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

Jansen, Willemijn J.; Ossenkoppele, Rik LU ; Tijms, Betty M.; Fagan, Anne M.; Hansson, Oskar LU ; Klunk, William E.; Van Der Flier, Wiesje M.; Villemagne, Victor L.; Frisoni, Giovanni B. and Fleisher, Adam S., et al. (2018) In JAMA Psychiatry 75(1). p.84-95
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... (More)

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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keywords
amyloid-β , cognitive functioning , No dementia
in
JAMA Psychiatry
volume
75
issue
1
pages
12 pages
publisher
American Medical Association
external identifiers
  • scopus:85040468555
  • pmid:29188296
ISSN
2168-622X
DOI
10.1001/jamapsychiatry.2017.3391
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English
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3ab52246-eebe-4f88-8211-9fe063a468a8
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2018-02-05 14:32:25
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2018-06-17 05:30:21
@article{3ab52246-eebe-4f88-8211-9fe063a468a8,
  abstract     = {<p>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 &lt; .001) and low MMSE (mean difference, 14%[95%CI, 12%-17%], P &lt; .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.</p>},
  author       = {Jansen, Willemijn J. and Ossenkoppele, Rik and Tijms, Betty M. and Fagan, Anne M. and Hansson, Oskar and Klunk, William E. and Van Der Flier, Wiesje M. and Villemagne, Victor L. and Frisoni, Giovanni B. and Fleisher, Adam S. and Lleó, Alberto and Mintun, Mark A. and Wallin, Anders and Engelborghs, Sebastiaan and Na, Duk L. and Chételat, Gäel and Molinuevo, José Luis and Landau, Susan M. and Mattsson, Niklas and Kornhuber, Johannes and Sabri, Osama and Rowe, Christopher C. and Parnetti, Lucilla and Popp, Julius and Fladby, Tormod and Jagust, William J. and Aalten, Pauline and Lee, Dong Young and Vandenberghe, Rik and De Oliveira, Catarina Resende and Kapaki, Elisabeth and Froelich, Lutz and Ivanoiu, Adrian and Gabryelewicz, Tomasz and Verbeek, Marcel M. and Sanchez-Juan, Páscual and Hildebrandt, Helmut and Camus, Vincent and Zboch, Marzena and Brooks, David J. and Drzezga, Alexander and Rinne, Juha O. and Newberg, Andrew and De Mendonça, Alexandre and Sarazin, Marie and Rabinovici, Gil D. and Blennow, Kaj and Stomrud, Erik and Wallin, Åsa K. and Zetterberg, Henrik and , },
  issn         = {2168-622X},
  keyword      = {amyloid-β ,cognitive functioning ,No dementia },
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {84--95},
  publisher    = {American Medical Association},
  series       = {JAMA Psychiatry},
  title        = {Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia},
  url          = {http://dx.doi.org/10.1001/jamapsychiatry.2017.3391},
  volume       = {75},
  year         = {2018},
}