DECREASED ALPHA-SECRETASE-CLEAVED AMYLOID PRECURSOR PROTEIN AS A DIAGNOSTIC MARKER FOR ALZHEIMERS-DISEASE

The neuropathologic hallmarks of Alzheimer's disease (AD) are extracel lular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is beta-amyloid, a hydrophobic peptide of 39- 43 amino acids(1) and a fragment of the amyloid precursor protein (APP ). APP can be metabolized by at least two pathways, one of which invol ves generation of soluble APP by an unidentified enzyme named alpha-se cretase. This cleavage generates alpha-secretase-cleaved, soluble APP (alpha-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 APP(670/671) (ref. 2). Family members who car ry the mutation and are diagnosed with AD had low levels of alpha-sAPP (160 +/- 48 ng ml(-1)), with no overlap compared with non-carriers (2 57 +/- 48 ng ml(-1)). Carriers of the presymptomatic mutation showed i ntermediate alpha-sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of alpha-sAPP represents a new and promising diagnostic marker.