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The impact of cardiorespiratory fitness on Alzheimer's disease biomarkers and their relationships with cognitive decline

Authors

A J Paulsen, I Driscoll, B M Breidenbach, M P Glittenberg, S R Lose, Y Ma, M A Sager, C M Carlsson, C L Gallagher, B P Hermann, K Blennow, H Zetterberg, S Asthana, S C Johnson, T J Betthauser, B T Christian, D B Cook, O C Okonkwo
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Abstract

medRxiv [Preprint]. 2025 Mar 6:2025.03.03.25323245. doi: 10.1101/2025.03.03.25323245.

ABSTRACT

INTRODUCTION: Relationships between core Alzheimer's disease (AD) biomarker accumulation and cognitive decline are well-established and the literature generally suggests a favorable relationship of cardiorespiratory fitness (CRF) on AD biomarker accumulation and cognition. Differences in risk of biomarker status conversion or accumulation rates by CRF, or their potential interactive relationships with cognitive decline remain largely unknown.

METHODS: Participants (N=533; MeanAGE=65, 70% female) from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention underwent serial blood draws, and cognitive and imaging assessments (MeanFollow-up=6.0 years). PET imaging of amyloid-β (Aβ) and tau (T) and plasma phosphorylated tau-217 (pTau-217) were used to determine biomarker status (+/-). Sex-specific estimated CRF (eCRF) tertiles were created using a validated equation. Kaplan-Meier survival curves and Cox-proportional hazards models characterized the risk of becoming biomarker-positive. Linear mixed effects models estimated associations between baseline eCRF and core AD biomarker accumulation and whether eCRF modified relationships between biomarker accumulation and cognitive decline. Analyses were stratified by biomarker +/- status.

RESULTS: No significant relationships were observed between eCRF and biomarker trajectories. However, those in the high eCRF group who were also Aβ- (HR[95%CI]=0.42[0.20, 0.88]) and pTau-217-(HR[95%CI]=0.45[0.21, 0.97]) at baseline had a significantly lower risk of becoming biomarker-positive. There was a significant attenuation of the detrimental relationship between Aβ accumulation and cognitive decline for those with high eCRF and Aβ+/T+.

DISCUSSION: While CRF did not influence core AD biomarker accumulation trajectories, high CRF did seem to protect against becoming biomarker-positive and attenuate the known deleterious relationship between biomarker accumulation and cognitive decline in Aβ+/T+.

PMID:40093252 | PMC:PMC11908334 | DOI:10.1101/2025.03.03.25323245