Journal
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Volume 313, Issue 19, Pages 1924-1938Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jama.2015.4668
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Funding
- GE Healthcare
- Piramal
- Merck
- EU/EFPIA Innovative Medicines Initiative Joint Undertaking
- EU Joint Programme-Neurodegenerative Disease Research (JPND)
- ZonMw
- Bristol-Myers Squibb
- Astra-Zeneca
- H. Lundbeck
- Novartis Pharmaceuticals
- GE Health
- Siemens Healthcare
- Roche Diagnostics
- IBL International
- Novartis
- Eli Lilly
- French Ministry of Health
- National Institutes of Health (NIH)
- AVID/Lilly
- NIH
- Fred Simmons
- Olga Mohan, and Charles and Joanne Knight Alzheimer's Research Initiative of the Washington University Knight Alzheimer's Disease Research Center
- Roche
- AbbVie
- NIA
- Avid Radiopharmaceutical
- Boehringer Ingelheim
- Piramal Imaging
- Bayer
- GE
- Lilly
- Lundbeck
- Elan
- AstraZeneca
- Pfizer
- Taurx
- Wyeth
- Baxter
- Avid
- Alzheimer's Association
- Indian Council of Medical Research, New Delhi, India
- Boehringer Ingelheim Pharmaceuticals
- Boehringer-Ingelheim
- Eisai
- sanofi-aventis
- Roche Pharmaceuticals and Diagnostics
- GlaxoSmithKline Biologicals
- Jung-Diagnostics
- Cytox
- Medical Faculty, University of Freiburg
- Banner Alzheimer Institute/Genentech
- Synarc/Bioclinica
- Indian Council of Medical Research, India
- European Union (European Regional Development Fund [ERDF])
- Greek national funds through the Operational Program Competitiveness and Entrepreneurship
- University of Pittsburgh
- Bayer Healthcare/Piramal Imaging (Berlin, Germany)
- University of Antwerp Research Fund
- Alzheimer Research Foundation (SAO-FRA)
- Research Foundation Flanders (FWO)
- Agency for Innovation by Science and Technology (IWT)
- Belgian Science Policy Office Interuniversity Attraction Poles (IAP) program
- Flemish Government-initiated Methusalem excellence grant
- Fundação para a Ciência e a Tecnologia [SFRH/BD/98266/2013, POCTI/MAT/37670/2001] Funding Source: FCT
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IMPORTANCE Cerebral amyloid-beta 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-epsilon 4 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 epsilon 4 epsilon 4 carriers, 50 years for epsilon 2 epsilon 4 carriers, 55 years for epsilon 3 epsilon 4 carriers, 65 years for epsilon 3 epsilon 3 carriers, and 95 years for epsilon 2 epsilon 3 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.
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