title: Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.
abstract: There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kiddle
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Steves
authors.affiliation: Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Mehta
authors.affiliation: 1] Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Simmons
authors.affiliation: 1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Newhouse
authors.affiliation: 1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Sattlecker
authors.affiliation: 1] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK [2] Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Ashton
authors.affiliation: 1] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK [2] Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bazenet
authors.affiliation: Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Killick
authors.affiliation: Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Adnan
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Instituet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Westman
authors.affiliation: SomaLogic, Boulder, CO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nelson
authors.affiliation: 1] Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland [2] NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Department of Old Age Psychiatry and Psychotic disorders, Medical University of Łódź, Łódź, Poland.
authors.forename: I
authors.initials: I
authors.lastname: Kloszewska
authors.affiliation: Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Mecocci
authors.affiliation: 3rd Department of Neurology, Aristotle University, Thessaloniki, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Department of Internal Medicine and Geriatric Medicine, INSERM University of Toulouse, Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Vellas
authors.affiliation: 1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Curtis
authors.affiliation: 1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Breen
authors.affiliation: Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: S C R
authors.initials: SC
authors.lastname: Williams
authors.affiliation: Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors.forename: T D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: 1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK [2] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
authors.forename: R J B
authors.initials: RJ
authors.lastname: Dobson
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000473:pathology; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000473:pathology*; D058068:Endophenotypes; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood*; D048670:MAP Kinase Kinase 4 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases / Q000097:blood*; D014427:Twins / Q000235:genetics* / Q000523:psychology
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human