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Primary age-related tauopathy (PART): a common pathology associated with human aging
Open accessAbstract
We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
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“Perivascular, subpial, and periventricular p-tau immunoreactive NFTs and astrocytic tangles in the neocortex have been reported to be characteristic of both primary age-related tauopathy (PART) [35] and age-related tau astrogliopathy (ARTAG) [36].”
From The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features (2017) · cites this paper as [35]
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“Primary age-related tauopathy (PART) and aging-related tau astrogliopathy (ARTAG) are independent tau pathologies commonly observed in patients over 80 years of age, and PART may account for a proportion of the misdiagnosed clinical AD cases in the elderly [130, 141, 142].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [142]
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“Lesions are found in the hippocampus and adjacent regions similar to those observed in Braak I-IV, but PART is distinct from AD in that it lacks amyloid plaques, and it has distinct morbidity and age range [130, 142].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [142]
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“PART refers to neuronal tau pathology and ARTAG is characterized by astrocytic tau pathology, although they are not mutually exclusive, and appear to be more a manifestation of age than a subtype of neurodegenerative disease.”
From The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features (2017) · cites this paper as [35]
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“Many studies, from the histopathology of Braak and Braak4 to longitudinal studies of Tau positron emission tomography imaging27,28, demonstrate that MTG is a transition zone between aging-related or preclinical AD-related medial temporal lobe pTau and more advanced stages of AD, where neocortical pTau extends across the brain and is strongly correlated with dementia4,29–31.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [29]
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“It should be noted that tau aggregation in the brain is associated with older age and is generally uncommon in healthy young adults (Braak et al., 2011; Crary et al., 2014).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Crary et al., 2014
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“LATE and PART are common neuropathologies, indicating the importance of addressing potential relationships between AD-Mimics, and LATE and PART pathology in future research (20,22).”
From Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy (2020) · cites this paper as [22]
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“AD-Mimics and definite PART are both defined as having no neuritic plaques, and like the AD-Mimics in this study, PART participants are generally older and experience less severe cognitive dysfunction (22,23).”
From Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy (2020) · cites this paper as [22]
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“The compact NFTs observed are morphologically most like those seen in primary age-related tauopathy (PART) [4], Alzheimer’s disease (AD) [22], and chronic traumatic encephalopathy (CTE) [13, 14], but the topographical distribution and immunostaining characteristics differ from these more common tauopathies in several respects.”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [4]
In the citing paper
“APOE4 significantly aggravated tau-mediated neurodegeneration in a tauopathy mouse model and induced tau aggregates in brain, while genetic ablation of APOE attenuated tau-induced neurodegeneration [469, 470].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [470]
In the citing paper
“In AD and PART, the tau aggregates are a mixture of three-repeat and four-repeat tau isoforms, whereas four-repeat sequences dominate in PSP and CBD and three-repeat sequences predominate in Pick disease14,18,19,21.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [14]
In the citing paper
“More recently, Crary et al. coined the term “primary age-related tauopathy” (PART) after observing that the postmortem brains of many elderly individuals harbor NFTs indistinguishable from those of AD but in the absence of Aβ plaques or cognitive decline [44].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [44]
In the citing paper
“The panel did not ultimately accept all of the a priori criteria for CTE; they did not include pathology known to be associated with aging (i.e.primary age-related tauopathy [PART] [16] and aging-related tau astrogliopathy [ARTAG] [17]).”
From Mild Chronic Traumatic Encephalopathy Neuropathology in People With No Known Participation in Contact Sports or History of Repetitive Neurotrauma (2019) · cites this paper as [16]
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“The latter, when frequent, are associated with memory complaints observed in the elderly [130, 142].”
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Metadata
- Authors
- Crary, J. F., Trojanowski, J. Q., Schneider, J. A., Abisambra, J. F., Abner, E. L., Alafuzoff, I., Arnold, S. E., Attems, J., Beach, T. G., Bigio, E. H., Cairns, N. J., Dickson, D. W., Gearing, M., Grinberg, L. T., Hof, P. R., Hyman, B. T., Jellinger, K., Jicha, G. A., Kovacs, G. G., Knopman, D. S., Kofler, J., Kukull, W. A., Mackenzie, I. R., Masliah, E., McKee, A., Montine, T. J., Murray, M. E., Neltner, J. H., Santa-Maria, I., Seeley, W. W., Serrano-Pozo, A., Shelanski, M. L., Stein, T., Takao, M., Thal, D. R., Toledo, J. B., Troncoso, J. C., Vonsattel, J. P., White, C. L., Wisniewski, T., Woltjer, R. L., Yamada, M., & Nelson, P. T.
