Altered mitochondrial DNA methylation in blood in individuals with mild cognitive impairment

Previous studies reported that altered mitochondrial methylation in Alzheimer’s disease (AD), however, whether epigenetic modifications in mitochondrial genomes contribute to preclinical AD remains unclear. This study aimed to investigate mitochondrial methylation changes in individuals with cognitive decline. We examined whole mitochondrial genome methylation in 50 individuals with mild cognitive impairment (MCI) and 50 individuals without MCI, using bisulfite amplicon sequencing, assessing methylation at 366 Cytosine-guanine oligodeoxynucleotide (CpG) sites. We found the overall methylation level of mitochondrial DNA (mtDNA) in each subject was relatively low, ranging from 0% to 15%. Global methylation was significantly higher in individuals with cognitive decline compared to controls (3.86% vs. 3.46%, p = 0.037), with 34 differentially methylated CpG sites identified. Methylation differences (MD) between cognitive decline individuals and controls were 22.93 ± 5.60% at chrM6465 (Q = 0.013), 12.55 ± 3.02% at chrM9612 (Q = 0.013), 11.45 ± 3.88% at chrM11762 (Q = 0.159) and 11.03 ± 3.88% at chrM11766 (Q = 0.172), respectively, while the level of MD at chrM15812 was −13.11 ± 4.31% (Q = 0.159) after Benjamini-Hochberg FDR adjusted. Furthermore, Methylation at specific sites were significantly correlated with Mini-Mental State Examination scores, distinguishing individuals with cognitive decline from controls. Our study provides an mtDNA methylation map and suggests a role for these sites in preclinical AD pathogenesis. Alzheimer’s disease is a brain condition that causes memory loss and thinking problems. Before the disease becomes serious, people may show early signs like forgetting things or having trouble focusing. This stage is called “mild cognitive impairment” or MCI. Finding it early can help doctors provide better care. In this study, we looked at small chemical changes in cell parts called mitochondria. These changes, called DNA methylation, can affect how genes work. We took blood samples from 50 older adults with memory problems and compared them to 50 healthy people of the same age and gender. We used a special test to check over 300 spots in the mitochondrial DNA. We found that some of these spots were more changed in people with memory problems. These changes were linked to lower memory test scores and could help tell who has early memory decline. This research shows that changes in mitochondrial DNA might be early warning signs of Alzheimer’s disease. In the future, a simple blood test may help find the disease before it gets worse.