Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits.

Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer's disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice.

Age of onset predicted by Aβ profiling in a novel PSEN1 (I180F) mutation.

We describe a novel I180F mutation in PSEN1 in which biomarker-supported Alzheimer's disease (AD) segregated in two affected family members. The affected amino acid is highly conserved across species and in silico models predict pathogenicity for AD. The mean age of onset was 56 which was reasonably predicted by the pattern of Aβ species produced in an in vitro model.

Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset.

Familial Alzheimer's disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO.