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JAMA. 2015 May 19;313(19):1924-38. doi: 10.1001/jama.2015.4668.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

Jansen WJ1, Ossenkoppele R2, Knol DL3, Tijms BM4, Scheltens P4, Verhey FR1, Visser PJ5; Amyloid Biomarker Study Group, Aalten P1, Aarsland D6, Alcolea D7, Alexander M8, Almdahl IS9, Arnold SE10, Baldeiras I11, Barthel H12, van Berckel BN13, Bibeau K14, Blennow K15, Brooks DJ16, van Buchem MA17, Camus V18, Cavedo E19, Chen K20, Chetelat G21, Cohen AD22, Drzezga A23, Engelborghs S24, Fagan AM25, Fladby T9, Fleisher AS26, van der Flier WM27, Ford L28, Förster S29, Fortea J7, Foskett N8, Frederiksen KS30, Freund-Levi Y31, Frisoni GB32, Froelich L33, Gabryelewicz T34, Gill KD35, Gkatzima O36, Gómez-Tortosa E37, Gordon MF38, Grimmer T39, Hampel H40, Hausner L33, Hellwig S41, Herukka SK42, Hildebrandt H43, Ishihara L44, Ivanoiu A45, Jagust WJ46, Johannsen P47, Kandimalla R48, Kapaki E49, Klimkowicz-Mrowiec A50, Klunk WE22, Köhler S1, Koglin N51, Kornhuber J52, Kramberger MG53, Van Laere K54, Landau SM46, Lee DY55, de Leon M56, Lisetti V57, Lleó A7, Madsen K58, Maier W59, Marcusson J60, Mattsson N61, de Mendonça A62, Meulenbroek O63, Meyer PT64, Mintun MA65, Mok V66, Molinuevo JL67, Møllergård HM9, Morris JC25, Mroczko B68, Van der Mussele S24, Na DL69, Newberg A70, Nordberg A71, Nordlund A15, Novak GP28, Paraskevas GP49, Parnetti L57, Perera G72, Peters O73, Popp J74, Prabhakar S75, Rabinovici GD76, Ramakers IH1, Rami L67, Resende de Oliveira C11, Rinne JO77, Rodrigue KM78, Rodríguez-Rodríguez E79, Roe CM25, Rot U53, Rowe CC80, Rüther E81, Sabri O12, Sanchez-Juan P79, Santana I11, Sarazin M82, Schröder J83, Schütte C43, Seo SW69, Soetewey F24, Soininen H42, Spiru L84, Struyfs H24, Teunissen CE85, Tsolaki M36, Vandenberghe R86, Verbeek MM87, Villemagne VL80, Vos SJ1, van Waalwijk van Doorn LJ87, Waldemar G30, Wallin A15, Wallin ÅK61, Wiltfang J81, Wolk DA10, Zboch M88, Zetterberg H89.

