The Curious Case of a Heterozygous Loss-of-Function PSEN1 variant associated with Early-Onset Alzheimer's Disease

Over 300 mutations in PSEN1 have been identified as causes of early-onset Alzheimer's disease (EOAD). While these include missense mutations and a few insertions, deletions, or duplications, none result in open reading frame shifts, and all alter γ-secretase function to increase the long/short Aβ ratio.

We identified a novel heterozygous PSEN1 nonsense variant, c.325A > T, in a patient and his father, both presenting with EOAD, resulting in the substitution of lysine 109 with a premature stop codon at position (p.K109*). This produces a truncated 109 amino acid (aa) N-terminal PSEN1 fragment. Functional characterization was performed using overexpression models and a heterozygous mouse model (Psen1^K109*/+).

In overexpression models, downstream ATGs serve as alternative starting codons, generating a > 37kDa and a > 27 kDa PSEN1 C-terminal fragment (PSEN1-CTF_A and PSEN1-CTF_B, respectively) that retain the two catalytic aspartates of γ-secretase. Heterozygous Psen1^K109*/+ mice exhibited subtle phenotypic defects, including reduced Pen2 expression and mild APP-CTF accumulation. Notably, aged mice demonstrated significantly increased Psen2 protein expression, potentially contributing to an elevated Aβ42/Aβ38 ratio.

These findings indicate that PSEN1 c.325A > T (p.K109*) is not a complete loss-of-function mutation. However, to what extent and by what mechanism it contributes to EOAD pathogenesis remains unclear.