A key finding in Alzheimer's disease (AD) is the presence of amyloid deposits, which are primarily composed of the β/A4 protein (Aβ). This study identified two previously unknown peptides, X and Y, in addition to Aβ in amyloid preparations. These peptides were used to raise antibodies that specifically stained amyloid in neuritic and diffuse plaques, as well as vascular amyloid. Electron microscopy confirmed that the staining was localized on amyloid fibrils. A full-length cDNA encoding a 140-amino-acid protein, NACP, was isolated, which contains the two unknown peptides, X and Y, in tandem within its most hydrophobic domain. The 35-amino-acid peptide NAC, a non-Aβ component of AD amyloid, was tentatively named, along with its precursor NACP. NAC is the second component identified chemically in purified AD amyloid. Secondary structure predictions suggest that NAC has a strong tendency to form β-structures, consistent with its association with amyloid. NACP was detected as a 19,000 Mr protein in the cytosolic fraction of brain homogenates and comigrates with NACP synthesized in Escherichia coli from NACP cDNA. NACP mRNA is expressed mainly in the brain but is also present in low concentrations in other tissues except the liver, suggesting its brain-specific functions. The availability of the full-length NACP cDNA should help elucidate the mechanisms of amyloidosis in AD. The study also identified that NAC is an intrinsic component of amyloid, as opposed to other components associated with plaque core amyloid, which are detected only by immunological probes. The presence of NAC in amyloid suggests it may play a role in promoting the formation of insoluble amyloid from soluble Aβ. The study provides evidence that NAC is an unrecognized component of AD amyloid and may be involved in the pathogenesis of the disease.A key finding in Alzheimer's disease (AD) is the presence of amyloid deposits, which are primarily composed of the β/A4 protein (Aβ). This study identified two previously unknown peptides, X and Y, in addition to Aβ in amyloid preparations. These peptides were used to raise antibodies that specifically stained amyloid in neuritic and diffuse plaques, as well as vascular amyloid. Electron microscopy confirmed that the staining was localized on amyloid fibrils. A full-length cDNA encoding a 140-amino-acid protein, NACP, was isolated, which contains the two unknown peptides, X and Y, in tandem within its most hydrophobic domain. The 35-amino-acid peptide NAC, a non-Aβ component of AD amyloid, was tentatively named, along with its precursor NACP. NAC is the second component identified chemically in purified AD amyloid. Secondary structure predictions suggest that NAC has a strong tendency to form β-structures, consistent with its association with amyloid. NACP was detected as a 19,000 Mr protein in the cytosolic fraction of brain homogenates and comigrates with NACP synthesized in Escherichia coli from NACP cDNA. NACP mRNA is expressed mainly in the brain but is also present in low concentrations in other tissues except the liver, suggesting its brain-specific functions. The availability of the full-length NACP cDNA should help elucidate the mechanisms of amyloidosis in AD. The study also identified that NAC is an intrinsic component of amyloid, as opposed to other components associated with plaque core amyloid, which are detected only by immunological probes. The presence of NAC in amyloid suggests it may play a role in promoting the formation of insoluble amyloid from soluble Aβ. The study provides evidence that NAC is an unrecognized component of AD amyloid and may be involved in the pathogenesis of the disease.