Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years

a cross-sectional study

Clifford R Jr. Jack, Heather J. Wiste, Stephen D. Weigand, Terry M Therneau, David S Knopman, Val Lowe, Prashanthi D Vemuri, Michelle M Mielke, Rosebud O Roberts, Mary Margaret Machulda, Matthew L. Senjem, Jeffrey L. Gunter, Walter A Rocca, Ronald Carl Petersen

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Background A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older. Methods All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50–89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A−) or abnormal (A+) amyloid using amyloid PET, normal (T−) or abnormal (T+) tau using tau PET, and normal (N−) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging. Findings The numbers of participants in each profile group were 165 A−T−N−, 35 A−T+N−, 63 A−T−N+, 19 A−T+N+, 44 A+T−N−, 25 A+T+N−, 35 A+T−N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55–64) in A–T–N– and 57 years (54–64) in A–T+N– to a median 80 years (75–84) in A+T–N+ and 79 years (73–87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A– group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N−, A+T−N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A−T+N−, A−T−N+, and A−T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A−T−N− prevalence declined and A+T+N+ and A−T+N+ prevalence increased. In both men and women, A−T−N− was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities. Interpretation Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired. Funding National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation.

Original languageEnglish (US)
Pages (from-to)435-444
Number of pages10
JournalThe Lancet Neurology
Volume16
Issue number6
DOIs
StatePublished - Jun 1 2017

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Tauopathies
Amyloid
Cross-Sectional Studies
Biomarkers
Medical Record Linkage
Alzheimer Disease
Wounds and Injuries
National Institute on Aging (U.S.)
Population
Amyloid angiopathy
National Institutes of Health (U.S.)
Amyloidosis
Research
Neuroimaging

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{c1cc14cfb4544a6085ba782304e1ac3f,
title = "Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study",
abstract = "Background A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older. Methods All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50–89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A−) or abnormal (A+) amyloid using amyloid PET, normal (T−) or abnormal (T+) tau using tau PET, and normal (N−) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging. Findings The numbers of participants in each profile group were 165 A−T−N−, 35 A−T+N−, 63 A−T−N+, 19 A−T+N+, 44 A+T−N−, 25 A+T+N−, 35 A+T−N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55–64) in A–T–N– and 57 years (54–64) in A–T+N– to a median 80 years (75–84) in A+T–N+ and 79 years (73–87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A– group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N−, A+T−N+, and A+T+N+; 86{\%} at age 65 years and 51{\%} at age 80 years) or with suspected non-Alzheimer's pathophysiology (A−T+N−, A−T−N+, and A−T+N+; 92{\%} at age 65 years and 78{\%} at age 80 years). From age 50 years, A−T−N− prevalence declined and A+T+N+ and A−T+N+ prevalence increased. In both men and women, A−T−N− was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90{\%} of men and women had one or more biomarker abnormalities. Interpretation Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired. Funding National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation.",
author = "Jack, {Clifford R Jr.} and Wiste, {Heather J.} and Weigand, {Stephen D.} and Therneau, {Terry M} and Knopman, {David S} and Val Lowe and Vemuri, {Prashanthi D} and Mielke, {Michelle M} and Roberts, {Rosebud O} and Machulda, {Mary Margaret} and Senjem, {Matthew L.} and Gunter, {Jeffrey L.} and Rocca, {Walter A} and Petersen, {Ronald Carl}",
year = "2017",
month = "6",
day = "1",
doi = "10.1016/S1474-4422(17)30077-7",
language = "English (US)",
volume = "16",
pages = "435--444",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
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}

TY - JOUR

T1 - Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years

T2 - a cross-sectional study

AU - Jack, Clifford R Jr.

AU - Wiste, Heather J.

AU - Weigand, Stephen D.

AU - Therneau, Terry M

AU - Knopman, David S

AU - Lowe, Val

AU - Vemuri, Prashanthi D

AU - Mielke, Michelle M

AU - Roberts, Rosebud O

AU - Machulda, Mary Margaret

AU - Senjem, Matthew L.

AU - Gunter, Jeffrey L.

AU - Rocca, Walter A

AU - Petersen, Ronald Carl

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older. Methods All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50–89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A−) or abnormal (A+) amyloid using amyloid PET, normal (T−) or abnormal (T+) tau using tau PET, and normal (N−) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging. Findings The numbers of participants in each profile group were 165 A−T−N−, 35 A−T+N−, 63 A−T−N+, 19 A−T+N+, 44 A+T−N−, 25 A+T+N−, 35 A+T−N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55–64) in A–T–N– and 57 years (54–64) in A–T+N– to a median 80 years (75–84) in A+T–N+ and 79 years (73–87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A– group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N−, A+T−N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A−T+N−, A−T−N+, and A−T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A−T−N− prevalence declined and A+T+N+ and A−T+N+ prevalence increased. In both men and women, A−T−N− was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities. Interpretation Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired. Funding National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation.

AB - Background A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older. Methods All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50–89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A−) or abnormal (A+) amyloid using amyloid PET, normal (T−) or abnormal (T+) tau using tau PET, and normal (N−) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging. Findings The numbers of participants in each profile group were 165 A−T−N−, 35 A−T+N−, 63 A−T−N+, 19 A−T+N+, 44 A+T−N−, 25 A+T+N−, 35 A+T−N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55–64) in A–T–N– and 57 years (54–64) in A–T+N– to a median 80 years (75–84) in A+T–N+ and 79 years (73–87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A– group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N−, A+T−N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A−T+N−, A−T−N+, and A−T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A−T−N− prevalence declined and A+T+N+ and A−T+N+ prevalence increased. In both men and women, A−T−N− was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities. Interpretation Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired. Funding National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation.

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DO - 10.1016/S1474-4422(17)30077-7

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EP - 444

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

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