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

Y1 - 2018

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

VL - 75

SP - 84

EP - 95

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 1

ER -