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 (Abeta) 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 Abeta precursor protein in vitro as well as the Abeta species in brain tissue.
Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Abeta(42) and Abeta(40) species and a 60% increase of secreted Abeta precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Abeta 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 Abeta aggregates' composition.