title: The effects of different familial Alzheimer's disease mutations on APP processing in vivo.
abstract: BACKGROUND
  Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer's disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective.
  
  
  METHODS
  In the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families.
  
  
  RESULTS
  We observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42that was found with all mutations.
  
  
  CONCLUSIONS
  These findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology.
authors.affiliation: Department NVS, Division of Neurogeriatrics, Center for Alzheimer Disease Research, Karolinska Institutet, 141 57, Huddinge, Sweden. steinunn.thordardottir@ki.se.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. steinunn.thordardottir@ki.se.
authors.forename: Steinunn
authors.identifier: http://orcid.org/0000-0001-8311-7260
authors.initials: S
authors.lastname: Thordardottir
authors.affiliation: Department NVS, Division of Neurogeriatrics, Center for Alzheimer Disease Research, Karolinska Institutet, 141 57, Huddinge, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
authors.forename: Anne
authors.initials: A
authors.lastname: Kinhult Ståhlbom
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57, Huddinge, Sweden.
authors.forename: Ove
authors.initials: O
authors.lastname: Almkvist
authors.affiliation: Department NVS, Division of Neurogeriatrics, Center for Alzheimer Disease Research, Karolinska Institutet, 141 57, Huddinge, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Thonberg
authors.affiliation: Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.|Department NVS, Division for Clinical Geriatrics, Center for Alzheimer Disease Research, Karolinska Institutet, 141 57, Huddinge, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksdotter
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-431 80, Mölndal, Sweden.|UCL Insitute of Neurology, Queen Square, London, UK.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, SE-431 80, Mölndal, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-431 80, Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, SE-431 80, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department NVS, Division of Neurogeriatrics, Center for Alzheimer Disease Research, Karolinska Institutet, 141 57, Huddinge, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics; D003430:Cross-Sectional Studies; D005190:Family; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer’s disease; Amyloid precursor protein; Biomarkers; Cerebrospinal fluid; Genetics