Preclinical AD Workgroup staging: Pathological correlates and potential challenges
Open accessAbstract
The National Institute on Aging Preclinical Alzheimer's disease Workgroup (PADW) has issued a preliminary report with recommendations for classifying preclinical Alzheimer's disease (pAD) according to 3 early disease stages. Here we examine the PADW recommendations in relation to neuropathological features in a large, consecutive series of cognitively intact elderly persons, autopsied within a year after cognitive testing (n = 126 cognitively intact patients with mean age 83.7 years at death). Subjects were grouped based on a hypothetical construct correlating pathological features with PADW stages. Many cognitively intact individuals were classifiable as pAD (53/126 or 43%), as expected based on epidemiological and biomarker studies. Of these, most (48%) were in "stage 3", which corresponds to amyloid pathology with early neurodegeneration. As with prior studies, our data indicate that the development of neocortical neurofibrillary tangles is the key pathological event that is not observed in pAD cases: Braak stages III or IV pathology are hence not truly a substrate for "intermediate likelihood" that cognitive impairment is due to Alzheimer's disease (AD). We also stress the importance of comorbid non-Alzheimer's disease brain pathologies (hippocampal sclerosis, neocortical alpha-synucleinopathy, cerebrovascular disease, and brains with hippocampal neurofibrillary tangles but no cortical amyloid plaques) that can contribute to the development of cognitive impairment, or which may serve as confounds in the application of the PADW recommendations. While the final recommendations from the PADW working group have not yet been released, this preliminary analysis provides a perspective on those recommendations from a neuropathological point of view.
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The severity and distribution of AD neuropathologic changes are much different (lower) in preclinical cases than in cases with clinically severe ADD.
“Significantly, the severity and distribution of AD neuropathologic changes are much different (lower) in preclinical cases than in cases with clinically severe ADD (48, 108, 148-150).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [48]
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“In the same way, A A Ps may be a key pathologic factor in AD without equating with the clinical features of ADD.”
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Challenges in the Neuropathological Diagnosis of Dementias
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- Authors
- Jicha, G. A., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Riley, K. P., Cooper, G. E., Stiles, N., Mendiondo, M. S., Smith, C. D., Van Eldik, L. J., & Nelson, P. T.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Jicha, Gregory A.
- Nelson, Peter T.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 33
- Issue
- 3
- Pages
- 622.e1-622.e16
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3245887
- OpenAlex
- W2028623023
- Cited by
- 71
- References
- 120
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 9 · 2016: 7 · 2015: 3 · 2014: 11 · 2013: 7 · 2012: 8
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH/NIA (R01 NS061933, P30 AG028383)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- preclinical Alzheimer's disease, disease staging, neuropathology, amyloid plaques, neurofibrillary tangles, Braak staging, hippocampal sclerosis, synucleinopathies, cerebrovascular disease, cognitive impairment
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Nerve Degeneration, Neurofibrillary Tangles, Disease Progression, Early Diagnosis, Plaque, Amyloid, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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