Platelet APP isoform ratios in asymptomatic young adults expressing an AD-related presenilin-1 mutation

The Alzheimer's disease (AD) related amyloid precursor protein (APP) is sto red, cleaved and released similarly from neurons and from platelets. We hav e reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP p resent in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years b efore the onset of cognitive loss, we have also compared platelet APP ratio s of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determin e whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these su bjects at this time. We will continue to monitor these subjects as they nea r the mean age of AD onset in these families. As the magnitude of the APP r atio reduction is proportional to the severity of cognitive loss in sporadi c AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. A lternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-I AD subjects to manifest altered A PPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of contr ols with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD. (C) 2001 Elsevier Science B.V. All rights reserved.