Insights into the Biomarker Potential of Humanin and Mots-c Expression and Telomere Length in Alzheimer’s Disease

Humanin (HN) and MOTS-c are mitochondrial-derived peptides (MDPs) known for their neuroprotective and metabolic functions. Their circulating and tissue levels decline with age and in neurodegenerative diseases such as Alzheimer's disease (AD). This study aimed to evaluate whether blood and plasma gene expression and plasma protein levels of HN and MOTS-c are associated with AD markers, their role in the conversion from mild cognitive impairment (MCI) to AD, and their overall association with the disease. A case-control study was conducted, including patients with AD and MCI, and individuals with subjective cognitive decline (SCD) as controls. Gene expression levels were quantified from total RNA isolated from blood and plasma, normalised to mitochondrial DNA copy number (mtDNA-CN). ELISA was used to measure plasma HN and MOTS-c protein concentrations. HN and MOTS-c transcript levels differed significantly among study groups, whereas plasma protein concentrations did not discriminate between AD and MCI. In silico and RNA decay assays revealed faster degradation of HN mRNA and delayed but stable recovery of MOTS-c mRNA. Overall, blood and plasma transcript levels-but not circulating protein levels-of these MDPs were significantly reduced in AD compared to SCD, suggesting their potential as early biomarkers of Alzheimer's disease.