Extreme Cerebrospinal Fluid Amyloid Levels Identify Family with Late-Onset Alzheimer’s Disease Presenilin 1 Mutation

Objective: Aggregation and deposition of amyloid beta (A ) in the brain is thought to be central to the pathogenesis of Alzheimer’s disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) A levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change A levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF A levels as an endophenotype for AD. Methods: We sequenced the exons and flanking intronic regions of PSEN1 in clinically characterized research subjects with extreme values of CSF A levels. Results: This novel approach led directly to the identification of a disease-causing mutation in a family with late-onset AD. Interpretation: This finding suggests that CSF A may be a useful endophenotype for genetic studies of AD. Our results also suggest that PSEN1 mutations can cause AD with a large range in age of onset, spanning both earlyand late-onset AD.