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Cited by 333Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCancer-related cognitive impairment studies

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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

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Jack, Clifford R, Wiste, Heather J, Weigand, Stephen D, Therneau, Terry M, Knopman, David S, Lowe, Val, Vemuri, Prashanthi, Mielke, Michelle M, Roberts, Rosebud O, Machulda, Mary M, Senjem, Matthew L, Gunter, Jeffrey L, Rocca, Walter A, Petersen, Ronald C·2017·The Lancet Neurology
DOI 10.1016/s1474-4422(17)30077-7PMC PMC5516534
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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.

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Figure 1 Plots of ATN group characteristics Box plots of continuous variables and bar charts summarizing percentages of categorical variables from table 1 by ATN biomarker group. The box plots and estimated percentages reflect weighting the sample to match the age and sex distribution of Olmsted County, Minnesota residents who are clinically normal. Box and bar widths reflect relative sample sizes. As in Table 1, the 8 groups are sorted left-right hierarchically first on the basis of A- vs A+, then T- vs T+, then N- vs N+.
Figure 1 Plots of ATN group characteristics Box plots of continuous variables and bar charts summarizing percentages of categorical variables from table 1 by ATN biomarker group. The box plots and estimated percentages reflect weighting the sample to match the age and sex distribution of Olmsted County, Minnesota residents who are clinically normal. Box and bar widths reflect relative sample sizes. As in Table 1, the 8 groups are sorted left-right hierarchically first on the basis of A- vs A+, then T- vs T+, then N- vs N+.CC BY · PubMed Central
Figure 2 Estimated prevalence of the ATN biomarker groups by age and sex Panel A shows the estimated prevalence curves by age and sex for all ATN groups. Panel B shows the same curves as panel A (except for the A−T−N−, A−T+N+, and A+T+N+) on an enlarged scale with the estimated peak for each curve shown with a square and a 95% confidence interval.
Figure 2 Estimated prevalence of the ATN biomarker groups by age and sex Panel A shows the estimated prevalence curves by age and sex for all ATN groups. Panel B shows the same curves as panel A (except for the A−T−N−, A−T+N+, and A+T+N+) on an enlarged scale with the estimated peak for each curve shown with a square and a 95% confidence interval.CC BY · PubMed Central
Figure 3 Venn diagram of the estimated prevalence of each ATN group at age 65 and age 80 These estimates are averaged over men and women. Since estimates are for a given age among clinically normal individuals, weighting to the population is not necessary. 95% confidence intervals for the estimates are also shown.
Figure 3 Venn diagram of the estimated prevalence of each ATN group at age 65 and age 80 These estimates are averaged over men and women. Since estimates are for a given age among clinically normal individuals, weighting to the population is not necessary. 95% confidence intervals for the estimates are also shown.CC BY · PubMed Central

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Authors
Jack, C. R., Wiste, H. J., Weigand, S. D., Therneau, T. M., Knopman, D. S., Lowe, V., Vemuri, P., Mielke, M. M., Roberts, R. O., Machulda, M. M., Senjem, M. L., Gunter, J. L., Rocca, W. A., & Petersen, R. C.
Affiliations
Mayo Clinic (US)
Corresponding author
Jack, Clifford R
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2017-06
Volume
16
Issue
6
Pages
435-444
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(17)30077-7
PMC
PMC5516534
OpenAlex
W2608642452
Cited by
333
References
43
Citations by year
2026: 28 · 2025: 27 · 2024: 42 · 2023: 26 · 2022: 39 · 2021: 39 · 2020: 36 · 2019: 46 · 2018: 41 · 2017: 9
FWCI
29.66
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • PubMed Central (acceptedVersion, cc-by)
Funders
  • Mayo Clinic
  • National Institutes of Health
  • National Institute on Aging (R01AG034676, U01AG006786, R01AG011378, R01AG041851, R37AG011378)
  • National Institute of Neurological Disorders and Stroke (R01NS097495)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
Keywords
Alzheimer's disease biomarkers, tauopathy, neurodegeneration, cognitively unimpaired older adults, amyloid PET, tau PET, cortical thickness, prevalence, age-specific prevalence, sex differences, Mayo Clinic Study of Aging, cognitive aging, neuroimaging biomarkers, centiloid, standard uptake value ratio, multimodal neuroimaging
MeSH terms
Age Factors, Aged, Aged, 80 and over, Amyloidosis, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Minnesota, Sex Factors, Biomarkers, Prevalence, Amyloid beta-Peptides, Neurodegenerative Diseases, Tauopathies, Positron-Emission Tomography

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