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Brain. 2015 Sep;138(Pt 9):2701-15. doi: 10.1093/brain/awv199. Epub 2015 Jul 27.

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.

Collaborators (461)

Weiner MW, Aisen P, Weiner M, Aisen P, Petersen R, Jack CR Jr, Jagust W, Trojanowki JQ, Toga AW, Beckett L, Green RC, Saykin AJ, Morris J, Shaw LM, Khachaturian Z, Sorensen G, Carrillo M, Kuller L, Raichle M, Paul S, Davies P, Fillit H, Hefti F, Holtzman D, Mesulam M, Potter W, Snyder P, Schwartz A, Green RC, Montine T, Petersen R, Aisen P, Thomas RG, Donohue M, Walter S, Gessert D, Sather T, Jiminez G, Balasubramanian AB, Mason J, Sim I, Beckett L, Harvey D, Donohue M, Jack CR Jr, Bernstein M, Fox N, Thompson P, Schuff N, DeCArli C, Borowski B, Gunter J, Senjem M, Vemuri P, Jones D, Kantarci K, Ward C, Jagust W, Koeppe RA, Foster N, Reiman EM, Chen K, Mathis C, Landau S, Morris JC, Cairns NJ, Householder E, Taylor-Reinwald L, Shaw LM, Trojanowki JQ, Lee V, Korecka M, Figurski M, Toga AW, Crawford K, Neu S, Saykin AJ, Foroud TM, Potkin S, Shen L, Faber K, Kim S, Nho K, Weiner MW, Thal L, Khachaturian Z, Thal L, Buckholtz N, Weiner MW, Snyder PJ, Potter W, Paul S, Albert M, Frank R, Khachaturian Z, Hsiao J, Kaye J, Quinn J, Silbert L, Lind B, Carter R, Dolen S, Schneider LS, Pawluczyk S, Beccera M, Teodoro L, Spann BM, Brewer J, Vanderswag H, Fleisher A, Heidebrink JL, Lord JL, Petersen R, Mason SS, Albers CS, Knopman D, Johnson K, Doody RS, Villanueva-Meyer J, Chowdhury M, Rountree S, Dang M, Stern Y, Honig LS, Bell KL, Ances B, Morris JC, Carroll M, Creech ML, Franklin E, Mintun MA, Schneider S, Oliver A, Marson D, Griffith R, Clark D, Geldmacher D, Brockington J, Roberson E, Love MN, Grossman H, Mitsis E, Shah RC, deToledo-Morrell L, Duara R, Varon D, Greig MT, Roberts P, Albert M, Onyike C, D' Agostino D 2nd, Kielb S, Galvin JE, Cerbone B, Michel CA, Pogorelec DM, Rusinek H, de Leon MJ, Glodzik L, De Santi S, Doraiswamy P, Petrella JR, Borges-Neto S, Wong TZ, Coleman E, Arnold SE, Karlawish JH, Wolk D, Clark CM, Smith CD, Jicha G, Hardy P, Sinha P, Oates E, Conrad G, Lopez OL, Oakley M, Simpson DM, Porsteinsson AP, Goldstein BS, Martin K, Makino KM, Ismail M, Brand C, Mulnard RA, Thai G, Mc-Adams-Ortiz C, Womack K, Mathews D, Quiceno M, Levey AI, Lah JJ, Cellar JS, Burns JM, Swerdlow RH, Brooks WM, Apostolova L, Tingus K, Woo E, Silverman DH, Lu PH, Bartzokis G, Graff-Radford NR, Parfitt F, Kendall T, Johnson H, Farlow MR, Hake AM, Matthews BR, Brosch JR, Herring S, Hunt C, van Dyck CH, Carson RE, MacAvoy MG, Varma P, Chertkow H, Bergman H, Hosein C, Black S, Stefanovic B, Caldwell C, Hsiung GY, Feldman H, Mudge B, Assaly M, Finger E, Pasternack S, Rachisky I, Trost D, Kertesz A, Bernick C, Munic D, Mesulam MM, Lipowski K, Weintraub M, Bonakdarpour B, Kerwin D, Wu CK, Johnson N, Sadowsky C, Villena T, Turner RS, Johnson K, Reynolds B, Sperling RA, Johnson KA, Marshall G, Yesavage J, Taylor JL, Lane B, Rosen A, Tinklenberg J, Sabbagh MN, Belden CM, Jacobson SA, Sirrel SA, Kowall N, Killiany R, Budson AE, Norbash A, Johnson PL, Obisesan TO, Wolday S, Allard J, Lerner A, Ogrocki P, Tatsuoka C, Fatica P, Fletcher E, Maillard P, Olichney J, DeCarli C, Carmichael O, Kittur S, Borrie M, Lee TY, Bartha R, Asthana S, Carlsson CM, Potkin SG, Preda A, Nguyen D, Tariot P, Burke A, Trncic N, Fleisher A, Reeder S, Bates V, Capote H, Rainka M, Scharre DW, Kataki M, Adeli A, Zimmerman EA, Celmins D, Brown AD, Pearlson GD, Blank K, Anderson K, Flashman LA, Seltzer M, Hynes ML, Santulli RB, Sink KM, Gordineer L, Williamson JD, Garg P, Watkins F, Ott BR, Querfurth H, Tremont G, Salloway S, Malloy P, Correia S, Rosen HJ, Miller BL, Perry D, Mintzer J, Spicer K, Bachman D, Finger E, Pasternak S, Rachinsky I, Rogers J, Kertesz A, Drost D, Pomara N, Hernando R, Sarrael A, Schultz SK, Ponto LL, Shim H, Smith KE, Relkin N, Chaing G, Lin M, Ravdin L, Smith A, Raj BA, Fargher K, Weiner MW, Aisen P, Weiner M, Aisen P, Petersen R, Green RC, Harvey D, Jack CR Jr, Jagust W, Morris JC, Saykin AJ, Shaw LM, Trojanowki JQ, Neylan T, Grafman J, Green RC, Montine T, Weiner M, Petersen R, Aisen P, Thomas RG, Donohue M, Gessert D, Sather T, Davis M, Morrison R, Jiminez G, Neylan T, Hayes J, Finley S, Harvey D, Donohue M, Jack CR Jr, Bernstein M, Borowski B, Gunter J, Senjem M, Kantarci K, Jagust W, Koeppe RA, Foster N, Reiman EM, Chen K, Landau S, Morris JC, Cairns NJ, Householder E, Shaw LM, Trojanowki JQ, Lee V, Korecka M, Figurski M, Toga AW, Crawford K, Neu S, Saykin AJ, Foroud TM, Potkin S, Shen L, Faber K, Kim S, Weiner MW, Schneider LS, Pawluczyk S, Beccera M, Brewer J, Vanderswag H, Stern Y, Honig LS, Bell KL, Fleischman D, Arfanakis K, Shah RC, Duara R, Varon D, Greig MT, Doraiswamy P, Petrella JR, James O, Porsteinsson AP, Goldstein B, Martin KS, Mulnard RA, Thai G, McAdams-Ortiz C, Mintzer J, Massoglia D, Brawman-Mintzer O, Sadowsky C, Martinez W, Villena T, Jagust W, Landau S, Rosen H, Perry D, Turner RS, Behan K, Reynolds B, Sperling RA, Johnson KA, Marshall G, Sabbagh MN, Jacobson SA, Sirrel SA, Obisesan TO, Wolday S, Allard J, Johnson SC, Fruehling J, Harding S, Peskind ER, Petrie EC, Li G, Yesavage JA, Taylor JL, Furst AJ, Chao S, Relkin N, Chaing G, Ravdin L.

