MAPT and Alzheimer disease: Both ubiquitin-independent mechanisms and the UPS are impaired in AD, and hyperphosphorylated tau forms paired helical filaments that can directly bind to 20S proteasome complexes, affecting both 26S and 20S degradation mechanisms, and can associate into large neurofibrillary tangles (Keck et al., 2003; Poppek et al., 2006; Rankin et al., 2007; Min et al., 2010; Rawat et al., 2022).