PSEN1 and familial Alzheimer disease: However, more recent analysis using mammalian cells has shown that while a vast majority of the studied PS1 mutations do lead to increased Aß42/Aß40 ratios, a majority of these variants significantly decrease production of both Aß42 and Aß40 and have no significant correlation to mean age at onset of fAD for the corresponding mutations [10], casting doubt on the widely accepted assumption that pathogenic PS1 variants lead to fAD by favoring production of Aß42 over Aß40.