Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

  1. Peter R Millar  Is a corresponding author
  2. Brian A Gordon
  3. Patrick H Luckett
  4. Tammie LS Benzinger
  5. Carlos Cruchaga
  6. Anne M Fagan
  7. Jason Hassenstab
  8. Richard J Perrin
  9. Suzanne E Schindler
  10. Ricardo F Allegri
  11. Gregory S Day
  12. Martin Rhys Farlow
  13. Hiroshi Mori
  14. Georg Nübling
  15. The Dominantly Inherited Alzheimer Network
  16. Randall J Bateman
  17. John C Morris
  18. Beau M Ances
  1. Washington University in St. Louis, United States
  2. Institute for Neurological Research (FLENI), Argentina
  3. Mayo Clinic Florida, United States
  4. Indiana University, United States
  5. Osaka Metropolitan University, Japan
  6. 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

  1. Peter R Millar

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    For correspondence
    pmillar@wustl.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4588-739X
  2. Brian A Gordon

    Department of Radiology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    No competing interests declared.
  3. Patrick H Luckett

    Department of Neurosurgery, Washington University in St. Louis, St. Louis, United States
    Competing interests
    No competing interests declared.
  4. Tammie LS Benzinger

    Department of Radiology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    Tammie LS Benzinger, received doses (AV45, AV1451) and partial support for PET scanning through an investigator-initiated research grant awarded to Washington University from Avid Radiopharmaceuticals (a wholly-owned subsidiary of Eli Lilly and Company). The author received consulting fees from Eisai, Siemens, and received payment for Biogen speaker's bureau. Tammie Benzinger acts as site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen and Roche. The author has no other competing interests to declare..
  5. Carlos Cruchaga

    Department of Psychiatry, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    Carlos Cruchaga, has received research support from Biogen, EISAI, Alector and Parabon. Carlos Cruchaga is a member of the advisory board of Vivid Genetics, Circular Genomics and Alector. The author has no other competing interests to declare..
  6. Anne M Fagan

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    Anne M Fagan, has received consulting fees from DiamiR and Siemens Healthcare Diagnostics Inc. and has received consulting fees for participation on Scientific advisory boards for Roche Diagnostics, Genentech and Diadem. The author has received travel support for in-person attendance at ABC-DS Meeting/Retreat and travel support/honorarium for in-person attendance at Scientific Advisory Board meeting for South Texas Alzheimer's Disease Research Center (ADRC). The author has no other competing interests to declare..
  7. Jason Hassenstab

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    Jason Hassenstab, has received consulting fees from Roche and Parabon Nanolabs. The author has no other competing interests to declare..
  8. Richard J Perrin

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    No competing interests declared.
  9. Suzanne E Schindler

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    Suzanne E Schindler, received personal honoraria for presenting lectures from the University of Wisconsin, St. Luke's Hospital, Houston Methodist Medical Center, personal Honoraria for serving on the Alzheimer Disease Center Clinical Task Force from University of Washington and personal honoraria for serving on the National Centralized Repository for Alzheimer's Disease biospecimen review committee from University of Indiana. The author received travel support from National Institute on Aging grant R01AG070941, and is a board member of the Greater Missouri Alzheimer's Association. The author received plasma Ab42/Ab40 data provided by C2N Diagnostics at no cost. No payments/research funding was provided by C2N Diagnostics. No gifts/financial incentives of any kind have been provided to Dr. Schindler by C2N Diagnostics. The author has no other competing interests to declare..
  10. Ricardo F Allegri

    Department of Cognitive Neurology, Institute for Neurological Research (FLENI), Buenos Aires, Argentina
    Competing interests
    No competing interests declared.
  11. Gregory S Day

    Department of Neurology, Mayo Clinic Florida, Jacksonville, United States
    Competing interests
    Gregory S Day, received fees for consulting and for acting as Dementia Topic Editor from DynaMed (EBSCO Health) and received fees for consulting, grant writing / implementation Parabon Nanonlabs. The author received payment for CME Content development from PeerView Media and Continuing Education Inc, payment for educational content development and focus group participation from Eli Lilly Co, and payment for continuum manuscript authorship from the American Academy of Neurology. The author received payment for expert testimony in the case of Wernicke encephalopathy from Barrow Law. Gregory S Day acts as Clinical Director for Anti-NMDA Receptor Encephalitis Foundation, Inc. The author has stock holdings at ANI Pharmaceuticals, Inc and stock options at Parabon Nanolabs. The author has no other competing interests to declare..
  12. Martin Rhys Farlow

