Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

Grazia Daniela Femminella, Nicholas R Livingston, Sanara Raza, Thalia van der Doef, Eleni Frangou, Sharon Love, Gail Busza, Valeria Calsolaro, Stefan Carver, Clive Holmes, Craig W Ritchie, Robert M Lawrence, Brady McFarlane, George Tadros, Basil H Ridha, Carol Bannister, Zuzana Walker, Hilary Archer, Elizabeth Coulthard, Ben UnderwoodAparna Prasanna, Paul Koranteng, Salman Karim, Kehinde Junaid, Bernadette McGuinness, Anthony Peter Passmore, Ramin Nilforooshan, Ajayverma Macharouthu, Andrew Donaldson, Simon Thacker, Gregor Russell, Naghma Malik, Vandana Mate, Lucy Knight, Sajeev Kshemendran, Tricia Tan, Christian Holscher, John Harrison, David J Brooks, Clive Ballard, Paul Edison

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.

METHODS: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.

RESULTS: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.

CONCLUSIONS: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Original languageEnglish
Article number47
JournalAlzheimer's research & therapy
Issue number1
Publication statusPublished - 17 Feb 2021

Bibliographical note

© The Author(s). 2021 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Funding Information:
This study was funded by Alzheimer’s Drug Discovery Foundation, US, Alzheimer’s Society, UK, Novo Nordisk A/S, Van Geest Foundation, NIHR Biomedical Research Centre, Imperial College London and Kings College London. Dr. Edison was funded by the Medical Research Council and now by the Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research, UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society, UK, Novo Nordisk, GE Healthcare, Astra Zeneca, Pfizer, Eli Lilly and Piramal Life Sciences.


  • Alzheimer Disease
  • Insulin Resistance
  • Magnetic Resonance Imaging
  • Positron-Emission Tomography Imaging


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