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bioRxiv · 10.64898/2026.06.03.729204

Why diabetes matters in dementia studies. Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimers disease

Kaikini, A.·Shi, A.·Francis, P.·Swerdlow, R. H.·Troakes, C.·Kennedy, J.·Hodgkinson, A.·Malik, A. N.
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Abstract

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSDiabetes is a major risk factor for Alzheimers 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. METHODSPost-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. RESULTSOverall, 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. DISCUSSIONThese 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.

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Kaikini, A., Shi, A., Francis, P., Swerdlow, R. H., Troakes, C., Kennedy, J., Hodgkinson, A., Malik, A. N.. 2026-06-08. Why diabetes matters in dementia studies. Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimers disease. https://doi.org/10.64898/2026.06.03.729204

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