title: LRP-1 polymorphism is associated with global and regional amyloid load in Alzheimer's Disease in humans in-vivo.
abstract: OBJECTIVE
  Impaired amyloid clearance has been proposed to contribute to β-amyloid deposition in sporadic late-onset Alzheimer's disease (AD). Low density lipoprotein receptor-related protein 1 (LRP-1) is involved in the active outward transport of β-amyloid across the blood-brain barrier (BBB). The C667T polymorphism (rs1799986) of the LRP-1 gene has been inconsistently associated with AD in genetic studies. We aimed to elucidate the association of this polymorphism with in-vivo brain amyloid load of AD patients using amyloid PET with [(11)C]PiB.
  
  
  METHODS
  72 patients with very mild to moderate AD were examined with amyloid PET and C667T polymorphism was obtained using TaqMan PCR assays. The association of C667T polymorphism with global and regional amyloid load was calculated using linear regression and voxel based analysis, respectively. The effect of the previously identified modulator of amyloid uptake, the apolipoprotein E genotype, on this association was also determined.
  
  
  RESULTS
  The regression analysis between amyloid load and C667T polymorphism was statistically significant (p = 0.046, β = 0.236). In an additional analysis ApoE genotype and gender were identified to explain further variability of amyloid load. Voxel based analysis revealed a significant (p < 0.05) association between C667T polymorphism and amyloid uptake in the temporo-parietal cortex bilaterally. ApoE did not interact significantly with the LRP-1 polymorphism.
  
  
  CONCLUSIONS
  In conclusion, C667T polymorphism of LRP-1 is moderately but significantly associated with global and regional amyloid deposition in AD. The relationship appears to be independent of the ApoE genotype. This finding is compatible with the hypothesis that impaired amyloid clearance contributes to amyloid deposition in late-onset sporadic AD.
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Grimmer
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goldhardt
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Liang-Hao
authors.initials: LH
authors.lastname: Guo
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany ; Pharmaceutical Radiochemistry, Faculties of Chemistry and Medicine, Technische Universität München, Walther-Meißner-Str. 3, 85748 Garching, Germany.
authors.forename: Behrooz H
authors.initials: BH
authors.lastname: Yousefi
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Förster
authors.affiliation: Department of Nuclear Medicine, University Hospital of Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drzezga
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Sorg
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Alexopoulos
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Förstl
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany ; Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Perneczky
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000503:physiopathology*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000814:Aniline Compounds; D052160:Benzothiazoles / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013844:Thiazoles; D014018:Tissue Distribution
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D058227:Amyloidogenic Proteins; D000814:Aniline Compounds; D052160:Benzothiazoles; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019275:Radiopharmaceuticals; D013844:Thiazoles
keywords: Alzheimer's disease (AD); Apolipoprotein E (ApoE); C667T polymorphism; Low density lipoprotein receptor related protein 1 (LRP-1); Pittsburgh compound B ([11C]PiB); Positron emission tomography (PET)