Author information

1
1 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
2
2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 3 UCL Institute of Neurology, Department of Molecular Neuroscience, Queen Square, London, UK.
3
4 Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
4
5 Centre for Brain Health, Department of Psychiatry, New York University School of Medicine, New York, USA.
5
6 Department of Neurology, Centre for Research and Advanced Therapies. Fundación CITA-Alzheimer Fundazioa, Donostia/San Sebastián, Spain.
6
7 IRCCS Centro San Giovanni di Dio FBF, Brescia, Italy 8 Faculty of Psychology, eCampus University, Novedrate (Como), Italy.
7
9 Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic i Universitari, Barcelona, Spain.
8
10 Department of Clinical Sciences, Lund University, Lund, Sweden 11 Memory clinic, Skåne University Hospital, Lund, Sweden.
9
11 Memory clinic, Skåne University Hospital, Lund, Sweden.
10
13 Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Belgium 14 Reference Centre for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
11
15 ADx NeuroSciences, Technologiepark 4, Gent, Belgium.
12
16 Fujirebio Europe nv, Technologiepark 6, Gent, Belgium.
13
17 AXA Research Fund and UPMC, Université Pierre et Marie Curie, Paris, France 18 Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) & Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpétrière, Paris, France.
14
19 Department of Psychosomatic Medicine, University Medicine Rostock, Rostock, Germany 20 DZNE, German Centre for Neurodegenerative Diseases, Rostock, Germany.
15
21 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
16
22 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
17
23 Department of Neurology, University General Hospital of Alicante, Alicante, Spain.
18
24 Neuroscience Unit, Biodonostia Research Institute, San Sebastian, Spain.
19
25 Neurochemistry Lab and Biobank, Dept. of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Centre Amsterdam, The Netherlands.
20
12 Massachusetts Alzheimer's Disease Research Centre, Harvard Aging Brain Study, Department of Neurology; Massachusetts General Hospital, Harvard Medical School, Boston, MA,USA.
21
7 IRCCS Centro San Giovanni di Dio FBF, Brescia, Italy 26 University Hospitals and University of Geneva, Geneva, Switzerland.
22
4 Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands 27 Department of Epidemiology/Biostatistics, VU University Medical Centre, USA.
23
2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 27 Department of Epidemiology/Biostatistics, VU University Medical Centre, USA.
24
1 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA trojanow@mail.med.upenn.edu.

Abstract

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

KEYWORDS:

Alzheimer’s disease; biomarkers; cognitive ageing; dementia; imaging

PMID:
26220940
PMCID:
PMC4643624
DOI:
10.1093/brain/awv199
[Indexed for MEDLINE]
Free PMC Article

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