A method of screening for genetic vulnerabilities associated with tau aggregation, comprising: (a) providing an aggregation-positive population of cells and an aggregation-negative population of cells, wherein each population of cells comprises a Cas protein, a first tau repeat domain linked to a first reporter, and a second tau repeat domain linked to a second reporter, wherein the cells are mammalian cells, wherein the first reporter and the second reporter are fluorescent proteins, and wherein the first reporter and the second reporter are a fluorescence resonance energy transfer (FRET) pair, wherein the aggregation-positive population of cells comprises aggregates of the first tau repeat domain linked to the first reporter and the second tau repeat domain linked to the second reporter, and wherein the aggregation-negative population of cells does not comprise aggregates of the first tau repeat domain linked to the first reporter and the second tau repeat domain linked to the second reporter; (b) introducing into each population of cells a library comprising a plurality of unique guide RNAs that target a plurality of genes, wherein the plurality of unique guide RNAs form complexes with the Cas protein, and the Cas protein cleaves the plurality of genes resulting in knockout of gene function; and (c) determining abundance of each of the plurality of unique guide RNAs at a plurality of time points over a time course in each population of cells, wherein the plurality of time points comprises at least three time points, wherein there is more than 1 day between each time point, wherein depletion of a guide RNA in the aggregation-positive population of cells but not in the aggregation-negative population of cells or a faster rate of depletion of a guide RNA over the time course in the aggregation-positive population of cells relative to the aggregation-negative population of cells indicates that the gene targeted by the guide RNA exhibits synthetic lethality with tau protein aggregates and is a genetic vulnerability associated with tau aggregation. (a) providing an aggregation-positive population of cells and an aggregation-negative population of cells, wherein each population of cells comprises a Cas protein, a first tau repeat domain linked to a first reporter, and a second tau repeat domain linked to a second reporter, wherein the cells are mammalian cells, wherein the first reporter and the second reporter are fluorescent proteins, and wherein the first reporter and the second reporter are a fluorescence resonance energy transfer (FRET) pair, wherein the aggregation-positive population of cells comprises aggregates of the first tau repeat domain linked to the first reporter and the second tau repeat domain linked to the second reporter, and wherein the aggregation-negative population of cells does not comprise aggregates of the first tau repeat domain linked to the first reporter and the second tau repeat domain linked to the second reporter; wherein the cells are mammalian cells, wherein the first reporter and the second reporter are fluorescent proteins, and wherein the first reporter and the second reporter are a fluorescence resonance energy transfer (FRET) pair, wherein the aggregation-positive population of cells comprises aggregates of the first tau repeat domain linked to the first reporter and the second tau repeat domain linked to the second reporter, and wherein the aggregation-negative population of cells does not comprise aggregates of the first tau repeat domain linked to the first reporter and the second tau repeat domain linked to the second reporter; (b) introducing into each population of cells a library comprising a plurality of unique guide RNAs that target a plurality of genes, wherein the plurality of unique guide RNAs form complexes with the Cas protein, and the Cas protein cleaves the plurality of genes resulting in knockout of gene function; and (c) determining abundance of each of the plurality of unique guide RNAs at a plurality of time points over a time course in each population of cells, wherein the plurality of time points comprises at least three time points, wherein there is more than 1 day between each time point, wherein depletion of a guide RNA in the aggregation-positive population of cells but not in the aggregation-negative population of cells or a faster rate of depletion of a guide RNA over the time course in the aggregation-positive population of cells relative to the aggregation-negative population of cells indicates that the gene targeted by the guide RNA exhibits synthetic lethality with tau protein aggregates and is a genetic vulnerability associated with tau aggregation. wherein the plurality of time points comprises at least three time points, wherein there is more than 1 day between each time point, wherein depletion of a guide RNA in the aggregation-positive population of cells but not in the aggregation-negative population of cells or a faster rate of depletion of a guide RNA over the time course in the aggregation-positive population of cells relative to the aggregation-negative population of cells indicates that the gene targeted by the guide RNA exhibits synthetic lethality with tau protein aggregates and is a genetic vulnerability associated with tau aggregation.