As the world population ages, new molecular targets in aging and Alzheimer's Disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in prevalence in the hippocampus with both age and with AD severity. We further found that neurofibrillary tangles (NFTs) contained rG4s, that rG4 structure can drive tau aggregation, and that rG4 formation depended on APOE genotype in the human tissue examined. Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation drives proteostasis collapse. We propose that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.