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Peer-reviewedCC BYAlzheimer's & dementia : the journal of the Alzheimer's Association

Why diabetes matters in dementia studies: Failure to account for diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.

  • Aakruti Kaikini1
  • Anqi Shi1
  • Paul Francis2
  • Russell Swerdlow3
  • Claire Troakes4
  • Jaimee Kennedy4
  • Alan Hodgkinson5
  • Afshan N Malik1
5 affiliations
  1. 1King's College London, Diabetes and Obesity, School of Cardiovascular Medicine and Metabolic Sciences, Faculty of Life Sciences and Medicine, London, England.
  2. 2Dept of Clinical and Biomedical Sciences, University of Exeter, University of Exeter Medical School, London, England.
  3. 3University of Kansas Alzheimer's Disease Research Center, University of Kansas School of Medicine, Fairway, Kansas, USA.
  4. 4Neurodegenerative Diseases Brain Bank, Department of Clinical and Basic Neuroscience, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London, England.
  5. 5Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, England.
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Abstract

Introduction

Diabetes is a major risk factor for Alzheimer's disease (AD), and both diseases involve mitochondrial dysfunction. Changes in mitochondrial DNA (mtDNA) can influence energy metabolism, cellular signaling, and epigenetic programming, thereby affecting cellular health. We hypothesized that AD is associated with reduced mtDNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes.Methods

MtDNA-CN was quantified by absolute quantitative polymerase chain reaction (qPCR) in post-mortem hippocampus, amygdala, and cerebellum from cognitive controls (CCs), AD, and diabetes groups (CC+D, AD+D; N = 66-77).Results

MtDNA-CN differed by region, being highest in amygdala, intermediate in hippocampus, and lowest in cerebellum (503, 421, and 160 copies/cell; p < 0.0001). Pooled analyses showed modestly lower mtDNA-CN in AD. However, inclusion of diabetes appeared to mask differences. Donors with diabetes (CC+D and AD+D combined) had higher mtDNA-CN than non-diabetic (CC and AD combined) in hippocampus (+37.5%; p = 0.0012), amygdala (+30.6%; p = 0.0057), and cerebellum (+48.5%; p = 0.0002). This diabetes-associated increase was also present within AD, where AD+D had higher mtDNA-CN than AD in all regions. Removal of diabetic donors showed that AD was associated with a 19%-30% lower mtDNA-CN, reaching significance in the amygdala and cerebellum after correction for multiple testing.Discussion

We show that AD is associated with multiregional mtDNA-CN loss most clearly in donors without diabetes, whereas diabetes is associated with higher mtDNA-CN and can mask AD-related mitochondrial changes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes acts as an effect modifier has important implications for dementia studies.

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Cite

BibTeXRIS
BibTeX
@article{kaikini2026diabetes,
  title = {{Why diabetes matters in dementia studies: Failure to account for diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.}},
  author = {Aakruti Kaikini and Anqi Shi and Paul Francis and Russell Swerdlow and Claire Troakes and Jaimee Kennedy and Alan Hodgkinson and Afshan N Malik},
  journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
  year = {2026},
  month = oct,
  doi = {10.1002/alz.71870},
  url = {https://europepmc.org/article/MED/42899478},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Why diabetes matters in dementia studies: Failure to account for diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.
AU  - Aakruti Kaikini
AU  - Anqi Shi
AU  - Paul Francis
AU  - Russell Swerdlow
AU  - Claire Troakes
AU  - Jaimee Kennedy
AU  - Alan Hodgkinson
AU  - Afshan N Malik
PY  - 2026
DA  - 2026/10/01
JO  - Alzheimer's & dementia : the journal of the Alzheimer's Association
DO  - 10.1002/alz.71870
UR  - https://europepmc.org/article/MED/42899478
AB  - Introduction  Diabetes is a major risk factor for Alzheimer's disease (AD), and both diseases involve mitochondrial dysfunction. Changes in mitochondrial DNA (mtDNA) can influence energy metabolism, cellular signaling, and epigenetic programming, thereby affecting cellular health. We hypothesized that AD is associated with reduced mtDNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes.Methods  MtDNA-CN was quantified by absolute quantitative polymerase chain reaction (qPCR) in post-mortem hippocampus, amygdala, and cerebellum from cognitive controls (CCs), AD, and diabetes groups (CC+D, AD+D; N = 66-77).Results  MtDNA-CN differed by region, being highest in amygdala, intermediate in hippocampus, and lowest in cerebellum (503, 421, and 160 copies/cell; p < 0.0001). Pooled analyses showed modestly lower mtDNA-CN in AD. However, inclusion of diabetes appeared to mask differences. Donors with diabetes (CC+D and AD+D combined) had higher mtDNA-CN than non-diabetic (CC and AD combined) in hippocampus (+37.5%; p = 0.0012), amygdala (+30.6%; p = 0.0057), and cerebellum (+48.5%; p = 0.0002). This diabetes-associated increase was also present within AD, where AD+D had higher mtDNA-CN than AD in all regions. Removal of diabetic donors showed that AD was associated with a 19%-30% lower mtDNA-CN, reaching significance in the amygdala and cerebellum after correction for multiple testing.Discussion  We show that AD is associated with multiregional mtDNA-CN loss most clearly in donors without diabetes, whereas diabetes is associated with higher mtDNA-CN and can mask AD-related mitochondrial changes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes acts as an effect modifier has important implications for dementia studies.
SN  - 1552-5260
SN  - 1552-5279
ER  -