“New Old Pathologies”: AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS)
Open accessAbstract
The pathology-based classification of Alzheimer's disease (AD) and other neurodegenerative diseases is a work in progress that is important for both clinicians and basic scientists. Analyses of large autopsy series, biomarker studies, and genomics analyses have provided important insights about AD and shed light on previously unrecognized conditions, enabling a deeper understanding of neurodegenerative diseases in general. After demonstrating the importance of correct disease classification for AD and primary age-related tauopathy, we emphasize the public health impact of an underappreciated AD "mimic," which has been termed "hippocampal sclerosis of aging" or "hippocampal sclerosis dementia." This pathology affects >20% of individuals older than 85 years and is strongly associated with cognitive impairment. In this review, we provide an overview of current hypotheses about how genetic risk factors (GRN, TMEM106B, ABCC9, and KCNMB2), and other pathogenetic influences contribute to TDP-43 pathology and hippocampal sclerosis. Because hippocampal sclerosis of aging affects the "oldest-old" with arteriolosclerosis and TDP-43 pathologies that extend well beyond the hippocampus, more appropriate terminology for this disease is required. We recommend "cerebral age-related TDP-43 and sclerosis" (CARTS). A detailed case report is presented, which includes neuroimaging and longitudinal neurocognitive data. Finally, we suggest a neuropathology-based diagnostic rubric for CARTS.
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As TDP-43 distribution increases from limbic regions to other parts of the brain, it is associated with worsening cognition and medial temporal atrophy on antemortem brain imaging.
“As the distribution of TDP-43 increases from limbic regions to other parts of the brain, it is associated with worsening cognition and with medial temporal atrophy on antemortem brain imaging [130, 132, 133].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]
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 misdiagnosed clinical AD cases in the elderly.
“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 [130]
Hippocampal sclerosis of aging almost always includes TDP-43 deposits and sometimes arteriolosclerosis.
“Hippocampal sclerosis of aging is now recognized to almost always include TDP-43 deposits and sometimes arteriolosclerosis that lead to intracellular and neuritic deposits of TDP-43 in the hippocampus during the preclinical state and eventually hippocampal sclerosis and cerebral atrophy in the disease state [130, 131].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]
PART lesions are found in hippocampus and adjacent regions similar to Braak I-IV, but PART lacks amyloid plaques and has distinct morbidity and age range.
“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 [130]
ARTAG represents astrocytic tau pathology distinct from primary tauopathies including PSP, CBD and GGT, associated with 4R tau deposits in subpial or perivascular thorn-shaped astrocytes or granular fuzzy astrocytes in gray matter.
“ARTAG represents astrocytic tau pathology distinct from that observed in primary tauopathies including PSP, CBD and GGT. It is associated with 4R tau deposits in subpial or perivascular thorn-shaped astrocytes or granular fuzzy astrocytes in gray matter [130].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]
The frequency of PART increases in the 80s and 90s when AD prevalence is level or declining.
“The frequency of PART increases in the 80s and 90s when AD prevalence is level or declining [130].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]
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Self-citationABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology
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Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A
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Self-citationInvolvement of mitochondrial K+ release and cellular efflux in ischemic and apoptotic neuronal death
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The MAPT H1 haplotype is associated with tangle-predominant dementia
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Self-citationUnique Hard Scleral Lens Post‐LASIK Ectasia Fitting
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The neuropathological diagnosis of Alzheimer's disease
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Self-citationA Data-Driven Hydrophobicity Scale for Predicting Liquid–Liquid Phase Separation of Proteins
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Alzheimer's disease including focal presentations
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Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges
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Self-citationOverlapping but distinct TDP‐43 and tau pathologic patterns in aged hippocampi
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Self-citationAlzheimer’s Disease Neuropathological Comorbidities are Common in the Younger-Old
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Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration
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Self-citationPathobiological Subtypes of Alzheimer Disease
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Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis
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Self-citationBiomarkers for diseases with TDP-43 pathology
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Self-citationHippocampal Sclerosis, Argyrophilic Grain Disease, and Primary Age-Related Tauopathy
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Self-citationKovács, G. G. (2019) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000664 · Cited by 44 · see citing works
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RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration
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Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease
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Self-citationIf Human Brain Organoids Are the Answer to Understanding Dementia, What Are the Questions?
