Transcriptomic Evidence of Mitochondrial Double‐Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease

Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt-dsRNA 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-dsRNA-driven inflammation. In AD brains, mt-dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration and identify mt-dsRNA as a potential driver of chronic inflammation in the brain.