Sex-specific regulation of angiogenin in Alzheimer’s disease

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease that inhibits apoptosis by generating 5′-tRNA fragments, is a candidate whose expression and regulation in AD is not understood. Here, we investigated ANG expression and regulation using AD cell and animal models, postmortem human brain tissue, and transcriptomic datasets ( n = 645). We found that ANG is dysregulated in AD in a sex-dependent manner, altering downstream levels of 5′-tiRNA Gly-GCC . Our analysis revealed female-specific molecular subtypes, absent in males: Subtype 1 featured low ANG levels with increased inflammation and neuronal death; subtype 2 exhibited higher ANG expression and intermediate pathology; subtype 3, marked by the highest ANG levels, showed reduced inflammation, slower cognitive decline, and extended survival. These findings position ANG as a key modulator of neuroinflammation and apoptosis in AD, highlighting its potential as a treatment strategy.