- Affiliations
- Columbia University Irving Medical Center (US)
- University of Pennsylvania (US)
- Rush University Medical Center (US)
- University of Kentucky (US)
- Uppsala University (SE)
- Newcastle University (GB)
- Banner Sun Health Research Institute (US)
- Northwestern University (US)
- Washington University in St. Louis (US)
- Mayo Clinic (US)
- Emory University (US)
- Universidade de São Paulo (BR)
- Icahn School of Medicine at Mount Sinai (US)
- Harvard University (US)
- University of Pittsburgh Medical Center (US)
- University of Washington (US)
- University of British Columbia (CA)
- University of California San Diego (US)
- Boston University (US)
- University of California, San Francisco (US)
- Tokyo Metropolitan Geriatric Hospital (JP)
- Universität Ulm (DE)
- The University of Texas Southwestern Medical Center (US)
- Oregon Health & Science University (US)
- Kanazawa University (JP)
- Corresponding author
- Crary, John F.
- Nelson, Peter T.
- ORCID
- Crary, John F.
- Trojanowski, John Q.
- Schneider, Julie A.
- Abisambra, Jose F.
- Abner, Erin L.
- Alafuzoff, Irina
- Arnold, Steven E.
- Attems, Johannes
- Beach, Thomas G.
- Bigio, Eileen H.
- Dickson, Dennis W.
- Gearing, Marla
- Grinberg, Lea T.
- Hof, Patrick R.
- Hyman, Bradley T.
- Jellinger, Kurt
- Jicha, Gregory A.
- Knopman, David S.
- Kofler, Julia
- Kukull, Walter A.
- Mackenzie, Ian R.
- Masliah, Eliezer
- McKee, Ann
- Montine, Thomas J.
- Murray, Melissa E.
- Neltner, Janna H.
- Seeley, William W.
- Shelanski, Michael L.
- Stein, Thor
- Takao, Masaki
- Thal, Dietmar R.
- Troncoso, Juan C.
- White, Charles L.
- Woltjer, Randall L.
- Yamada, Masahito
- Nelson, Peter T.
- Venue
- Acta Neuropathologica
- Published
- 2014-10-28
- Volume
- 128
- Issue
- 6
- Pages
- 755-766
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4257842
- OpenAlex
- W1971032265
- Cited by
- 1,467
- References
- 160
- Citations by year
- 2026: 85 · 2025: 126 · 2024: 154 · 2023: 123 · 2022: 154 · 2021: 142 · 2020: 143 · 2019: 131 · 2018: 107 · 2017: 119 · 2016: 105 · 2015: 68 · 2014: 9
- FWCI
- 66.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Alzheimer's Association (P30 AG013854, P30AG010124, P01 AG003991, P50 AG025688, P50 AG005681, NIRG-11-204450, P50 AG005136, P50 AG005146)
- BrightFocus Foundation (U01 AG006786, P50 AG016574, P50 AG005136)
- Mayo Foundation for Medical Education and Research (AG016574)
- Alzheimer Forschung Initiative (#13803)
- Alzheimer's Society (AS-PG-2013-011)
- National Institute for Health and Care Research
- Bundesministerium für Bildung und Forschung
- National Institutes of Health (AG028 383, 5r01ag038651-10, AG016574, AG010124, AG005138, AG005133, AG005131, AG008051, AG005681, AG019610, AG003991, AG013854, AG025688, AG003949, AG005136, AG011378)
- Medical Research Council (G0400074, U01 AG006786)
- Japan Society for the Promotion of Science (26430060)
- National Institute on Aging (AG008051, R01‐AG038651, R01AG037212, P30AG028383, P01AG007232, P30AG012300, R37AG018440, P50AG005133, AG184440, U01AG016976, P50AG005131, P50AG005138, U01AG006786, P01AG003949, P30AG010124, AG005131, R01AG011378, P30AG008051, P50AG008702, P50AG005681, P30AG036453, P30AG019610, P50AG005146, P01AG003991, P30AG013846, P50AG005136, P30AG013854, P50AG025688, R01AG041851, P01AG002219, P01AG019724, P50AG016574)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- primary age-related tauopathy, neurofibrillary tangles, tau pathology, Alzheimer's disease, nomenclature, temporal lobe atrophy, tau biomarkers, tau imaging, brain aging, cognitive impairment
- MeSH terms
- Aging, Brain, Diagnosis, Differential, Humans, Terminology as Topic, Tauopathies, Plaque, Amyloid
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