Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype

Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe beta-amyloid (A beta) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of A beta precursor protein in vitro as well as the A beta species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted A beta(42) and A beta(40) species and a 60% increase of secreted A precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated A beta species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the A beta aggregates' composition.