title: Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.
abstract: 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: APPα, APPβ or Aβ42, 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 APPα, APPβ, and Aβ42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα 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 APPα levels in an AD specific manner.
authors.affiliation: Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA, USA. lbekris@u.washington.edu
authors.forename: L M
authors.initials: LM
authors.lastname: Bekris
authors.forename: N M
authors.initials: NM
authors.lastname: Galloway
authors.forename: S
authors.initials: S
authors.lastname: Millard
authors.forename: D
authors.initials: D
authors.lastname: Lockhart
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: D R
authors.initials: DR
authors.lastname: Galasko
authors.forename: M R
authors.initials: MR
authors.lastname: Farlow
authors.forename: C M
authors.initials: CM
authors.lastname: Clark
authors.forename: J F
authors.initials: JF
authors.lastname: Quinn
authors.forename: J A
authors.initials: JA
authors.lastname: Kaye
authors.forename: G D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: J B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: P
authors.initials: P
authors.lastname: Seubert
authors.forename: D W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: E R
authors.initials: ER
authors.lastname: Peskind
authors.forename: C E
authors.initials: CE
authors.lastname: Yu
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072197:ADAM10 Protein; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid* / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D008565:Membrane Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human