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Introduction Major depressive disorder (MDD) and frailty are common disorders in elderly populations. These conditions are associated with a higher rate of negative health outcomes and comorbidity. In previous studies, the measurement of circulating cell-free mtDNA (ccf-mtDNA) has been used as biomarkers for cellular stress from increased oxidative stress. No study has yet examined if there are synergistic effects of MDD and frailty in older adults through ccf-mtDNA levels. We hypothesized that individuals diagnosed with both frailty and MDD will have higher ccf-mtDNA levels in comparison to individuals with those conditions in isolation. Methods Fifty-three older adults (21 with MDD and 32 controls who were never-depressed) were included in this analysis. Pre-Frail/Frail status was determined by the FRAIL scale. Plasma samples were collected from peripheral blood collections through venipuncture in EDTA tubes. The DNA was extracted from the plasma samples using the QIAmp 96 DNA Blood Kit. The ccf-mtDNA was quantified by RT-PCR. Results There were 5 subjects classified as never-depressed and pre-frail/frail. In addition, 23 subjects were identified as depressed and pre-frail/frail. The ccf-mtDNA was significantly higher in those with MDD compared to the control group (p Conclusions We found a significant interaction between MDD and frailty increasing the ccf-mtDNA. The higher levels of ccf-mtDNA could indicate worsened cellular stress and mitochondrial dysfunction among those with MDD and Frailty. Our data suggest that frailty and MDD have synergistic effects that increase co-morbidity. Future directions could include increasing the sample size to ensure the validity of the findings. Funding Funding was provided by the National Institute of Mental Health (NIMH), USA, and other Canadian funding agencies.

Objective The clinical–epidemiological relationship between major depressive disorder (MDD) and Alzheimer disease (AD) suggests that they may share common neurobiologic abnormalities. Methods The authors conducted a systematic review and identified microRNAs abnormally expressed in both AD and MDD. The pattern of microRNA regulation in each disorder and the genes regulated by each microRNA and the biologic processes and pathways regulated by these genes were identified. Results Seventy-four microRNAs were abnormally expressed in AD and 30 in MDD; 7 were common for both disorders (hsa-let-7f-5p, hsa-miR-664a-3p, hsa-miR-361-5p, hsa-let-7g-5p, hsa-let-7d-5p, hsa-miR-191-5p, hsa-miR-26b-5p). These microRNAs interact with 45 validated genes, and the main biologic pathways and processes regulated by them were proteostasis control, maintenance of genomic integrity, regulation of transcriptional activity, immune-inflammatory control, and neurotrophic support. Conclusion The current results suggest that the maintenance of genomic integrity, proteostasis control, immune-inflammatory regulation, and neurotrophic support are key neurobiologic links between these conditions. A comprehensive hypothetical model for the interaction between MDD, aging, and the development of AD is provided.