Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

Willemijn J Jansen; Rik Ossenkoppele; Dirk L Knol; Betty M Tijms; Philip Scheltens; Frans R J Verhey; Pieter Jelle Visser; Pauline Aalten; Dag Aarsland; Daniel Alcolea; Myriam Alexander; Ina S Almdahl; Steven E Arnold; Inês Baldeiras; Henryk Barthel; Bart N M van Berckel; Kristen Bibeau; Kaj Blennow; David J Brooks; Mark A van Buchem; Vincent Camus; Enrica Cavedo; Kewei Chen; Gael Chetelat; Ann D Cohen; Alexander Drzezga; Sebastiaan Engelborghs; Anne M Fagan; Tormod Fladby; Adam S Fleisher; Wiesje M van der Flier; Lisa Ford; Stefan Förster; Juan Fortea; Nadia Foskett; Kristian S Frederiksen; Yvonne Freund-Levi; Giovanni B Frisoni; Lutz Froelich; Tomasz Gabryelewicz; Kiran Dip Gill; Olymbia Gkatzima; Estrella Gómez-Tortosa; Mark Forrest Gordon; Timo Grimmer; Harald Hampel; Lucrezia Hausner; Sabine Hellwig; Peter Johannsen; Gunhild Waldemar; Amyloid Biomarker Study Group

doi:10.1001/jama.2015.4668

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

Willemijn J Jansen, Rik Ossenkoppele, Dirk L Knol, Betty M Tijms, Philip Scheltens, Frans R J Verhey, Pieter Jelle Visser, Pauline Aalten, Dag Aarsland, Daniel Alcolea, Myriam Alexander, Ina S Almdahl, Steven E Arnold, Inês Baldeiras, Henryk Barthel, Bart N M van Berckel, Kristen Bibeau, Kaj Blennow, David J Brooks, Mark A van BuchemVincent Camus, Enrica Cavedo, Kewei Chen, Gael Chetelat, Ann D Cohen, Alexander Drzezga, Sebastiaan Engelborghs, Anne M Fagan, Tormod Fladby, Adam S Fleisher, Wiesje M van der Flier, Lisa Ford, Stefan Förster, Juan Fortea, Nadia Foskett, Kristian S Frederiksen, Yvonne Freund-Levi, Giovanni B Frisoni, Lutz Froelich, Tomasz Gabryelewicz, Kiran Dip Gill, Olymbia Gkatzima, Estrella Gómez-Tortosa, Mark Forrest Gordon, Timo Grimmer, Harald Hampel, Lucrezia Hausner, Sabine Hellwig, Peter Johannsen, Gunhild Waldemar, Amyloid Biomarker Study Group

Department of Clinical Medicine

678 Citations (Scopus)

Abstract

IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE andWeb of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION: AND SYNTHESIS: Individual recordswere provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95%CI, 8%-13%) to 44%(95%CI, 37%-51%) among participants with normal cognition; from 12%(95%CI, 8%-18%) to 43%(95%CI, 32%-55%) among patients with SCI; and from 27%(95%CI, 23%-32%) to 71%(95%CI, 66%-76%) among patients with MCI. APOE-ϵ4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ϵ4ϵ4 carriers, 50 years for ϵ2ϵ4 carriers, 55 years for ϵ3ϵ4 carriers, 65 years for ϵ3ϵ3 carriers, and 95 years for ϵ2ϵ3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Original language	English
Journal	J A M A: The Journal of the American Medical Association
Volume	313
Issue number	19
Pages (from-to)	1924-38
Number of pages	15
ISSN	0098-7484
DOIs	https://doi.org/10.1001/jama.2015.4668
Publication status	Published - 19 May 2015

Keywords

Adult
Age Factors
Aged
Aged, 80 and over
Amyloid beta-Peptides
Apolipoprotein E4
Biomarkers
Brain
Cerebrospinal Fluid
Dementia
Female
Genotype
Humans
Male
Middle Aged
Mild Cognitive Impairment
Positron-Emission Tomography
Prevalence
Risk Factors

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Jansen, W. J., Ossenkoppele, R., Knol, D. L., Tijms, B. M., Scheltens, P., Verhey, F. R. J., Visser, P. J., Aalten, P., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I. S., Arnold, S. E., Baldeiras, I., Barthel, H., van Berckel, B. N. M., Bibeau, K., Blennow, K., Brooks, D. J., ... Amyloid Biomarker Study Group (2015). Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. J A M A: The Journal of the American Medical Association, 313(19), 1924-38. https://doi.org/10.1001/jama.2015.4668

Jansen, WJ, Ossenkoppele, R, Knol, DL, Tijms, BM, Scheltens, P, Verhey, FRJ, Visser, PJ, Aalten, P, Aarsland, D, Alcolea, D, Alexander, M, Almdahl, IS, Arnold, SE, Baldeiras, I, Barthel, H, van Berckel, BNM, Bibeau, K, Blennow, K, Brooks, DJ, van Buchem, MA, Camus, V, Cavedo, E, Chen, K, Chetelat, G, Cohen, AD, Drzezga, A, Engelborghs, S, Fagan, AM, Fladby, T, Fleisher, AS, van der Flier, WM, Ford, L, Förster, S, Fortea, J, Foskett, N, Frederiksen, KS, Freund-Levi, Y, Frisoni, GB, Froelich, L, Gabryelewicz, T, Gill, KD, Gkatzima, O, Gómez-Tortosa, E, Gordon, MF, Grimmer, T, Hampel, H, Hausner, L, Hellwig, S, Johannsen, P, Waldemar, G & Amyloid Biomarker Study Group 2015, 'Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis', J A M A: The Journal of the American Medical Association, vol. 313, no. 19, pp. 1924-38. https://doi.org/10.1001/jama.2015.4668

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title = "Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis",

abstract = "IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE andWeb of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION: AND SYNTHESIS: Individual recordswere provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95%CI, 8%-13%) to 44%(95%CI, 37%-51%) among participants with normal cognition; from 12%(95%CI, 8%-18%) to 43%(95%CI, 32%-55%) among patients with SCI; and from 27%(95%CI, 23%-32%) to 71%(95%CI, 66%-76%) among patients with MCI. APOE-ϵ4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ϵ4ϵ4 carriers, 50 years for ϵ2ϵ4 carriers, 55 years for ϵ3ϵ4 carriers, 65 years for ϵ3ϵ3 carriers, and 95 years for ϵ2ϵ3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.",

keywords = "Adult, Age Factors, Aged, Aged, 80 and over, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Brain, Cerebrospinal Fluid, Dementia, Female, Genotype, Humans, Male, Middle Aged, Mild Cognitive Impairment, Positron-Emission Tomography, Prevalence, Risk Factors",

author = "Jansen, {Willemijn J} and Rik Ossenkoppele and Knol, {Dirk L} and Tijms, {Betty M} and Philip Scheltens and Verhey, {Frans R J} and Visser, {Pieter Jelle} and Pauline Aalten and Dag Aarsland and Daniel Alcolea and Myriam Alexander and Almdahl, {Ina S} and Arnold, {Steven E} and In{\^e}s Baldeiras and Henryk Barthel and {van Berckel}, {Bart N M} and Kristen Bibeau and Kaj Blennow and Brooks, {David J} and {van Buchem}, {Mark A} and Vincent Camus and Enrica Cavedo and Kewei Chen and Gael Chetelat and Cohen, {Ann D} and Alexander Drzezga and Sebastiaan Engelborghs and Fagan, {Anne M} and Tormod Fladby and Fleisher, {Adam S} and {van der Flier}, {Wiesje M} and Lisa Ford and Stefan F{\"o}rster and Juan Fortea and Nadia Foskett and Frederiksen, {Kristian S} and Yvonne Freund-Levi and Frisoni, {Giovanni B} and Lutz Froelich and Tomasz Gabryelewicz and Gill, {Kiran Dip} and Olymbia Gkatzima and Estrella G{\'o}mez-Tortosa and Gordon, {Mark Forrest} and Timo Grimmer and Harald Hampel and Lucrezia Hausner and Sabine Hellwig and Peter Johannsen and Gunhild Waldemar and {Amyloid Biomarker Study Group}",

year = "2015",

month = may,

day = "19",

doi = "10.1001/jama.2015.4668",

language = "English",

volume = "313",

pages = "1924--38",

journal = "J A M A: The Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "19",