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Primary Age-Related Tauopathy: An Elderly Brain Pathology Frequently Encountered during Autopsy
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Neuropathology of supercentenarians - four autopsy case studies
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Cykowski, M. D., Powell, S. Z., Schulz, P. E., Takei, H., Rivera, A. L., Jackson, R. E., Roman, G., Jicha, G. A., & Nelson, P. T. (2017) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2016-0469-sa · Cited by 33 · see citing works
Self-citationFischer, C. E., Qian, W., Schweizer, T. A., Ismail, Z., Smith, E. E., Millikin, C. P., & Muñoz, D. G. (2017) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.06.001 · Cited by 33 · see citing works
Nelson, P. T., Gal, Z. T., Wang, W., Niedowicz, D. M., Artiushin, S., Wycoff, S., Wei, A. L., Jicha, G. A., & Fardo, D. W. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.01.013 · Cited by 32 · see citing works
Self-citationHippocampal Sclerosis in the Oldest Old: A Finnish Population-Based Study
Kero, M., Raunio, A., Polvikoski, T. M., Tienari, P. J., Paetau, A. E., & Myllykangas, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-171068 · Cited by 32 · see citing works
Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging
Initiative, A. D. N., Nelson, P. T., Katsumata, Y., Nho, K. T., Artiushin, S., Jicha, G. A., Wang, W., Abner, E. L., Saykin, A. J., Kukull, W. A., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1641-2 · Cited by 31 · see citing works
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Mikhailenko, E., Colangelo, K., Tuimala, J., Kero, M., Savola, S. E., Raunio, A., Kok, E., Tanskanen, M., Mäkelä, M., Puttonen, H. A. J., et al. (2024) · Brain · doi:10.1093/brain/awae212 · Cited by 29 · see citing works
Primary age‐related tauopathy in a Finnish population‐based study of the oldest old (Vantaa 85+)
Savola, S. E., Kaivola, K., Raunio, A., Kero, M., Mäkelä, M., Pärn, K., Palta, P., Tanskanen, M., Tuimala, J., Polvikoski, T. M., et al. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12788 · Cited by 28 · see citing works
TDP-43 and Alzheimer’s Disease Pathologic Subtype in Non-Amnestic Alzheimer’s Disease Dementia
Sahoo, A., Bejanin, A., Murray, M. E., Tosakulwong, N., Weigand, S. D., Serie, A. M., Senjem, M. L., Machulda, M. M., Parisi, J. E., Boeve, B. F., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180169 · Cited by 28 · see citing works
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Self-citationRelative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease
Ihara, R., Vincent, B. D., Baxter, M. R., Franklin, E. E., Hassenstab, J. J., Xiong, C., Morris, J. C., & Cairns, N. J. (2018) · Annals of Neurology · doi:10.1002/ana.25344 · Cited by 27 · see citing works
TDP ‐43 Pathology Exacerbates Cognitive Decline in Primary Age‐Related Tauopathy
Smirnov, D. S., Salmon, D. P., Galasko, D. R., Edland, S. D., Pizzo, D. P., Goodwill, V., & Hiniker, A. O. (2022) · Annals of Neurology · doi:10.1002/ana.26438 · Cited by 26 · see citing works
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Brenowitz, W. D., Han, F., Kukull, W. A., & Nelson, P. T. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.10.004 · Cited by 23 · see citing works
Self-citationTrajectories of cognitive decline differ in hippocampal sclerosis and Alzheimer's disease
Smirnov, D. S., Galasko, D. R., Hansen, L. A., Edland, S. D., Brewer, J. B., & Salmon, D. P. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.11.015 · Cited by 22 · see citing works
TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study
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TDP-43 and Limbic-Predominant Age-Related TDP-43 Encephalopathy
Zhang, L., Chen, Y., Liu, M., Wang, Y., & Peng, G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00376 · Cited by 21 · see citing works
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Phenotypic diversity in ALS and the role of poly-conformational protein misfolding
Ayers, J. I., & Borchelt, D. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02222-x · Cited by 21 · see citing works
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The Neurological Consequences of Engaging in Australian Collision Sports
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Cerebrospinal Fluid Biomarker Profile in TDP-43-Related Genetic Frontotemporal Dementia
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Tauopathy with hippocampal 4‐repeat tau immunoreactive spherical inclusions: a report of three cases
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Self-citationGal, J., Katsumata, Y., Zhu, H., Srinivasan, S., Chen, J., Johnson, L. A., Wang, W.-X., Golden, L. R., Wilcock, D. M., Jicha, G. A., et al. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.11.013 · Cited by 17 · see citing works
Self-citationAlzheimer Mythology: A Time to Think Out of the Box
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Combined Pathologies in FTLD-TDP Types A and C
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In vivo Brainstem Imaging in Alzheimer’s Disease: Potential for Biomarker Development
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Observational studies in Alzheimer disease: bridging preclinical studies and clinical trials
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Prediction of neuropathologic lesions from clinical data
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Mechanisms of Aging-Related Cognitive Decline
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Associations Between Loneliness and Cognitive Resilience to Neuropathology in Older Adults
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The unique neuropathological vulnerability of the human brain to aging
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Pathologies Underlying Longitudinal Cognitive Decline in the Oldest Old
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Hippocampal tau distribution in primary age‐related tauopathy: The Vantaa 85+ Study
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- Authors
- Nelson, P. T., Trojanowski, J. Q., Abner, E. L., Al-Janabi, O. M., Jicha, G. A., Schmitt, F. A., Smith, C. D., Fardo, D. W., Wang, W.-X., Kryscio, R. J., Neltner, J. H., Kukull, W. A., Cykowski, M. D., Van Eldik, L. J., & Ighodaro, E. T.
- Affiliations
- Houston Methodist (US)
- ORCID
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-05-21
- Volume
- 75
- Issue
- 6
- Pages
- 482-498
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC6366658
- OpenAlex
- W2400971574
- Cited by
- 158
- References
- 281
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 6 · 2023: 12 · 2022: 11 · 2021: 11 · 2020: 21 · 2019: 19 · 2018: 28 · 2017: 21 · 2016: 10
- FWCI
- 23.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute on Aging (P30AG028383, U01AG016976, P30AG010124, P01AG017586, K25AG043546, U19AG010483)
- National Institute of Neurological Disorders and Stroke (F30NS090714)
- 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 › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, primary age-related tauopathy, TDP-43 pathology, CART, disease classification, genetic risk factors, gene regulatory networks, TMEM106B, ABCC9, arteriolosclerosis, oldest old, cognitive impairment
- MeSH terms
- Aged, 80 and over, Aging, Alzheimer Disease, Animals, DNA-Binding Proteins, Female, Hippocampus, Humans, Sclerosis, Tauopathies
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