The presenilin 1 mutation P436S causes familial Alzheimer’s disease with elevated Aβ43 and atypical clinical manifestations

Abstract

Structured AbstractBACKGROUNDFamilial Alzheimer’s disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of Alzheimer’s disease more widely. The pathogenicity of the P436S mutation inPSEN1remains unclassified.METHODSTo determine the pathogenicity of thePSEN1P436S mutation, we studied an expanded kindred of 8 affected individuals, with MRI (2 individuals), patient-derived iPSC models (2 donors) and post-mortem histology (1 donor).RESULTSAn autosomal dominant pattern of inheritance of fAD was seen with an average age at symptom onset of 46 years and atypical features including late spastic paraparesis and non-memory led cognitive impairment in some individuals. iPSC models and post- mortem tissue supported high production of Aβ43. PSEN1 peptide maturation was unimpaired, unlike previously reported atypical mutations R278I and E280G. CONCLUSIONS: We confirm that the P436S mutation inPSEN1causes atypical fAD. The location of the mutation in the critical PSEN1 PALP motif may explain the early age of onset despite appropriate protein maturation.