Moreover, our study, for the first time, identify RSK1 as an upstream regulator of AKT-GSK3β signaling cascade, enhancing AKT signaling while simultaneously inhibiting GSK3β activity, thereby underscoring the critical role of RSK1 in Tau phosphorylation and associated illnesses, such as HAND and Alzheimer's disease. Here, MAPT is linked to early-onset autosomal dominant Alzheimer disease.