Differential effects of PSEN1 mutations (p.P117L with ataxia and p.P264L without ataxia) in early-onset Alzheimer's disease

Presenilin 1 (PSEN1) plays a pivotal role in early-onset Alzheimer's disease (EOAD). The clinical phenotype of EOAD is typically marked by cognitive decline, with ataxia rarely reported. We identified mutations at different positions of PSEN1 in two Chinese patients with EOAD. Interestingly, one patient carrying the PSEN1 p.P117L mutation manifested symptoms of ataxia, while another patient harboring the PSEN1 p.P264L mutation did not exhibit any signs of this disorder. Computational analyses using PolyPhen-2, SIFT, Provean, and Mutation Taster predicted both mutations as pathogenic, while structural predictions using SOPMA, TMHMM 2.0, and PyMOL. Our findings expand the spectrum of atypical PSEN1-associated phenotypes.