Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation.

Background Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation. Methods A 71-years old female patient with progressive cognitive decline in the past three years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-PET and extensive genetic screening with a next generation sequencing technique. Results The diagnostic work-up revealed mixed behavioural and amnestic disease features on neuropsychological tests, MRI, and FDG-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening unraveled the presence of the rare R377W mutation in the PSEN1 gene. Conclusions Extensive genetic screening is advisable also for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.