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 (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.