Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses.

  1. Botond Antal
  2. Liam P McMahon
  3. Sayed Fahad Sultan
  4. Andrew Lithen
  5. Deborah J Wexler
  6. Bradford C Dickerson
  7. Eva Maria Ratai
  8. Lilianne Rivka Mujica-Parodi  Is a corresponding author
  1. State University of New York, United States
  2. Massachusetts General Hospital, United States

Abstract

Background: Type 2 diabetes mellitus is known to be associated with neurobiological and cognitive deficits; however, their extent, overlap with aging effects, and the effectiveness of existing treatments in the context of the brain are currently unknown.

Methods: We characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HC). We also evaluated in a cohort of T2DM diagnosed individuals using UK Biobank how disease chronicity and metformin treatment interact with the identified neurocognitive effects.

Results: The UK Biobank dataset included cognitive and neuroimaging data (N=20,314) including 1,012 T2DM and 19,302 HC, aged between 50 and 80 years. Duration of T2DM ranged from 0-31 years (mean 8.5±6.1 years); 498 were treated with metformin alone, while 352 were unmedicated. Our meta-analysis evaluated 34 cognitive studies (N=22,231) and 60 neuroimaging studies: 30 of T2DM (N=866) and 30 of aging (N=1,088). As compared to age, sex, education, and hypertension-matched HC, T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen, with reorganization of brain activity (decreased in the caudate and premotor cortex and increased in the subgenual area, orbitofrontal cortex, brainstem and posterior cingulate cortex). The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. Metformin treatment status was not associated with improved neurocognitive outcomes.

Conclusions: The neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging; disease duration was associated with increased neurodegeneration. Mechanistically, our results suggest a neurometabolic component to brain aging. Clinically, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects.

Funding: The research described in this paper was funded by the W. M. Keck Foundation (to LRMP), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRMP), and the Baszucki Brain Research Fund (to LRMP). None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. DJW reports serving on data monitoring committees for Novo Nordisk. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this manuscript.

Data availability

All analyses reported in this manuscript were on either publicly available data (UK Biobank) or meta-analyses of listed published articles. Source code for all analyses conducted for this manuscript is uploaded as Source Code (Github Repo).

The following previously published data sets were used

Article and author information

Author details

  1. Botond Antal

    Department of Biomedical Engineering, State University of New York, Stony Brook, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0775-6033
  2. Liam P McMahon

    Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  3. Sayed Fahad Sultan

    Department of Biomedical Engineering, State University of New York, Stony Brook, United States
    Competing interests
    No competing interests declared.
  4. Andrew Lithen

    Department of Biomedical Engineering, State University of New York, Stony Brook, United States
    Competing interests
    No competing interests declared.
  5. Deborah J Wexler

    Diabetes Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    Deborah J Wexler, is part of a Novo Nordisk data monitoring committee service for semaglutide in SOUL and FLOW trials. The author has no other competing interests to declare..
  6. Bradford C Dickerson

    MGH Frontotemporal Disorders Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    Bradford C Dickerson, received royalties from Cambridge University Press and Oxford University Press, and consulting fees from Acadia, Alector, Arkuda, Biogen, Denali, Lilly, Merck, Novartis, Takeda, Wave LifeSciences (unrelated to the present work). Also participates in a Lilly Data Safety Monitoring Board (unrelated to the present work) and participates in leadership roles in Alzheimer's Association and Association for Frontotemporal Degeneration. The author has no other competing interests to declare..
  7. Eva Maria Ratai

    Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, United States
    Competing interests
    Eva Maria Ratai, received honoraria from Harvard Catalyst. The author has no other competing interests to declare..
  8. Lilianne Rivka Mujica-Parodi

    Department of Biomedical Engineering, State University of New York, Stony Brook, United States
    For correspondence
    lilianne.strey@stonybrook.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3752-5519

Funding

W. M. Keck Foundation

  • Lilianne Rivka Mujica-Parodi

National Science Foundation (NSFNCS-FR 1926781)

  • Lilianne Rivka Mujica-Parodi

Baszucki Brain Research Fund

  • Lilianne Rivka Mujica-Parodi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Pankaj Kapahi, Buck Institute for Research on Aging, United States

Publication history

  1. Preprint posted: May 26, 2021 (view preprint)
  2. Received: August 17, 2021
  3. Accepted: April 26, 2022
  4. Accepted Manuscript published: May 24, 2022 (version 1)
  5. Version of Record published: May 25, 2022 (version 2)

Copyright

© 2022, Antal 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. Botond Antal
  2. Liam P McMahon
  3. Sayed Fahad Sultan
  4. Andrew Lithen
  5. Deborah J Wexler
  6. Bradford C Dickerson
  7. Eva Maria Ratai
  8. Lilianne Rivka Mujica-Parodi
(2022)
Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses.
eLife 11:e73138.
https://doi.org/10.7554/eLife.73138

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    Funding:

    This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).