Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study
- Washington University in St. Louis, United States
- Institute for Neurological Research (FLENI), Argentina
- Mayo Clinic Florida, United States
- Indiana University, United States
- Osaka Metropolitan University, Japan
- Ludwig-Maximilians-Universität München, Germany
Abstract
Background: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD), but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural magnetic resonance imaging (MRI), but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored.
Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A-) participants (18-89 years old). In independent samples of 144 CN/A-, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite.
Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A-. In CI participants only, elevated S-BAG and S+FC-BAG were associated with more advanced AD pathology and lower cognitive performance.
Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences.
Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01-AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer’s Association (SG-20-690363-DIAN).
Data availability
This project utilized datasets obtained from the Knight ADRC and DIAN. The Knight ADRC and DIAN encourage and facilitate research by current and new investigators, and thus, the data and code are available to all qualified researchers after appropriate review. Requests for access to the data used in this study may be placed to the Knight ADRC Leadership Committee (https://knightadrc.wustl.edu/professionals-clinicians/request-center-resources/) and the DIAN Steering Committee (https://dian.wustl.edu/our-research/for-investigators/dian-observational-study-investigator-resources/data-request-form/). Requests for access to the Ances lab data may be placed to the corresponding author. Code used in this study is available at https://github.com/peterrmillar/MultimodalBrainAge.
Article and author information
Author details
Funding
National Institutes of Health (P01-AG026276)
- John C Morris
National Institutes of Health (P01-AG03991)
- John C Morris
National Institutes of Health (P30-AG066444)
- John C Morris
National Institutes of Health (5-R01-AG052550)
- Beau M Ances
National Institutes of Health (5-R01-AG057680)
- Beau M Ances
National Institutes of Health (U19-AG032438)
- Randall J Bateman
BrightFocus Foundation (A2022014F)
- Peter R Millar
Alzheimer's Association (SG-20-690363-DIAN)
- Randall J Bateman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Karla L Miller, University of Oxford, United Kingdom
Ethics
Human subjects: All participants provided written informed consent in accordance with the Declaration of Helsinki and their local institutional review board. All procedures were approved by the Human Research Protection Office at WUSTL (IRB ID # 201204041).
Version history
- Received: July 14, 2022
- Preprint posted: August 27, 2022 (view preprint)
- Accepted: December 30, 2022
- Accepted Manuscript published: January 6, 2023 (version 1)
- Version of Record published: March 6, 2023 (version 2)
Copyright
© 2023, Millar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study
eLife 12:e81869.
https://doi.org/10.7554/eLife.81869
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