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. 2018 Jan 1;75(1):84-95.
doi: 10.1001/jamapsychiatry.2017.3391.

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

Willemijn J Jansen  1 , Rik Ossenkoppele  2   3   4   5 , Betty M Tijms  2 , Anne M Fagan  6 , Oskar Hansson  7 , William E Klunk  8 , Wiesje M van der Flier  2   9 , Victor L Villemagne  10 , Giovanni B Frisoni  11   12 , Adam S Fleisher  13   14   15 , Alberto Lleó  16 , Mark A Mintun  17 , Anders Wallin  18 , Sebastiaan Engelborghs  19 , Duk L Na  20 , Gäel Chételat  21 , José Luis Molinuevo  22 , Susan M Landau  5 , Niklas Mattsson  7 , Johannes Kornhuber  23 , Osama Sabri  24 , Christopher C Rowe  6   10 , Lucilla Parnetti  25 , Julius Popp  26 , Tormod Fladby  27 , William J Jagust  5 , Pauline Aalten  1 , Dong Young Lee  28 , Rik Vandenberghe  29 , Catarina Resende de Oliveira  30 , Elisabeth Kapaki  31 , Lutz Froelich  32 , Adrian Ivanoiu  33 , Tomasz Gabryelewicz  34 , Marcel M Verbeek  35 , Páscual Sanchez-Juan  36 , Helmut Hildebrandt  37 , Vincent Camus  38 , Marzena Zboch  39 , David J Brooks  40 , Alexander Drzezga  41 , Juha O Rinne  42 , Andrew Newberg  43 , Alexandre de Mendonça  44 , Marie Sarazin  45 , Gil D Rabinovici  4 , Karine Madsen  46 , Milica G Kramberger  47 , Agneta Nordberg  48 , Vincent Mok  49 , Barbara Mroczko  50 , David A Wolk  51 , Philipp T Meyer  52 , Magda Tsolaki  53 , Philip Scheltens  2 , Frans R J Verhey  1 , Pieter Jelle Visser  1   2 ; Amyloid Biomarker Study Group; Dag Aarsland  54 , Daniel Alcolea  16 , Myriam Alexander  55 , Ina S Almdahl  27 , Steven E Arnold  51 , Inês Baldeiras  30 , Henryk Barthel  24 , Bart N M van Berckel  3 , Kaj Blennow  18   56 , Mark A van Buchem  57 , Enrica Cavedo  11   58   59 , Kewei Chen  13 , Elena Chipi  25 , Ann D Cohen  8 , Stefan Förster  60 , Juan Fortea  16 , Kristian S Frederiksen  61 , Yvonne Freund-Levi  62 , Olymbia Gkatzima  53 , Mark Forrest Gordon  63 , Timo Grimmer  64 , Harald Hampel  58   59   65 , Lucrezia Hausner  32 , Sabine Hellwig  66 , Sanna-Kaisa Herukka  67 , Peter Johannsen  68 , Aleksandra Klimkowicz-Mrowiec  69 , Sebastian Köhler  1 , Norman Koglin  70 , Koen van Laere  71 , Mony de Leon  72 , Viviana Lisetti  25 , Wolfgang Maier  73 , Jan Marcusson  74 , Olga Meulenbroek  75 , Hanne M Møllergård  27 , John C Morris  6 , Arto Nordlund  18 , Gerald P Novak  76 , George P Paraskevas  31 , Gayan Perera  55   77 , Oliver Peters  78 , Inez H G B Ramakers  1 , Lorena Rami  22 , Eloy Rodríguez-Rodríguez  36 , Catherine M Roe  6 , Uros Rot  47 , Eckart Rüther  79 , Isabel Santana  30 , Johannes Schröder  80 , Sang W Seo  20 , Hilkka Soininen  67 , Luiza Spiru  81 , Erik Stomrud  7 , Hanne Struyfs  19 , Charlotte E Teunissen  82 , Stephanie J B Vos  1 , Linda J C van Waalwijk van Doorn  35 , Gunhild Waldemar  60 , Åsa K Wallin  7 , Jens Wiltfang  79 , Henrik Zetterberg  18   56   83
Affiliations

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

Willemijn J Jansen et al. JAMA Psychiatry. .

Erratum in

  • Incorrect Spelling of Coauthor Surname.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2018 Mar 1;75(3):303. doi: 10.1001/jamapsychiatry.2017.4558. JAMA Psychiatry. 2018. PMID: 29417129 Free PMC article. No abstract available.

