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Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study

Molecular Psychiatry (2024)Cite this article

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Abstract

Background

Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia.

Methods

Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p-values under consecutive timeframes preceding the diagnosis of dementia.

Findings

During a median follow-up of 13.7 [Interquartile range, IQR 12.9–14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63–0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76–0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11–1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67–1.91]), stroke (OR 2.34 [2.1–1.37]), diabetes (OR 2.03 [1.89–2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3–5 year, overall time of activity, OR 0.82 [0.73–0.92]), drowsiness (3–5 year, sleep duration, OR 1.13 [1.04–1.24]) and weight loss (0–5 year, weight, OR 0.9 [0.83–0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis.

Interpretation

Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.

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Fig. 1: Flowchart of the case-control participants’ selection.
Fig. 2: Study design illustration.
Fig. 3: Odds ratio trajectories of clinical assessments and health conditions of dementia.
Fig. 4: Trajectories of health conditions preceding diagnosis of additional incidence rates of dementia, Alzheimer’s disease, and vascular dementia over healthy controls.

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Data availability

All data used in this study were accessed from the publicly available UK Biobank Resource under application number 19542. These data cannot be shared with other investigators.

Code availability

All analyses were performed with the StatsModel (v0.11.1) and ScikitLearn (v0.24.1) packages in Python (v3.6). The code can be accessed through https://github.com/jasonHKU0907/DementiaPhenoTrajectory/.

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Acknowledgements

This study utilized the UK Biobank Resource under application number 19542. We want to thank all the participants and researchers from the UK Biobank. This study was funded by grants from the National Key Research and Development Program of China (grant no. 2023YFC3605400), Science and Technology Innovation 2030 Major Projects (2022ZD0211600), Shanghai Pujiang Program (23PJD006), National Key R&D Program of China (2018YFC1312904, 2019YFA0709502), National Natural Science Foundation of China (82071201, 81971032, 82071997). Further, we would like to thank the support from the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), Research Start-up Fund of Huashan Hospital (2022QD002), Excellence 2025 Talent Cultivation Program at Fudan University (3030277001), Shanghai Rising-Star Program (21QA1408700), the 111 Project (No. B18015) and Shanghai Center for Brain Science and Brain-Inspired Technology, ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University.

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Author notes

  1. These authors contributed equally: Jia You, Yu Guo.

Authors and Affiliations

  1. Institute of Science and Technology for Brain-Inspired Intelligence, Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

    Jia You, Yu Guo, Yu-Jia Wang, Yi Zhang, Hui-Fu Wang, Lin-Bo Wang, Ju-Jiao Kang, Jian-Feng Feng, Jin-Tai Yu & Wei Cheng

  2. Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai, China

    Jian-Feng Feng & Wei Cheng

  3. Zhangjiang Fudan International Innovation Center, Shanghai, China

    Jian-Feng Feng

  4. School of Data Science, Fudan University, Shanghai, China

    Jian-Feng Feng

  5. Fudan ISTBI—ZJNU Algorithm Centre for Brain-inspired Intelligence, Zhejiang Normal University, Zhejiang, China

    Jian-Feng Feng & Wei Cheng

  6. Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Transfer Center, Shanghai, China

    Wei Cheng

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Contributions

WC, JTY, and JFF conceived, designed, and supervised the project. JY implemented statistical analyses. YG, YJW, YZ, HFW, LBW, and JJK supported the study and contributed to the discussion of the results. JY and YG drafted the manuscript and accessed and verified the underlying data reported in the manuscript. investigator was blinded to the group allocation during the experiment and/or when assessing the outcome. All authors had full access to all the study data and accepted the responsibility to submit it for publication.

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Correspondence to Jian-Feng Feng, Jin-Tai Yu or Wei Cheng.

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You, J., Guo, Y., Wang, YJ. et al. Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02570-0

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