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

Adam J Paulsen; Ira Driscoll; Brianne M Breidenbach; Matthew Glittenberg; Sarah R Lose; Yue Ma; Mark A Sager; Cynthia M Carlsson; Catherine L Gallagher; Bruce P Hermann; Kaj Blennow; Henrik Zetterberg; Sanjay Asthana; Sterling C Johnson; Tobey J Betthauser; Bradley T Christian; Dane B Cook; Ozioma C Okonkwo

doi:10.1002/trc2.70122

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

Alzheimers Dement (N Y). 2025 Jun 24;11(2):e70122. doi: 10.1002/trc2.70122. eCollection 2025 Apr-Jun.

Authors

Adam J Paulsen^{1

2}, Ira Driscoll^{1

2}, Brianne M Breidenbach^{1

2}, Matthew Glittenberg^{1

2}, Sarah R Lose^{1

2}, Yue Ma¹, Mark A Sager¹, Cynthia M Carlsson^{1

2

3}, Catherine L Gallagher^{3

4}, Bruce P Hermann^{2

4}, Kaj Blennow^{5

6

7

8}, Henrik Zetterberg^{1

5

6

9

10

11}, Sanjay Asthana^{1

2

3}, Sterling C Johnson^{1

2}, Tobey J Betthauser^{1

2}, Bradley T Christian¹², Dane B Cook^{13

14}, Ozioma C Okonkwo^{1

2

3}

Affiliations

¹ Wisconsin Alzheimer's Disease Research Center Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.
² Wisconsin Alzheimer's Institute Madison Wisconsin USA.
³ Geriatric Research Education and Clinical Center William S. Middleton VA Hospital Madison Wisconsin USA.
⁴ Department of Neurology University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.
⁵ Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg, Gothenburg Mölndal Sweden.
⁶ Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Göteborg Sweden.
⁷ Paris Brain Institute ICM, Pitié-Salpêtrière Hospital, Sorbonne University Paris France.
⁸ Neurodegenerative Disorder Research Center Division of Life Sciences and Medicine and Department of Neurology Institute on Aging and Brain Disorders University of Science and Technology of China and First Affiliated Hospital of USTC Hefei Anhui P.R. China.
⁹ Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK.
¹⁰ UK Dementia Research Institute at UCL London London UK.
¹¹ Hong Kong Center for Neurodegenerative Diseases Clear Water Bay Science Park Hong Kong PR China.
¹² Department of Medical Physics Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.
¹³ William S. Middleton Memorial Veterans Hospital Madison Wisconsin USA.
¹⁴ Department of Kinesiology University of Wisconsin School of Education 1300 University Avenue, 285 Medical Sciences Center Madison Wisconsin USA.

Abstract

Introduction: The accumulation of core Alzheimer's disease (AD) pathology contributes to cognitive decline. Cardiorespiratory fitness (CRF) influences AD pathological progression resulting in improvement or maintenance of cognitive function with age. CRF-related differences in accumulation rates or risk of reaching clinically relevant AD biomarker levels, and potentially interactive effects of core AD pathology and CRF on cognitive decline, remain largely unknown.

Methods: Participants (N = 533; Mean_AGE = 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 (Mean_Follow-up = 6.0 years). Positron emission tomography (PET) imaging of amyloid beta (Aβ) and tau (T) and plasma phosphorylated tau-217 (p-tau217) 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 examined the risk of becoming biomarker-positive. Linear mixed-effects models, stratified by biomarker status, estimated associations between baseline eCRF and core AD biomarker accumulation, and whether eCRF modified relationships between biomarker accumulation and cognitive decline.

Results: There were no significant relationships between eCRF and biomarker trajectories. However, those in high eCRF group who were Aβ- at baseline had a significantly lower risk of becoming biomarker-positive (Aβ-PET: HR, 95% confidence interval [CI] = 0.42, 0.20-0.88; p-tau-217: 0.45, 0.21-0.97) compared to the low eCRF group. The detrimental relationship between Aβ accumulation and cognitive decline was significantly attenuated for Aβ+/T+ with high eCRF.

Discussion: Although eCRF did not influence core AD biomarker accumulation trajectories, high eCRF seems protective against becoming biomarker-positive and attenuates the known deleterious relationship between biomarker accumulation and cognitive decline in Aβ+/T+.

Highlights: High estimated cardiorespiratory fitness (eCRF) is associated with a lesser likelihood of becoming AD biomarker positive.High eCRF did not alter biomarker accumulation in those positive for Alzheimer's disease (AD) pathology.High eCRF attenuated the relationship between AD biomarkers and cognitive decline.Innovative methods: Stratifying analyses by amyloid beta and tau status.

Keywords: Alzheimer's disease; biomarkers; cardiorespiratory fitness; exercise; physical activity.

Abstract

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