Phenotypic heterogeneity of the rare R377W PSEN1 mutation: Late‐onset presentation with mixed Alzheimer’s and frontotemporal dementia features

Abstract

AbstractBackgroundAutosomal dominant mutations in the PSEN1 gene have been associated with the earliest Alzheimer’s disease onset and a typical amnestic syndrome of the hippocampal type, although behavioural and psychiatric presentations have also been reported. The R377W PSEN1 mutation has only been found in two patients until now. Here, we want to describe an unusual presentation of the rare R377W PSEN1 mutation in an Italian patient with a late age of onset, and to provide for the first time antemortem pathological evidence for this mutation.MethodA 71‐years old female patient with progressive cognitive decline in the past three years underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid‐PET and extensive genetic screening with a next generation sequencing technique.ResultThe diagnostic work‐up revealed mixed frontotemporal dementia and typical Alzheimer’s disease features on neuropsychological tests, MRI and FDG‐PET. Amyloid‐PET detected amyloid deposition in the frontal areas as well as in the parietal lobes and the precunei. The genetic screening unraveled the presence of the rare R377W mutation in the PSEN1 gene.ConclusionExtensive genetic screening is advisable also for late onset presentations of Alzheimer’s disease, especially in the presence of a positive family history.