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We examined mt\u2010dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in\u00a0vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt\u2010dsRNA signatures increased after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt\u2010dsRNA\u2010driven inflammation. In AD brains, mt\u2010dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin\u2010dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt\u2010dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age\u2010 and AD\u2010related neurodegeneration and identify mt\u2010dsRNA as a potential driver of chronic inflammation in the brain.<\/jats:p>","DOI":"10.1111\/acel.70616","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:58:58Z","timestamp":1783655938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptomic Evidence of Mitochondrial Double\u2010Stranded\n                    <scp>RNA<\/scp>\n                    Accumulation in Brain Aging and Alzheimer's Disease"],"prefix":"10.1111","volume":"25","author":[{"given":"Rachel L.","family":"Doser","sequence":"first","affiliation":[{"name":"Department of Health and Exercise Science Colorado State University  Fort Collins Colorado USA"},{"name":"Columbine Health Systems Center for Healthy Aging Colorado State University  Fort Collins Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2393-7299","authenticated-orcid":false,"given":"Thomas J.","family":"LaRocca","sequence":"additional","affiliation":[{"name":"Department of Health and Exercise Science Colorado State University  Fort Collins Colorado USA"},{"name":"Columbine Health Systems Center for Healthy Aging Colorado State University  Fort Collins Colorado 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