Background: Familial 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 in PSEN1 remains unclassified. Methods: To determine the pathogenicity of the PSEN1 P436S 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). Results: An 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 in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 PALP motif may explain the early age of onset despite appropriate protein maturation.

The authors have declared no competing interest.

CA was supported by an Alzheimer's Society fellowship (AS-JF-18-008). SW was supported by senior research fellowship from Alzheimer's Research UK (ARUK-SRF2016B-2). FT was supported by an EMBO scientific exchange grant (No. 9297). RG was part of the of the UCL Neurogenetic Therapies Programme, generously funded by The Sigrid Rausing Trust. YB is supported by the Association of Frontotemporal Dementia. NSR was supported by a University of London Chadburn Academic Clinical Lectureship. This work was supported by the Medical Research Council (MR/M02492X/1), the UK Dementia Research Institute at UCL (which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and ARUK), and by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre.

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