Fig. 5. Models for the aggregation time course observed in human disease. (A) The decline of chaperone capacity during ageing leads to a decrease in the effective critical protein concentration. Once the monomer concentration exceeds this threshold, aggregation is initiated. (B) Similar as model A, but the critical concentration remains constant, whereas the monomer concentration increases. The concentration curves in A and B can have any shape, as long as the two curves intersect. (C) The monomer is already expressed beyond the critical threshold, yet the aggregation propensity (i.e., the rate constant for nucleation or other microscopic steps) increases due to a decline in chaperone capacity. The accumulation of a co-factor would cause a similar scenario. (D) The aggregation mechanism is strongly dominated by secondary processes, which lead to cooperative kinetics with a long lag phase.