the association between changes in fitness over time and ADRD risk remains unknown. This study aims to identify clusters of metabolic equivalents (METs) trajectories and examine their correlation with incident ADRD.

Methods: A retrospective cohort study was conducted among Veterans with ≥3 standardized exercise treadmill tests (ETT) between 2000 and 2017. The exposure was change in fitness expressed in metabolic equivalents (METs). METs are based on treadmill speed, grade, and time. One MET is equivalent to 3.5 ml per kg of body weight per minute. The outcome was incident ADRD after the final ETT test, identified by diagnosis codes. Standardized METs scores were generated using mean and standard deviation for each age and sex stratum. Latent class growth analysis (LCGA) identified trajectory clusters. We assessed the association between clusters and ADRD using unadjusted Kaplan-Meier curves (overall and by age groups) and a multivariate Cox regression model adjusted for baseline characteristics at the first ETT.

Results: A total of 75,851 veterans were included. The average number of ETTs was 4.0 ± 1.8, with the average time gap of 6.5 ± 3.8 years between first and last test. We identified five trajectory clusters: Group 1 (n = 22,485), Group 2 (n = 22,694), Group 3 (n = 6691), Group 4 (n = 19,386), and Group 5 (n = 4595). All groups, except for Group 3, showed a stable and slight improvement or decline over time, differing only in their initial standardized METs scores: Group 5 had the highest initial score, Group 1 had the lowest initial score, while Group 3 started out with a score almost as high as Group 4 and dropped to as low as Group 1. Compared to Group 1, Group 3 had a 12 % reduced risk of developing ADRD (HR = 0.88; 95 % CI: 0.77 - 1.01; p = 0.0660), with a greater reduction than Group 2 (10 %) but less than Group 4 (17 %) or Group 5 (24 %).

Discussion: Our findings underscore the potential benefits of maintaining fitness to reduce the risk of ADRD with age. Although declining fitness levels are associated with an increased risk, the initial higher baseline fitness provides a degree of ongoing protection against ADRD.

Keywords: Alzheimer's and related dementias; Analysis; Cardiorespiratory fitness; Cluster; Trajectory.

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Conflict of interest statement

Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qing Zeng-Treitler reports financial support was provided by National Institute on Aging. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig 1
Fig. 1
Flowchart of Cohort Selection.
Fig 2
Fig. 2
Joint Trajectory Clusters.
Fig 3
Fig. 3
Unadjusted Kaplan Meier in the Overall.
Fig 4
Fig. 4
Unadjusted Kaplan Meier in different age-specific subgroups.
Fig 5
Fig. 5
Unadjusted and Adjusted Hazard Ratio for Risk of ADRD.
See this image and copyright information in PMC

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