Abstract

Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.

Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.

Design, setting, and participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.

Main outcomes and measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.

Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.

Conclusions and relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Aarsland reports receiving research support or honoraria from AstraZeneca, H. Lundbeck, Novartis Pharmaceuticals, and GE Health. Dr Alexander reports being an employee of Roche Products. Dr Barthel reports receiving speaker, consultant honoraria, and travel expenses from Piramal Imaging (Berlin) and personal fees from Siemens Healthcare. Dr Blennow reports receiving personal fees (advisory boards or consulting) from Roche Diagnostics, IBL International, Novartis, Fujirebio Europe, and Eli Lilly and Company and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. Dr Chen reports receiving grants from the National Institutes of Health (NIH). Dr Drzezga reports receiving speaker honoraria and consulting fees from GE Healthcare, Avid Radiopharmaceuticals/Eli Lilly and Company, and Piramal. Dr Fagan reports receiving grants from the NIH, DiamiR, Fred Simmons and Olga Mohan, and Charles and Joanne Knight Alzheimer’s Research Initiative of the Washington University Knight Alzheimer’s Disease Research Center and personal fees from IBL International, Roche, and AbbVie. Dr Fladby reports having a patent on methods and compositions for monitoring phagocytic activity (PCT/US2011/062233) pending. Dr Fleisher reports having been a full-time employee of the Banner Alzheimer’s Institute; being a full-time employee of Eli Lilly and Company; maintaining a voluntary faculty appointment at the University of California, San Diego; having been a member of data and safety monitoring boards for Merck, Pfizer, and the National Institute of Aging (NIA); receiving grant funding from the NIA and Avid Radiopharmaceuticals; and having been a consultant for Eli Lilly and Company, Grifols, Avid Radiopharmaceuticals, and Siemens Imaging. Dr van der Flier reports receiving grants from Boehringer Ingelheim, Piramal Imaging, and Roche. Dr Förster reports receiving personal fees (consultancy) from Piramal, Bayer, and GE. Dr Frisoni reports receiving grants and/or personal fees from Eli Lilly and Company, Bristol-Myers Squibb, Bayer, Lundbeck, Elan, AstraZeneca, Pfizer, Taurx, Wyeth, GE, Baxter, Avid Radiopharmaceuticals, Roche, Piramal, and the Alzheimer’s Association. Dr Gordon reports being a salaried employee of Boehringer Ingelheim Pharmaceuticals. Dr Grimmer reports receiving personal fees from Eli Lilly and Company. Dr Hampel reports support from the AXA Research Fund, the Fondation Université Pierre et Marie Curie, and the Fondation pour la Recherche sur Alzheimer, Paris, France; receiving grants, personal fees, and/or nonfinancial support from Boehringer-Ingelheim, Bristol-Myers Squibb, Elan, Novartis, Eisai, Pfizer, Sanofi, Roche, GE Healthcare, Avid Radiopharmaceuticals, Eli Lilly and Company, GlaxoSmithKline Biologicals, Jung Diagnostics, and Cytox; and having a patent on method for predicting whether subjects with mild cognitive impairment will develop Alzheimer’s disease pending, a patent on 3-hydroxykynurenin in serum as diagnostic marker for Alzheimer-type dementia pending, a patent on neurodegenerative markers for 10 psychiatric conditions pending, a patent on plasma Aβ42/40 ratio for early and differential diagnosis of Alzheimer disease pending, a patent in liquor diagnostics in vitro procedures for the diagnosis of dementia and neuroinflammatory disease pending, and a patent on in vitro procedures for the diagnosis of neurodegenerative diseases pending. Dr Hansson reports receiving research support from GE Healthcare, Avid Radiopharmaceuticals, and Hoffmann-La Roche. Dr Hellwig reports receiving grants from GE Healthcare and Medical Faculty, University of Freiburg. Dr Jagust reports receiving personal fees from Banner Alzheimer Institute/Genentech, Synarc/Bioclinica, and Novartis. Dr Jansen reports receiving research support from Biogen. Dr Kapaki reports receiving grants from the European Union (European Regional Development Fund) and Greek national funds through the Operational Program “Competitiveness and Entrepreneurship” of the National Strategic Reference Framework Research Funding Program: Joint Programming Neurodegenerative Disease, “Biomarkers for Alzheimer’s Disease and Parkinson’s Disease.” Dr