    Department of Neurology, Indiana University, Bloomington, United States
    Competing interests
    Martin Rhys Farlow, received grants from AbbVie, Eisai, Novartis, ADCS Posiphen, Genentech and Suven Life Sciences (no grant numbers available). The author has received consulting fees from Artery Therapeutics, Avanir, Biogen, Cyclo Therapeutics, Green Valley, Lexeo, McClena, Nervive, Oligomerix, Pinteon, Prothena, Vaxinity, Athira, AZTherapies, Cognition Therapeutics, Gemvax, Ionis, Longeveron, Merck, Neurotrope Biosciences, Otsuka, Proclara and SToP-AD. The author has no other competing interests to declare..
  13. Hiroshi Mori

    Department of Clinical Neuroscience, Osaka Metropolitan University, Osaka, Japan
    Competing interests
    No competing interests declared.
  14. Georg Nübling

    Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    No competing interests declared.
  15. The Dominantly Inherited Alzheimer Network

  16. Randall J Bateman

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    Randall J Bateman, received funding and non-financial support for the DIAN-TU-001 trial from Avid Radiopharmaceuticals, and funding for the DIAN-TU-001 trial from Janssen, Hoffman La-Roche/Genentech, Eli Lilly & Co., Eisai, Biogen, AbbVie and Bristol Meyer Squibb. The author has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. The author received International Conference Lecture Honoraria from Korean Dementia Association and Conference Lecture Honoraria from Weill Cornell Medical College. The author received support for travel expenses from Alzheimer's Association Roundtable and Duke Margolis Alzheimer's Roundtable. The author participates on an unpaid Advisory Board for Roche Gantenerumab Steering Committee and Biogen - Combination Therapy for Alzheimer's Disease, and participates on an unpaid Scientific Advisory Board for UK Dementia Research Institute at University College London and Stanford University, Next Generation Translational Proteomics for Alzheimer's and Related Dementias. The author receives an income from C2N Diagnostics for serving on the scientific advisory board. The author has received equipment and materials from Avid Radiopharmaceuticals, Eli Lilly & Co, Hoffman La-Roche, Eisai and Janssen. Unrelated to this article, Randall Bateman serves as principal investigator of the DIAN-TU, which is supported by the Alzheimer's Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, and Janssen. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). In addition, in-kind support has been received from CogState and Signant Health. Unrelated to this article Randall Bateman has submitted the US nonprovisional patent application Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo" and provisional patent application "Plasma Based Methods for Detecting CNS Amyloid Deposition". The author has no other competing interests to declare.".
  17. John C Morris

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    John C Morris, has received consulting fees from Barcelona Brain Research Center BBRC and Native Alzheimer Disease-Related Resource Center in Minority Aging Research, Ext Adv Board. The author has received payment or honoraria for lectures from Montefiore Grand Rounds, NY and Tetra-Inst ADRC seminar series, Grand Rds, NY. The author has participated on the Research Strategy Council for the Cure Alzheimer's Fund, the Diverse VCID Observational Study Monitoring Board and the LEADS Advisory Board, Indiana University. The author has no other competing interests to declare..
  18. Beau M Ances

    Department of Neurology, Washington University in St. Louis, St. Louis, United States
    Competing interests
    No competing interests declared.

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.

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).

Reviewing Editor

  1. Karla L Miller, University of Oxford, United Kingdom

Publication history

  1. Received: July 14, 2022
  2. Accepted: December 30, 2022
  3. Accepted Manuscript published: January 6, 2023 (version 1)

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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  1. Peter R Millar
  2. Brian A Gordon
  3. Patrick H Luckett
  4. Tammie LS Benzinger
  5. Carlos Cruchaga
  6. Anne M Fagan
  7. Jason Hassenstab
  8. Richard J Perrin
  9. Suzanne E Schindler
  10. Ricardo F Allegri
  11. Gregory S Day
  12. Martin Rhys Farlow
  13. Hiroshi Mori
  14. Georg Nübling
  15. The Dominantly Inherited Alzheimer Network
  16. Randall J Bateman
  17. John C Morris
  18. Beau M Ances
(2023)
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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