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

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; Karine Madsen; Milica G Kramberger; Peter Johannsen; Gunhild Waldemar; Amyloid Biomarker Study Group

doi:10.1001/jamapsychiatry.2017.3391

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

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 KornhuberOsama 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, Karine Madsen, Milica G Kramberger, Peter Johannsen, Gunhild Waldemar, Amyloid Biomarker Study Group

Institut for Klinisk Medicin

71 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	JAMA Psychiatry
Vol/bind	75
Udgave nummer	1
Sider (fra-til)	84-95
Antal sider	12
ISSN	2168-622X
DOI	https://doi.org/10.1001/jamapsychiatry.2017.3391
Status	Udgivet - jan. 2018

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10.1001/jamapsychiatry.2017.3391

jamapsychiatry_jansen_2017_oi_170081.pdfForlagets udgivne version, 443 KB

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Jansen, W. J., Ossenkoppele, R., Tijms, B. M., Fagan, A. M., Hansson, O., Klunk, W. E., van der Flier, W. M., Villemagne, V. L., Frisoni, G. B., Fleisher, A. S., Lleó, A., Mintun, M. A., Wallin, A., Engelborghs, S., Na, D. L., Chételat, G., Molinuevo, J. L., Landau, S. M., Mattsson, N., ... Amyloid Biomarker Study Group (2018). Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia. JAMA Psychiatry, 75(1), 84-95. https://doi.org/10.1001/jamapsychiatry.2017.3391

Jansen, WJ, Ossenkoppele, R, Tijms, BM, Fagan, AM, Hansson, O, Klunk, WE, van der Flier, WM, Villemagne, VL, Frisoni, GB, Fleisher, AS, Lleó, A, Mintun, MA, Wallin, A, Engelborghs, S, Na, DL, Chételat, G, Molinuevo, JL, Landau, SM, Mattsson, N, Kornhuber, J, Sabri, O, Rowe, CC, Parnetti, L, Popp, J, Fladby, T, Jagust, WJ, Aalten, P, Lee, DY, Vandenberghe, R, Resende de Oliveira, C, Kapaki, E, Froelich, L, Ivanoiu, A, Gabryelewicz, T, Verbeek, MM, Sanchez-Juan, P, Hildebrandt, H, Camus, V, Zboch, M, Brooks, DJ, Drzezga, A, Rinne, JO, Newberg, A, de Mendonça, A, Sarazin, M, Rabinovici, GD, Madsen, K, Kramberger, MG, Johannsen, P, Waldemar, G & Amyloid Biomarker Study Group 2018, 'Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia', JAMA Psychiatry, bind 75, nr. 1, s. 84-95. https://doi.org/10.1001/jamapsychiatry.2017.3391

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title = "Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia",

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.",

author = "Jansen, {Willemijn J} and Rik Ossenkoppele and Tijms, {Betty M} and Fagan, {Anne M} and Oskar Hansson and Klunk, {William E} and {van der Flier}, {Wiesje M} and Villemagne, {Victor L} and Frisoni, {Giovanni B} and Fleisher, {Adam S} and Alberto Lle{\'o} and Mintun, {Mark A} and Anders Wallin and Sebastiaan Engelborghs and Na, {Duk L} and G{\"a}el Ch{\'e}telat and Molinuevo, {Jos{\'e} Luis} and Landau, {Susan M} and Niklas Mattsson and Johannes Kornhuber and Osama Sabri and Rowe, {Christopher C} and Lucilla Parnetti and Julius Popp and Tormod Fladby and Jagust, {William J} and Pauline Aalten and Lee, {Dong Young} and Rik Vandenberghe and {Resende de Oliveira}, Catarina and Elisabeth Kapaki and Lutz Froelich and Adrian Ivanoiu and Tomasz Gabryelewicz and Verbeek, {Marcel M} and P{\'a}scual Sanchez-Juan and Helmut Hildebrandt and Vincent Camus and Marzena Zboch and Brooks, {David J} and Alexander Drzezga and Rinne, {Juha O} and Andrew Newberg and {de Mendon{\c c}a}, Alexandre and Marie Sarazin and Rabinovici, {Gil D} and Karine Madsen and Kramberger, {Milica G} and Peter Johannsen and Gunhild Waldemar and {Amyloid Biomarker Study Group}",

year = "2018",

month = jan,

doi = "10.1001/jamapsychiatry.2017.3391",

language = "English",

volume = "75",

pages = "84--95",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "The JAMA Network",

number = "1",

}

TY - JOUR

T1 - Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

AU - Jansen, Willemijn J

AU - Ossenkoppele, Rik

AU - Tijms, Betty M

AU - Fagan, Anne M

AU - Hansson, Oskar

AU - Klunk, William E

AU - van der Flier, Wiesje M

AU - Villemagne, Victor L

AU - Frisoni, Giovanni B

AU - Fleisher, Adam S

AU - Lleó, Alberto

AU - Mintun, Mark A

AU - Wallin, Anders

AU - Engelborghs, Sebastiaan

AU - Na, Duk L

AU - Chételat, Gäel

AU - Molinuevo, José Luis

AU - Landau, Susan M

AU - Mattsson, Niklas

AU - Kornhuber, Johannes

AU - Sabri, Osama

AU - Rowe, Christopher C

AU - Parnetti, Lucilla

AU - Popp, Julius

AU - Fladby, Tormod

AU - Jagust, William J

AU - Aalten, Pauline

AU - Lee, Dong Young

AU - Vandenberghe, Rik

AU - Resende de Oliveira, Catarina

AU - Kapaki, Elisabeth

AU - Froelich, Lutz

AU - Ivanoiu, Adrian

AU - Gabryelewicz, Tomasz

AU - Verbeek, Marcel M

AU - Sanchez-Juan, Páscual

AU - Hildebrandt, Helmut

AU - Camus, Vincent

AU - Zboch, Marzena

AU - Brooks, David J

AU - Drzezga, Alexander

AU - Rinne, Juha O

AU - Newberg, Andrew

AU - de Mendonça, Alexandre

AU - Sarazin, Marie

AU - Rabinovici, Gil D

AU - Madsen, Karine

AU - Kramberger, Milica G

AU - Johannsen, Peter

AU - Waldemar, Gunhild

AU - Amyloid Biomarker Study Group

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

U2 - 10.1001/jamapsychiatry.2017.3391

DO - 10.1001/jamapsychiatry.2017.3391

M3 - Journal article

C2 - 29188296

SN - 2168-622X

VL - 75

SP - 84

EP - 95

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 1

ER -

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

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