UFM1 is an understudied ubiquitin-like modifier. Like ubiquitin, UFM1 is covalently conjugated to substrate proteins. The conjugation of UFM1 (UFMylation) is reversible, and this is mediated by UFSP2. UFMylation has been linked to important biological pathways such as the DNA damage response, the unfolded protein response, and autophagy. UFMylation is also crucial for healthy brain development, however a role of UFM1 for age-related brain diseases such as Alzheimer’s disease (AD) has not been established. Considering that pathological tau plays a critical role for AD, and has a physiological role for DNA damage, we hypothesized that tau might be UFMylated. We assessed the protein levels of UFM1, UFSP2 and other UFMylation pathway components by ELISA or western blot in AD post-mortem brain and controls. We performed immunoprecipitations and used mass spectrometry (LC-MS/MS) to detect UFMylation and identify conjugation sites.Using cell lysates, we detected the UFMylation of overexpressed tau and identified 17 putative conjugation sites. In human AD brain, we found a strong reduction of soluble UFSP2 that was concomitant with an increase of UFM1 compared to controls, potentially suggesting an increase of conjugated UFM1 in AD brain. We also detected tau signal in UFM1 immunoprecipitates from human brain, suggesting that endogenous tau is UFMylated. Together, our data indicates that the UFM1 pathway is altered in AD and that the AD-associated tau protein is UFMylated in vitro and in vivo. Additional studies are needed to assess the modification of physiological vs pathological tau and the biological relevance of such modification.