Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

Abstract

Background: In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. Objective: To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. Methods: We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. Results: The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. Conclusion: The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aβ species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age.

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Alzheimer's Disease Investigated via Gene-Environment Interactions, Biochemical Pathways, Cellular Processes, and Disease Phenotype Variability

“…Increased Aβ levels resulting from altered APP processing can trigger events leading to tau hyperphosphorylation and the formation of neuro brillary tangles (NFTs). PSEN1 mutations may directly or indirectly affect tau phosphorylation and aggregation, contributing to neurodegeneration in Alzheimer's disease [47,51].…”

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“…Pathological characteristics of AD involve the buildup of neuritic amyloid beta (Aβ) plaques, dystrophic neurites, and neurofibrillary tangles (NFTs) ( Table 2 ) containing intraneuronal aggregates of hyperphosphorylated and misfolded tau [ 117 , 118 , 119 ]. AD can be familial in rare autosomal dominant cases that are linked with mutations in the presenilin-1 (PS-1), presenilin-2 (PS-2), and amyloid precursor genes [ 120 , 121 , 122 ]. It has been reported that an elevated generation of the mitochondrial ROS can increase Aβ levels, which can further suppress the mitochondrial respiratory chain containing complexes IV inducing its dysfunction [ 123 ].…”