The Columbia mouse study in Nature Neuroscience reveals that blocking the neuroproteasome—a neuron-specific membrane disposal system—triggers tau paired helical filaments nearly identical to those in human Alzheimer's brains. This preclinical work (experimental, not RCT; sample sizes modest with n typically <20 per group in such models) identifies a mechanistic trigger missed by amyloid-focused coverage. ApoE4 reduces neuroproteasome density, amplifying tau aggregation, while ApoE2 protects it—linking genetics directly to pre-symptomatic protein quality control failure. This aligns with broader patterns in neurodegeneration, including early proteostasis collapse seen in Parkinson's (alpha-synuclein studies) and ALS. A 2023 Nature paper on neuronal proteasomes and a 2024 Lancet Neurology review on pre-clinical biomarkers both underscore that such disruptions precede symptoms by 10-20 years, an area under-covered versus late-stage tau antibodies. No conflicts noted beyond institutional funding; findings remain correlative until human validation.