title: Tau phosphorylation pathway genes and cerebrospinal fluid tau levels in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
authors.affiliation: Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, Washington 98108, USA. lbekris@u.washington.edu
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bekris
authors.forename: Steve
authors.initials: S
authors.lastname: Millard
authors.forename: Franziska
authors.initials: F
authors.lastname: Lutz
authors.forename: Gail
authors.initials: G
authors.lastname: Li
authors.forename: Doug R
authors.initials: DR
authors.lastname: Galasko
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kaye
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins