bioRxiv : the preprint server for biology · 2026
Why diabetes matters in dementia studies: Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.
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Kaikini Aakruti, Shi Anqi, Francis Paul, Swerdlow Russell, Troakes Claire, Kennedy Jaimee, Hodgkinson Alan, Malik Afshan N
Аннотация
INTRODUCTION: Diabetes is a major risk factor for Alzheimer's disease (AD), and both diseases involve mitochondrial dysfunction. We hypothesised that AD is associated with reduced mitochondrial DNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes.
METHODS: Post-mortem hippocampus, amygdala, and cerebellum samples (N=66-77) from non-cognitively impaired (NCI) and AD donors, with and without diabetes, were analysed. mtDNA-CN was quantified by absolute quantification.
RESULTS: Overall, mtDNA-CN was lower in AD. However, stratification by diabetes revealed opposite changes: non-diabetic AD cases showed reduced mtDNA-CN, whereas diabetic cases showed higher mtDNA-CN across all regions irrespective of cognitive status.
DISCUSSION: These findings confirm multiregional loss of mtDNA-CN in the AD brain, most evident in the absence of diabetes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes can mask effects has important implications for dementia studies.
METHODS: Post-mortem hippocampus, amygdala, and cerebellum samples (N=66-77) from non-cognitively impaired (NCI) and AD donors, with and without diabetes, were analysed. mtDNA-CN was quantified by absolute quantification.
RESULTS: Overall, mtDNA-CN was lower in AD. However, stratification by diabetes revealed opposite changes: non-diabetic AD cases showed reduced mtDNA-CN, whereas diabetic cases showed higher mtDNA-CN across all regions irrespective of cognitive status.
DISCUSSION: These findings confirm multiregional loss of mtDNA-CN in the AD brain, most evident in the absence of diabetes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes can mask effects has important implications for dementia studies.