Neurodegenerative diseases (NDs) are caused by proteins that misfold, aggregate, and give rise to different types of protein inclusions that then spread around the brain, induce aggregation in host neurons and cause their demise. Previous drug development efforts for NDs have failed for different reasons. First, these have been developed based on targeting only a few protein conformations that do not reproduce the biochemical and structural features or the complexity of pathogenic species detected in NDs, due to limitations in available technologies. Moreover, previous efforts have focused on targeting molecular events that are the consequences, rather than the initiators, of the pathogenic cascade that leads to ND, due to gaps in understanding the physiological properties and functions of the disease-causing proteins. In addition, these treatments are usually introduced late, once protein aggregates are already abundant and circulating in the brain, due to the lack of companion diagnostics for early detection. Lastly, current therapies due not account for the clinical heterogeneity of the disease and suffer from the lack robust assays for monitoring of disease progression, patient stratification and assessment of target engagement. In short, the lack of basic understanding of the normal biology of the disease-causing proteins and the inability to embrace and reproduce the pathological diversity of aggregates, and the complexity of pathological processes driving ND have been major barriers to develop effective therapeutics to cure and slow the progression of NDs.