Main neuropathological hallmarks of Alzheimers disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble ß-amyloid peptides (Aß), containing up to 43 amino acid residues derived from the ß-amyloid precursor protein. Such Aß-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, α-helical, lipophilic, antigenic folding domain of the Aßpeptide loop is a promising molecular target of ß-sheet breakers that thus prevent the polymerization of Aß into aggregates. It seems that di- and tetramers of Aß-peptides have a ß-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structureactivity relationships of peptidomimetic ß-sheet breakers. The anti-aggregatory potency of ß-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic α-helix / random-coils to ß-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from α- helical / random coil to ß-sheet conformation and thus abrogating their effects in a broad variety of disorders.