Brain Imaging and Behavior

, Volume 11, Issue 2, pp 368–382 | Cite as

Resting-state global functional connectivity as a biomarker of cognitive reserve in mild cognitive impairment

  • N. Franzmeier
  • M. Á. Araque Caballero
  • A. N. W. Taylor
  • L. Simon-Vermot
  • K. Buerger
  • B. Ertl-Wagner
  • C. Mueller
  • C. Catak
  • D. Janowitz
  • E. Baykara
  • B. Gesierich
  • M. Duering
  • M. Ewers
  • for the Alzheimer’s Disease Neuroimaging Initiative
SI: Resilience/Reserve in AD


Cognitive reserve (CR) shows protective effects in Alzheimer’s disease (AD) and reduces the risk of dementia. Despite the clinical significance of CR, a clinically useful diagnostic biomarker of brain changes underlying CR in AD is not available yet. Our aim was to develop a fully-automated approach applied to fMRI to produce a biomarker associated with CR in subjects at increased risk of AD. We computed resting-state global functional connectivity (GFC), i.e. the average connectivity strength, for each voxel within the cognitive control network, which may sustain CR due to its central role in higher cognitive function. In a training sample including 43 mild cognitive impairment (MCI) subjects and 24 healthy controls (HC), we found that MCI subjects with high CR (> median of years of education, CR+) showed increased frequency of high GFC values compared to MCI-CR- and HC. A summary index capturing such a surplus frequency of high GFC was computed (called GFC reserve (GFC-R) index). GFC-R discriminated MCI-CR+ vs. MCI-CR-, with the area under the ROC = 0.84. Cross-validation in an independently recruited test sample of 23 MCI subjects showed that higher levels of the GFC-R index predicted higher years of education and an alternative questionnaire-based proxy of CR, controlled for memory performance, gray matter of the cognitive control network, white matter hyperintensities, age, and gender. In conclusion, the GFC-R index that captures GFC changes within the cognitive control network provides a biomarker candidate of functional brain changes of CR in patients at increased risk of AD.


Cognitive reserve Biomarker Mild cognitive impairment Alzheimer’s disease Global functional connectivity Resting-state fMRI 


Compliance with ethical standards

The study at the ISD was approved by the ethics committee of the Ludwig Maximilian University of Munich. For the ADNI-sample ethical approval was obtained by the ADNI investigators. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All study participants provided written, informed consent to the study.


The research was funded by grants of the LMUexcellent Initiative and the European Commission (ERC, PCIG12-GA-2012-334259), Alzheimer’s Forschung Initiative (AFI, DE-15035). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Conflict of interest

The authors declare that they have no conflict of interest

Supplementary material

11682_2016_9599_Fig6_ESM.gif (14 kb)
Supplementary Fig. 1

Shown is the distribution of GFC voxels averaged across subjects within CR (CR+ vs. CR-) and diagnostic (MCI vs. HC) groups for the test sample. The graphs are equivalent to Fig. 2b of the main manuscript. (GIF 14 kb)

11682_2016_9599_MOESM1_ESM.tif (8.1 mb)
High Resolution image (TIF 8269 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • N. Franzmeier
    • 1
  • M. Á. Araque Caballero
    • 1
  • A. N. W. Taylor
    • 1
  • L. Simon-Vermot
    • 1
  • K. Buerger
    • 1
    • 2
  • B. Ertl-Wagner
    • 3
  • C. Mueller
    • 1
  • C. Catak
    • 1
  • D. Janowitz
    • 1
  • E. Baykara
    • 1
  • B. Gesierich
    • 1
  • M. Duering
    • 1
  • M. Ewers
    • 1
  • for the Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Institut für Schlaganfall-und Demenzforschung (ISD), Ludwig-Maximilians-Universität LMUKlinikum der Universität MünchenMunichGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE, Munich)MunichGermany
  3. 3.Institute for Clinical RadiologyKlinikum der Universität München, Ludwig-Maximilian UniversityMunichGermany

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