Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease

Abstract

Background: Neuronal and circuit level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD.

Methods: Using empirical spectra from magnetoencephalography (MEG) and computational modeling (neural mass model; NMM) we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography (PET), in patients with AD.

Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions.

Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD.

Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM & GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL and (KGR); 2019-A-013-SUP (KGR); a grant from the Alzheimer's Association: (PCTRB-13-288476) (KAV), and made possible by Part the CloudTM, (ETAC-09-133596); a grant from Tau Consortium (GDR & WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

Data availability

Data and materials availability: All data associated with this study are present in the paper or in the Supplementary Materials. Anonymized subject data will be shared on request from qualified investigators for the purposes of replicating procedures and results, and for other non-commercial research purposes within the limits of participants' consent. Correspondence and material requests should be addressed to Kamalini.ranasinghe@ucsf.edu

Article and author information

Author details

  1. Kamalini Ranasinghe

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    For correspondence
    kamalini.ranasinghe@ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4217-8785
  2. Parul Verma

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Chang Cai

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Xihe Xie

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Kiwamu Kudo

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5732-7229
  6. Xiao Gao

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  7. Hannah Lerner

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  8. Danielle Mizuiri

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Amelia Strom

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  10. Leonardo Iaccarino

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  11. Renaud La Joie

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2581-8100
  12. Bruce L Miller

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    Bruce L Miller, has the following disclosures: serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; and Scientific Advisory Board Member for the National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia, UK..
  13. Maria Luisa Gorno-Tempini

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  14. Katherine P Rankin

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  15. William J Jagust

    Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4458-113X
  16. Keith Vossel

    Department of Neurology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  17. Gil Rabinovici

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  18. Ashish Raj

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2414-2444
  19. Srikantan Nagarajan

    Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

Funding

National Institute on Aging (K08AG058749)

  • Kamalini Ranasinghe

National Institute on Aging (K23 AG038357)

  • Keith Vossel

National Institutes of Health

  • Bruce L Miller
  • William J Jagust
  • Gil Rabinovici
  • Ashish Raj
  • Srikantan Nagarajan

Alzheimer's Association

  • Kamalini Ranasinghe
  • Keith Vossel

Larry L. Hillblom Foundation

  • Kamalini Ranasinghe

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

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Ethics

Human subjects: Informed consent was obtained from all participants and the study was approved by the Institutional Review Board (IRB) at UCSF (UCSF-IRB 10-02245).

Version history

  1. Received: February 12, 2022
  2. Preprint posted: March 10, 2022 (view preprint)
  3. Accepted: May 19, 2022
  4. Accepted Manuscript published: May 26, 2022 (version 1)
  5. Version of Record published: June 22, 2022 (version 2)

Copyright

© 2022, Ranasinghe 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. Kamalini Ranasinghe
  2. Parul Verma
  3. Chang Cai
  4. Xihe Xie
  5. Kiwamu Kudo
  6. Xiao Gao
  7. Hannah Lerner
  8. Danielle Mizuiri
  9. Amelia Strom
  10. Leonardo Iaccarino
  11. Renaud La Joie
  12. Bruce L Miller
  13. Maria Luisa Gorno-Tempini
  14. Katherine P Rankin
  15. William J Jagust
  16. Keith Vossel
  17. Gil Rabinovici
  18. Ashish Raj
  19. Srikantan Nagarajan
(2022)
Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease
eLife 11:e77850.
https://doi.org/10.7554/eLife.77850

Share this article

https://doi.org/10.7554/eLife.77850

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