Background: Alcadein? (Alc?) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-β precursor protein (APP). Successive cleavage of APP by β- and γ-secretases generates the aggregatable amyloid-β peptide (Aβ), while cleavage of APP or Alc? by α- and γ-secretases generates non-aggregatable p3 or p3-Alc? peptides. Aβ and p3-Alc? can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alc? in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD). Results: Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alc ?, we determined levels of total p3-Alc? in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of Aβ40 correlated with levels of total p3-Alc? in all cohorts. Conclusions: We confirm that Aβ40 is the most abundant Aβ species, and we propose a model in which CSF p3- Alc? can serve as a either (1) a nonaggregatable surrogate marker for γ-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alc ? and Aβ40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of γ-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Aβ metabolism.