Diffuse Lewy Body Disease and Alzheimer Disease: Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation

In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.