Abstract
Familial early-onset Alzheimer's disease (EOAD) is a rare form of dementia often caused by autosomal dominant mutations in APP, PSEN1, or PSEN2. We report a novel PSEN2 missense variant (c.359T > G, p.Ile120Ser) that has been detected in four siblings; three of whom are affected by predominantly amnestic EOAD or mild cognitive impairment in their fifties (supported by neuroimaging biomarkers), while the youngest sibling is currently asymptomatic at age 50. Two of the siblings were also heterozygous for a variant in PSEN1 (c.118_120del, p.Asp40del). Between the two genes, the PSEN2 variant was deemed to be likely pathogenic based on segregation with EOAD, imaging biomarker analyses, and bioinformatic analyses. Reporting genetic findings in familial EOAD cases can help in classifying their pathogenic significance and improving genetic conceptualization within Alzheimer's disease.