@article{3107983,
    title = "Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia",
    author = "Jansen, W.J. and Ossenkoppele, R. and Tijms, B.M. and Fagan, A.M. and Hansson, O. and Klunk, W.E. and Van Der Flier, W.M. and Villemagne, V.L. and Frisoni, G.B. and Fleisher, A.S. and Lleó, A. and Mintun, M.A. and Wallin, A. and Engelborghs, S. and Na, D.L. and Chételat, G. and Molinuevo, J.L. and Landau, S.M. and Mattsson, N. and Kornhuber, J. and Sabri, O. and Rowe, C.C. and Parnetti, L. and Popp, J. and Fladby, T. and Jagust, W.J. and Aalten, P. and Lee, D.Y. and Vandenberghe, R. and De Oliveira, C.R. and Kapaki, E. and Froelich, L. and Ivanoiu, A. and Gabryelewicz, T. and Verbeek, M.M. and Sanchez-Juan, P. and Hildebrandt, H. and Camus, V. and Zboch, M. and Brooks, D.J. and Drzezga, A. and Rinne, J.O. and Newberg, A. and De Mendonça, A. and Sarazin, M. and Rabinovici, G.D. and Madsen, K. and Kramberger, M.G. and Nordberg, A. and Mok, V. and Mroczko, B. and Wolk, D.A. and Meyer, P.T. and Tsolaki, M. and Scheltens, P. and Verhey, F.R.J. and Visser, P.J. and Aarsland, D. and Alcolea, D. and Alexander, M. and Almdahl, I.S. and Arnold, S.E. and Baldeiras, I. and Barthel, H. and Van Berckel, B.N.M. and Blennow, K. and Van Buchem, M.A. and Cavedo, E. and Chen, K. and Chipi, E. and Cohen, A.D. and Förster, S. and Fortea, J. and Frederiksen, K.S. and Freund-Levi, Y. and Gkatzima, O. and Gordon, M.F. and Grimmer, T. and Hampel, H. and Hausner, L. and Hellwig, S. and Herukka, S.-K. and Johannsen, P. and Klimkowicz-Mrowiec, A. and Köhler, S. and Koglin, N. and Van Laere, K. and De Leon, M. and Lisetti, V. and Maier, W. and Marcusson, J. and Meulenbroek, O. and Møllergård, H.M. and Morris, J.C. and Nordlund, A. and Novak, G.P. and Paraskevas, G.P. and Perera, G. and Peters, O. and Ramakers, I.H.G.B. and Rami, L. and Rodríguez-Rodríguez, E. and Roe, C.M. and Rot, U. and Rüther, E. and Santana, I. and Schröder, J. and Seo, S.W. and Sorininen, H. and Spiru, L. and Stomrud, E. and Struyfs, H. and Teunissen, C.E. and Vos, S.J.B. and Van Waalwijk Van Doorn, L.J.C. and Waldemar, G. and Wallin, Å.K. and Wiltfang, J. and Zetterberg, H. and Amyloid Biomarker Study Group",
    journal = "JAMA Psychiatry",
    year = "2018",
    volume = "75",
    number = "1",
    pages = "84-95",
    publisher = "American Medical Association",
    issn = "2168-622X, 2168-6238",
    doi = "10.1001/jamapsychiatry.2017.3391",
    keywords = "amyloid beta protein[1-42];  apolipoprotein E2;  apolipoprotein E3;  apolipoprotein E4;  biological marker;  amyloid beta protein, adult;  age;  aged;  Alzheimer disease;  Article;  brain;  cerebrospinal fluid;  clinical assessment;  cognition;  cross-sectional study;  dementia;  diagnostic test accuracy study;  educational status;  episodic memory;  female;  genotype;  human;  learning test;  major clinical study;  male;  memory assessment;  middle aged;  mild cognitive impairment;  Mini Mental State Examination;  multicenter study;  positron emission tomography;  prevalence;  protein aggregation;  receiver operating characteristic;  sex;  verbal memory test;  verbal word learning test;  very elderly;  Alzheimer disease;  brain;  cerebrospinal fluid;  cognitive defect;  dementia assessment;  pathophysiology;  psychology;  reference value, Aged;  Alzheimer Disease;  Amyloid beta-Peptides;  Brain;  Cognition Disorders;  Cognitive Dysfunction;  Cross-Sectional Studies;  Female;  Humans;  Male;  Memory, Episodic;  Mental Status and Dementia Tests;  Middle Aged;  Positron-Emission Tomography;  Reference Values",
    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."
}