Klunk reports being a co-inventor of the amyloid imaging tracer PiB and having a financial interest in the license agreement (PiB intellectual property is owned by the University of Pittsburgh, and GE Healthcare holds a license agreement with the University of Pittsburgh based on the PiB technology described in this article. Dr Klunk receives inventors share payments from the University of Pittsburgh based on income from that license). Dr Koglin reports receiving personal fees from employment at Piramal Imaging. Dr Kornhuber reports receiving grants from the German Federal Ministry of Education and Research (grant 01GI0420 from the Kompetenznetz Demenzen and German Federal Ministry of Education and Research and grant 01GI1007A from the Frontotemporo-Lobar Degeneration Consortium) and having a patent on diagnosis of Alzheimer’s disease (PCT/ EP2004/003963) issued, a patent on large Aß-peptide binding particles in diagnosis and therapy of Alzheimer’s dementia (EP 1811304 A1) issued, a patent on immunoglobulin-bound Ab-peptides and immunoglobulins-binding Ab-peptides in diagnosis and therapy of Alzheimer’s dementia (WO2007/082750 A1) issued, a patent on methods of differentially diagnosing dementias (EP 2437067A2) issued, and a patent on new formulations for diagnosis of Alzheimer’s disease pending. Dr Van Laere reported having received grants through KU Leuven from Merck, Janssen Pharmaceuticals, UCB, Novartis, Pfizer, and GE Healthcare. Dr Landau reported having received grants from the NIH and personal fees from Biogen Idec, Genentech, and Synarc. Dr Lleo reports receiving grants PI10/ 01878, PI13/01532, PI11/242, and PI11/3035 from Instituto de Salud Carlos III (Fondo de Investigación Sanitario and the CIBERNED program). Dr Madsen reports receiving grants from the Lundbeck Foundation, Danish Medical Research Council, and Rigshospitalet. Dr Meyer reportd receiving money from GE Healthcare for an ongoing research study. Dr Mintun reports being an employee of Avid Radiopharmaceuticals. Dr Morris reports receiving grants P50AG005681, P01AG003991, P01AG026276, and U19AG032438 from the NIH. Dr Mroczko reports receiving grants and personal fees from the Leading National Research Centre (KNOW), Medical University of Bialystok, Poland, and consultation and/or lecture honoraria from Roche, Cormay, and Biameditek. Dr Novak reports being an employee of and holding stock in Janssen Research and Development. Dr Paraskevas reports receiving grants from the European Union (European Regional Development Fund) and Greek national funds through the Operational Program “Competitiveness and Entrepreneurship” of the National Strategic Reference Framework Research Funding Program: Joint Programming Neurodegenerative Disease, “Biomarkers for Alzheimer’s Disease and Parkinson’s Disease.” Dr Perera reports research support from grant ES/L002825/1 by the British Cross-research Council Lifelong Health and Wellbeing Programme under Extending Working Lives as part of an interdisciplinary consortium on Wellbeing, Health, Retirement and the Lifecourse and receiving funding from the National Institute for Health Research Biomedical Research Centre and Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. Dr Peters reports receiving grants and/or personal fees from Eli Lilly and Company, Roche, Genentech, Lundbeck, Affiris, Piramal, Novartis, and Trx-Pharmaceuticals. Dr Popp reports receiving grant 320030L_141179 from the Swiss National Science Foundation and from the Nestlé Institute of Health Sciences. Dr Rabinovici reports receiving grants from Avid Radiopharmaceuticals and personal fees from GE Healthcare and Piramal. Dr Rinne reports receiving grants from Sigrid Juselius Foundation and Turku University Hospital. Dr Rot reports receiving grants from EU Joint Programme–Neurodegenerative Disease Research–Biomarkers for Alzheimer Disease and Parkinson Disease. Dr Rowe reports receiving grants from Avid Radiopharmaceuticals, Piramal Imaging, AstraZeneca, GE Healthcare, Avid Radiopharmaceuticals/Eli Lilly and Company, Navidea, Australian Commonwealth Scientific Industrial and Research Organization, National Health and Medical Research Council, Alzheimer’s Association, and an anonymous foundation and having had a patent licensed for positron emission tomography image processing. Dr Sabri reports receiving grants and/or personal fees from Piramal Imaging, Bayer Healthcare, and Siemens Healthcare. Dr Sarazin reports receiving personal lecture fees from Novartis and Allianz. Dr Scheltens reports receiving grants from GE