An operational approach to National Institute on Aging–Alzheimer's Association criteria for preclinical Alzheimer disease
Open accessAbstract
OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines. METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria. RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP. INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.
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Initial studies in this emerging area have identified subgroups of older adults with subtle cognitive decline that do not conform to expected patterns and investigators have designated them as Suspected Non-Alzheimer Pathology (SNAP) and Unclassified groups.
“Initial studies in this emerging area have identified subgroups of older adults with subtle cognitive decline that do not conform to expected patterns and investigators have designated them as Suspected Non-Alzheimer Pathology (SNAP) and Unclassified groups [51, 52].”
From Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates (2014) · cites this paper as [51]
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Experimental — accuracy not yet measuredFor many subjects with suspected AD or increased risk, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes.
“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [212]
The finding of no significant influence of Aβ on subfield atrophy pattern is in line with recent studies showing that AD-type atrophy and/or hypometabolism can be found in both Aβ-negative healthy controls and Aβ-negative MCI patients.
“Yet, this finding is in line with recent studies showing that AD-type atrophy and/or hypometabolism can be found in both Aβ-negative healthy controls (Jack et al., 2012) and Aβ-negative MCI patients (Prestia et al., 2013).”
From Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia (2013) · cites this paper as Jack et al., 2012
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- Authors
- Jack, C. R., Knopman, D. S., Weigand, S. D., Wiste, H. J., Vemuri, P., Lowe, V., Kantarci, K., Gunter, J. L., Senjem, M. L., Ivnik, R. J., Roberts, R. O., Rocca, W. A., Boeve, B. F., & Petersen, R. C.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Jack, Clifford R.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2012-04-09
- Volume
- 71
- Issue
- 6
- Pages
- 765-775
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3586223
- OpenAlex
- W2044429455
- Cited by
- 602
- References
- 71
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 21 · 2023: 28 · 2022: 29 · 2021: 40 · 2020: 33 · 2019: 40 · 2018: 44 · 2017: 60 · 2016: 80 · 2015: 65 · 2014: 63 · 2013: 51 · 2012: 10
- FWCI
- 27.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Mayo Clinic
- Mayo Foundation for Medical Education and Research
- National Institute on Aging (R01AG11378, P50‐AG16574, U01AG006786, R01AG011378, R01AG041851, P50AG016574)
- National Center for Research Resources (C06RR018898)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- preclinical Alzheimer's disease, NIA-AA criteria, Pittsburgh compound B PET, cerebral amyloidosis, FDG-PET, hippocampal volume, neurodegeneration biomarkers, cognitively normal older adults, diagnostic classification
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Aniline Compounds, Brain, Cognition Disorders, Female, Humans, Longitudinal Studies, Male, Mental Status Schedule, Neuropsychological Tests, Thiazoles, United States, Biomarkers, Disease Progression, Fluorodeoxyglucose F18, Positron-Emission Tomography, National Institute on Aging (U.S.)
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