Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia

Research output: Contribution to journalArticle


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.


  • Willemijn J. Jansen
  • Rik Ossenkoppele
  • Betty M. Tijms
  • Anne M. Fagan
  • Oskar Hansson
  • William E. Klunk
  • Wiesje M. Van Der Flier
  • Victor L. Villemagne
  • Giovanni B. Frisoni
  • Adam S. Fleisher
  • Alberto Lleó
  • Mark A. Mintun
  • Anders Wallin
  • Sebastiaan Engelborghs
  • Duk L. Na
  • Gäel Chételat
  • José Luis Molinuevo
  • Susan M. Landau
  • Niklas Mattsson
  • Johannes Kornhuber
  • Osama Sabri
  • Christopher C. Rowe
  • Lucilla Parnetti
  • Julius Popp
  • Tormod Fladby
  • William J. Jagust
  • Pauline Aalten
  • Dong Young Lee
  • Rik Vandenberghe
  • Catarina Resende De Oliveira
  • Elisabeth Kapaki
  • Lutz Froelich
  • Adrian Ivanoiu
  • Tomasz Gabryelewicz
  • Marcel M. Verbeek
  • Páscual Sanchez-Juan
  • Helmut Hildebrandt
  • Vincent Camus
  • Marzena Zboch
  • David J. Brooks
  • Alexander Drzezga
  • Juha O. Rinne
  • Andrew Newberg
  • Alexandre De Mendonça
  • Marie Sarazin
  • Gil D. Rabinovici
  • Kaj Blennow
  • Erik Stomrud
  • Åsa K. Wallin
  • Henrik Zetterberg
  • Amyloid Biomarker Study Group
External organisations
  • Austin Health
  • Lilly Research Laboratories
  • University of California, San Diego
  • Avid Radiopharmaceuticals, Inc
  • Centre Hospitalier Privé Saint-Martin
  • University of California, Berkeley
  • Lausanne University Hospital
  • Seoul National University
  • Saint-Luc University Hospital
  • Polish Academy of Sciences
  • Hospital of Bremen-Ost
  • François Rabelais University
  • Wrocław Medical University
  • Imperial College London
  • University of Cologne
  • Turku PET Centre
  • Thomas Jefferson University
  • University of Lisbon
  • Paris Descartes University
  • University of Texas Health Science Centre
  • Sahlgrenska University Hospital
  • Maastricht University
  • VU University Medical Center
  • Washington University in St. Louis
  • University of Pittsburgh
  • Centro San Giovanni di Dio Fatebenefratelli
  • Hospital de Sant Pau
  • Sahlgrenska Academy
  • University of Antwerp
  • Sungkyunkwan University
  • Institutd' Investigacions Biomèdiques August Pi iSunyer (IDIBAPS)
  • Friedrich-Alexander University Erlangen-Nürnberg
  • Leipzig University
  • University of Perugia
  • Akershus University Hospital
  • Catholic University of Leuven
  • University Hospital of Coimbra
  • Eginition Hospital
  • Heidelberg University
  • Radboud University Nijmegen
  • University of Cantabria
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Geriatrics


  • amyloid-β , cognitive functioning , No dementia
Original languageEnglish
Pages (from-to)84-95
Number of pages12
JournalJAMA Psychiatry
Issue number1
Publication statusPublished - 2018 Jan 1
Publication categoryResearch