Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease

The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APP alpha, APP beta or A beta 42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APP alpha, APP beta, and A beta 42. AD risk and age-at-onset while taking into account age, gender, race and APOE epsilon 4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APP alpha levels. In controls, the rs514049 CC genotype had higher APP alpha levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APP alpha levels in an AD specific manner. (C) 2011 Elsevier Inc. All rights reserved.