title: Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels.
abstract: The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.
authors.affiliation: Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA. lbekris@u.washington.edu
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bekris
authors.forename: Steven P
authors.initials: SP
authors.lastname: Millard
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Galloway
authors.forename: Simona
authors.initials: S
authors.lastname: Vuletic
authors.forename: John J
authors.initials: JJ
authors.lastname: Albers
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.forename: Charles
authors.initials: C
authors.lastname: DeCarli
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.forename: Chris M
authors.initials: CM
authors.lastname: Clark
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kaye
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Debby
authors.initials: D
authors.lastname: Tsuang
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid*; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D017931:DNA Primers; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human