Author information

1
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
2
Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands3Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the.
3
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
4
Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
5
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands2Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience.
6
Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
7
Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
8
Roche Products, Welwyn Garden City, United Kingdom.
9
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
10
Department of Neurology, University of Pennsylvania, Philadelphia.
11
Center for Neuroscience and Cell Biology, Faculty of Medicine, Hospital Center University of Coimbra, Portugal.
12
Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.
13
Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
14
GlaxoSmithKline, Worldwide Epidemiology, Research Triangle Park, North Carolina.
15
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
16
Division of Neuroscience, Medical Research Council Clinical Sciences Centre, Imperial College London, London, United Kingdom.
17
Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
18
CHRU de Tours, CIC INSERM 1415, INSERM U930, and Université François Rabelais de Tours, Tours, France.
19
Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy20Sorbonne University, University Pierre et Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) and Institut.
20
Banner Alzheimer's Institute, Phoenix, Arizona.
21
Institut National de la Santé et de la Recherche Médicale (Inserm), U1077, Caen, France.
22
University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, Pennsylvania.
23
Department of Nuclear Medicine, University of Cologne, Cologne, Germany.
24
Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
25
Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
26
Banner Alzheimer's Institute, Phoenix, Arizona27Eli Lilly, Indianapolis, Indiana28Department of Neurosciences, University of California, San Diego.
27
Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands6Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
28
Janssen Research and Development, Titusville, New Jersey.
29
Department of Nuclear Medicine, Technischen Universitaet München, Munich, Germany.
30
Danish Dementia Research Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
31
Department of Geriatrics, Institution of NVS, Section of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
32
Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy88Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals, and University of Geneva, Geneva, Switzerland.
33
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
34
Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.
35
Postgraduate Institute of Medical Education and Research (PGIMER), Department of Biochemistry, Research Block-A, Chandigarh, India.
36
Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
37
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
38
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
39
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universitaet München, Munich, Germany.
40
AXA Research Fund and UPMC ChairSorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d'Alzheimer and INSERM U1127, Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Hôpital.
41
Center of Geriatrics and Gerontology, University Hospital Freiburg, Freiburg, Germany.
42
Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
43
Center for Neurology, Hospital of Bremen-Ost, Bremen, Germany.
44
GlaxoSmithKline, Worldwide Epidemiology, Epidemiology, Genetic Epidemiology and Neurology, United Kingdom.
45
Memory Clinic and Neurochemistry Laboratory, Saint Luc University Hospital, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
46
Helen Wills Neuroscience Institute, University of California, Berkeley.
47
Memory Clinic, Danish Dementia Research Center, Rigshospitalet, Copenhagen, Denmark.
48
Postgraduate Institute of Medical Education and Research (PGIMER), Department of Biochemistry, Research Block-A, Chandigarh, India46Radiation Oncology, Emory University, Atlanta, Georgia.
49
First Department of Neurology, Neurochemistry Unit and Cognitive and Movement Disorders Clinic, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece.
50
Jagiellonian University College of Medicine, Krakow, Poland.
51
Piramal Imaging, Berlin, Germany.
52
Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
53
Center for Cognitive Impairments, University Medical Centre Ljubljana, Ljubljana, Slovenia.
54
Department of Imaging and Pathology, Catholic University Leuven, Leuven, Belgium.
55
Department of Neuropsychiatry, Seoul National University, College of Medicine, Seoul, South Korea.
56
School of Medicine, Center for Brain Health, New York University, New York.
57
Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
58
Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark.
59
Department of Psychiatry and Psychotherapy, University of Bonn, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
60
Geriatric Medicine, Department of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden.
61
Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden.
62
Institute of Molecular Medicine and Faculty of Medicine, University of Lisbon, Portugal.
63
Department of Geriatric Medicine, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.
64
Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
65
Avid Radiopharmaceuticals, Philadelphia, Pennsylvania.
66
Lui Che Woo Institute of Innovative Medicine, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
67
Alzheimer's Disease and Other Cognitive Disorders Unit, IDIBAPS, Clinic University Hospital, Barcelona, Spain.
68
Department of Neurodegeneration Diagnostics, Leading National Research Centre in Bialystok (KNOW), Medical University of Bialystok, Bialystok, Poland.
69
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
70
Myrna Brind Center of Integrative Medicine, Thomas Jefferson University and Hospital, Philadelphia, Pennsylvania.
71
Dept NVS, Center for Alzheimer, Translational Alzheimer Neurobiology, Karolinska Institutet, and Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
72
Roche Products, Welwyn Garden City, United Kingdom69Department of Psychological Medicine, Institute of Psychiatry, Kings College London, London, United Kingdom.
73
Department of Psychiatry and Psychotherapy, Charité Berlin, German Center for Neurodegenrative Diseases (DZNE), Berlin, Germany.
74
Department of Psychiatry, Service of Old Age Psychiatry and Department of Clinical Neurosciences, Leenaards Memory Centre, University Hospital of Lausanne, Lausanne, Switzerland.
75
Postgraduate Institute of Medical Education and Research (PGIMER), Department of Neurology, Nehru Hospital, Chandigarh, India.
76
Department of Neurology, Memory and Aging Center, University of California, San Francisco.
77
Turku PET Centre and Division of Clinical Neurosciences Turku, University of Turku and Turku University Hospital, Turku, Finland.
78
Center for Vital Longevity, University of Texas at Dallas.
79
Neurology Service, Universitary Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain.
80
Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia.
81
Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany.
82
Neurologie de la Mémoire et du Langage, Centre Hospitalier Sainte-Anne, Université Paris 5, Paris, France.
83
Sektion Gerontopsychiatrie, Universität Heidelberg, Heidelberg, Germany.
84
Department of Geriatrics-Gerontology-Gerontopsychiatry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
85
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
86
Laboratory for Cognitive Neurology and Alzheimer Research Centre KU Leuven, Catholic University Leuven, Leuven, Belgium.
87
Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.
88
Alzheimer Center, Wroclaw Medical University, Scinawa, Poland.
89
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden87UCL Institute of Neurology, Queen Square, London, United Kingdom.

Abstract

IMPORTANCE:

Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.

OBJECTIVE:

To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).

DATA SOURCES:

Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.

STUDY SELECTION:

Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.

DATA EXTRACTION AND SYNTHESIS:

Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.

MAIN OUTCOMES AND MEASURES:

Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.

RESULTS:

The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.

CONCLUSIONS AND RELEVANCE:

Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

PMID:
25988462
PMCID:
PMC4486209
DOI:
10.1001/jama.2015.4668
[Indexed for MEDLINE]
Free PMC Article

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