Objective: Aggregation and deposition of amyloid beta (Aβ) in the brain is thought to be central to the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Aβ 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 Aβ levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Aβ 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 Aβ 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 Aβ 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 early- and late-onset AD.