}

TY - JOUR

T1 - Prevalence of cerebral amyloid pathology in persons without dementia

T2 - a meta-analysis

AU - Jansen, Willemijn J

AU - Ossenkoppele, Rik

AU - Knol, Dirk L

AU - Tijms, Betty M

AU - Scheltens, Philip

AU - Verhey, Frans R J

AU - Visser, Pieter Jelle

AU - Aalten, Pauline

AU - Aarsland, Dag

AU - Alcolea, Daniel

AU - Alexander, Myriam

AU - Almdahl, Ina S

AU - Arnold, Steven E

AU - Baldeiras, Inês

AU - Barthel, Henryk

AU - van Berckel, Bart N M

AU - Bibeau, Kristen

AU - Blennow, Kaj

AU - Brooks, David J

AU - van Buchem, Mark A

AU - Camus, Vincent

AU - Cavedo, Enrica

AU - Chen, Kewei

AU - Chetelat, Gael

AU - Cohen, Ann D

AU - Drzezga, Alexander

AU - Engelborghs, Sebastiaan

AU - Fagan, Anne M

AU - Fladby, Tormod

AU - Fleisher, Adam S

AU - van der Flier, Wiesje M

AU - Ford, Lisa

AU - Förster, Stefan

AU - Fortea, Juan

AU - Foskett, Nadia

AU - Frederiksen, Kristian S

AU - Freund-Levi, Yvonne

AU - Frisoni, Giovanni B

AU - Froelich, Lutz

AU - Gabryelewicz, Tomasz

AU - Gill, Kiran Dip

AU - Gkatzima, Olymbia

AU - Gómez-Tortosa, Estrella

AU - Gordon, Mark Forrest

AU - Grimmer, Timo

AU - Hampel, Harald

AU - Hausner, Lucrezia

AU - Hellwig, Sabine

AU - Johannsen, Peter

AU - Waldemar, Gunhild

AU - Amyloid Biomarker Study Group

PY - 2015/5/19

Y1 - 2015/5/19

N2 - IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE andWeb of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION: AND SYNTHESIS: Individual recordswere provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95%CI, 8%-13%) to 44%(95%CI, 37%-51%) among participants with normal cognition; from 12%(95%CI, 8%-18%) to 43%(95%CI, 32%-55%) among patients with SCI; and from 27%(95%CI, 23%-32%) to 71%(95%CI, 66%-76%) among patients with MCI. APOE-ϵ4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ϵ4ϵ4 carriers, 50 years for ϵ2ϵ4 carriers, 55 years for ϵ3ϵ4 carriers, 65 years for ϵ3ϵ3 carriers, and 95 years for ϵ2ϵ3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

AB - IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE andWeb of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION: AND SYNTHESIS: Individual recordswere provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95%CI, 8%-13%) to 44%(95%CI, 37%-51%) among participants with normal cognition; from 12%(95%CI, 8%-18%) to 43%(95%CI, 32%-55%) among patients with SCI; and from 27%(95%CI, 23%-32%) to 71%(95%CI, 66%-76%) among patients with MCI. APOE-ϵ4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ϵ4ϵ4 carriers, 50 years for ϵ2ϵ4 carriers, 55 years for ϵ3ϵ4 carriers, 65 years for ϵ3ϵ3 carriers, and 95 years for ϵ2ϵ3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

KW - Adult

KW - Age Factors

KW - Aged

KW - Aged, 80 and over

KW - Amyloid beta-Peptides

KW - Apolipoprotein E4

KW - Biomarkers

KW - Brain

KW - Cerebrospinal Fluid

KW - Dementia

KW - Female

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Mild Cognitive Impairment

KW - Positron-Emission Tomography

KW - Prevalence

KW - Risk Factors

U2 - 10.1001/jama.2015.4668

DO - 10.1001/jama.2015.4668

M3 - Journal article

C2 - 25988462

SN - 0098-7484

VL - 313

SP - 1924

EP - 1938

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

IS - 19

ER -

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

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