Background: Evidence supports a link between neurodegeneration, insulin resistance (IR) and type 2 diabetes (T2D), although the exact molecular mechanism(s) remain unknown. We previously showed that the transacting factor, HMGA1, is needed for proper expression of the insulin receptor (InsR) and other genes related to glucose metabolism. Further, IR and T2D were reported earlier in humans and mice with HMGA1 gene defects. Here, we focused on HMGA1 as a potential novel pathogenic factor of tauopathies, including Alzheimer’s disease (AD). Methods: Investigations were performed in vitro, in human and mouse neuronal cell models, and in vivo, in Hmga1-knockout mice. Immunoblot analyses, combined with protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays in living cells were carried out, in addition to immunohistochemical stains in Hmga1-knockout mouse brain. Furthermore, the relationship between HMGA1 and tau pathology was explored in tauopathy patients, carrying or not the HMGA1 rs146052672 variant, which negatively impacts HMGA1 protein production and increases the risk of IR and T2D. Results: Analysis of tau mRNA and protein levels in human and mouse neuronal cultures revealed an inverse correlation with HMGA1 expression. This relationship was further validated in Hmga1-knockout mice, which displayed elevated tau levels, reduced InsR expression, and decreased glucose uptake in the brain, compared to wild-type mice. Interestingly, the rs146052672 variant was found to be significantly more prevalent in patients with tauopathies (17.4%) compared to controls (5.0%), and was associated with greater severity of AD. Conclusions: In contrast to its role in promoting the expression of the insulin receptor and other genes involved in glucose metabolism, HMGA1 functions as a repressor of the tau gene. Based on our findings, it can be concluded that a deficiency in HMGA1 represents a novel causal mechanism through which neurodegenerative disorders may be linked to insulin resistance.