In polyglutamine (polyQ) containing fragments of the Huntington's disease protein huntingtin (htt), the N-terminal 17 amino acid httNT segment serves as the core of a-helical oligomers whose reversible assembly locally concentrates the polyQ segments, thereby facilitating polyQ amyloid nucleation. A variety of aggregation inhibitors have been described that achieve their effects by neutralizing this concentrating function of the httNT segment. In this paper we characterize the nature and limits of this inhibition for three means of suppressing httNT-mediated aggregation. We show that the previously described action of httNT peptide-based inhibitors is solely due to their ability to suppress the httNT-mediated aggregation pathway. That is, under httNT inhibition, nucleation of polyQ amyloid formation by a previously described alternative nucleation mechanism proceeds unabated and transiently dominates the aggregation process. Removal of the bulk of the httNT segment by proteolysis or mutagenesis also blocks the httNT-mediated pathway, allowing the alternative nucleation pathway to dominate. In contrast, the previously described immunoglobulin-based inhibitor, the antihttNT VL 12.3 protein, effectively blocks both amyloid pathways, leading to stable accumulation of nonamyloid oligomers. These data show that the httNT-dependent and -independent pathways of amyloid nucleation in polyQ-containing htt fragments are in direct kinetic competition. The results illustrate how amyloid polymorphism depends on assembly mechanism and kinetics and have implications for how the intracellular environment can influence aggregation pathways. [ABSTRACT FROM AUTHOR]