Healthcare, Piramal, and Merck paid to his institution. Dr Soininen reports receiving grants from the Academy of Finland, European Union 7ThFP 601055 VPH-DARE, Kuopio University Hospital VTR, and University of Eastern Finland. Dr Teunissen reports being a member of the international advisory board at Innogenetics and Roche and having research contracts at Probiodrug, Boehringer, Roche, EIP Pharma, and IBL. Dr Vandenberghe reports receiving clinical trial agreements with GE Health Care, Merck, Forum, and Roche; grants from Research Foundation–Flanders (FWO) and KU Leuven; and nonfinancial support from GEHC. Dr Verbeek reports serving on an advisory board for Roche. Dr Verhey reports receiving compensation as a speaker and consultant for Nutricia Advanced Medical Food. Dr Visser reports receiving research support from Biogen, grants from the European Federation of Pharmaceutical Industries and Associations (EFPIA) Innovative Medicines Initiative Joint Undertaking, EU Joint Programme–Neurodegenerative Disease Research, ZonMw, and Bristol-Myers Squibb; having served as member of the advisory board of Roche Diagnostics; and having received nonfinancial support from GE Healthcare. Dr Vos reports receiving research support from ZonMW and from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement 115372, resources that are composed of financial contributions from EU FP7 (FP7/2007-2013) and in-kind contributions from EFPIA. Dr Waldemar reports being a board member of the Lundbeck Foundation. Dr Anders Wallin reports receiving speakers’ bureau fees from Esai and Triolab and serving on the advisory board for Nutrica and Esai. Dr Wolk reports receiving personal fees from GE Healthcare and Piramal Pharma and grants from Avid Radiopharmaceuticals. Dr Zetterberg reports being a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. The authors received compensation (ie, salary) as employees of their respective organizations. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Frequencies of Low Memory and Low Mini-Mental State Examination (MMSE) Scores
A and B, Model with terms for age, amyloid status, and cognitive status and up to 3-way interactions among these terms (3-way interaction P = .002). C, and D, Model with terms for age, amyloid status, cognitive status, and interactions between amyloid status and age (P = .03) and between amyloid status and cognitive status (P < .001). Adjustment for sex and educational level did not change either model. Low score was defined as 10th percentile or lower of z scores for the memory score and 27 or lower for MMSE scores. Shading indicated 95% CIs.
Figure 2.
Figure 2.. Frequency of Low Memory Score According to Apolipoprotein E (APOE) Genotype
Model with terms for age, amyloid status, cognitive status, and up to 3-way interactions among these terms (3-way interaction P = .007), APOE genotype, and interactions among APOE genotype, amyloid status, and cognitive status (P = .02). Adjustment for sex and educational level did not change the model. Low score was defined as 10th percentile or lower of z scores.
Figure 3.
Figure 3.. Prevalence of Amyloid Positivity and Low Memory Score in Participants With Normal Cognition and of Alzheimer Disease (AD)–Type Dementia in the General Population
Prevalence estimates of amyloid positivity and low memory score were derived from separate models including age as a predictor. Prevalence estimates of AD-type dementia were derived from a meta-analysis of 14 studies. Low score was defined as 10th percentile or lower of z scores.
See this image and copyright information in PMC

References

    1. Jansen WJ, Ossenkoppele R, Knol DL, et al. ; Amyloid Biomarker Study Group . Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313(19):1924-1938. - PMC - PubMed
    1. Fagan AM, Xiong C, Jasielec MS, et al. ; Dominantly Inherited Alzheimer Network . Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci Transl Med. 2014;6(226):226ra30. - PMC - PubMed
    1. Jack CR Jr, Wiste HJ, Weigand SD, et al. . Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study. Lancet Neurol. 2014;13(10):997-1005. - PMC - PubMed
    1. Sperling RA, Johnson KA, Doraiswamy PM, et al. ; AV45-A05 Study Group . Amyloid deposition detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance in clinically normal older individuals. Neurobiol Aging. 2013;34(3):822-831. - PMC - PubMed
    1. Vos SJ, Xiong C, Visser PJ, et al. . Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013;12(10):957-965. - PMC - PubMed

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