One of the fundamental pathological hallmarks of Alzheimer’s disease (AD) is the accumulation and aggregation of a protein called tau. The majority, if not all, of our cellular and genetic models to study tau aggregation require mutations or overexpression of the tau protein in order to observe tau aggregation. This is highly problematic, because 95% of patients with AD do not carry tau mutations, nor do they overexpress the tau protein. Therefore, the fundamental molecular rationale for why and how otherwise normal tau aggregates in the brains of Alzheimer’s patients remains elusive. As an additional layer of complexity, the single largest genetic risk factor for AD, the APOE4 allele, can increase the probability for tau aggregation and is correlated with earlier disease onset, yet there currently is no underlying mechanistic understanding of how and why APOE4 increases the risk for tau aggregation. A mechanism that can provide answers for both of these issues not only would provide deep insights into the molecular etiology of AD, but also would be likely to generate an actionable molecular target for therapy. Our group has identified for the first time this potential connection: a neuronal–specific protein clearance mechanism (the neuroproteasome), which is molecularly linked to APOE and the failure of which directly results in the accumulation of endogenous tau aggregates in otherwise normal animals. We seek to build on this work and not only gain specific insights into how neuroproteasomes drive endogenous tau aggregation, but also to expand our knowledge of the interactions between APOE and the neuroproteasome necessary to therapeutically target this complex.