Decreased α-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's diseas

The neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is β-amyloid, a hydrophobic peptide of 39–43 amino acids1and a fragment of the amyloid precursor protein (APP). APP can be metabolized by at least two pathways, one of which involves generation of soluble APP by an unidentified enzyme named α-secretase. This cleavage generates α-secretase-cleaved, soluble APP (α–sAPP), which in this investigation was measured by a new assay in cerebrospinal fluid (CSF) from members of a Swedish AD family with a pathogenic mutation at APP670/671(ref. 2). Family members who carry the mutation and are diagnosed with AD had low levels of α–sAPP (160 ± 48 ng ml−1), with no overlap compared with non-carriers (257 ± 48 ng ml−1). Carriers of the presymptomatic mutation showed intermediate α–sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of α–sAPP represents a new and promising diagnostic marker.