Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy.

Background/purpose: Sporadic early-onset Alzheimer disease (sEOAD) and its visual variant, posterior cortical atrophy (PCA), have a disease onset at less than 65 years of age with no familial aggregation. The etiology and genetic basis of these diseases remain poorly understood. Our study aimed to identify additional mutations or variants associated with sEOAD and PCA and to further examine their genetic and phenotypic spectrums.

Methods: We performed whole-exome sequencing and analyzed the clinical and neuroimaging features of mutation carriers with 29 patients having sEOAD and 25 having PCA.

Results: Nine rare damaging variants were identified in 4 patients with sEOAD and 3 with PCA. A novel mutation (p.A136V) in PSEN1 was identified in a patient with sEOAD and a likely pathogenic variant (p.M239T) was identified for PSEN2 in a patient with PCA. In addition, 7 rare damaging variants were detected in other genes related to neurodegenerative diseases. The patient carrying the PSEN1 p.A136V mutation presented with typical clinical and imaging features of sEOAD, and the PCA patient with the PSEN2 p.M239T mutation presented with visuospatial impairment as the initial symptom.

Conclusion: Our study expands the PSEN1 mutation spectrum of sEOAD and highlights the importance of screening PSEN1 and/or PSEN2 mutations in PCA patients.