Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation

▶ A novel mutation in the PSEN1 gene causes an amino acid substitution in the fourth transmembrane region of the Presenilin-1 protein (S212Y), causing early-onset Alzheimer's disease. ▶ Cerebrospinal fluid levels of tau in an affected person were among the highest and levels of beta-amyloid among the lowest we have seen in Alzheimer's disease. ▶ Binding of the PET ligand, FDDNP, was particularly evident in the striatum where excessive tau pathology was found in the affected brother of the imaged index patient. ▶ We performed an in vitro experiment in which the novel mutation was introduced into a cellular construct to assay its effect on APP processing which confirmed an effect in elevating Aβ42 levels.