AccScience Publishing / AN / Online First / DOI: 10.36922/an.2603

Limbic-predominant age-related TDP-43 encephalopathy: Amnestic-predominant cognitive decline beyond Alzheimer’s disease

Miren Maltuna1,2,3*
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1 Center for Research and Advanced Therapies, CITA-Alzhéimer Foundation, Donostia-San Sebastian, Spain
2 Debabarrena Integrated Health Organization, Osakidetza Basque Health Service, Gipuzkoa, Spain
3 Department of Medicine, Faculty of Health Sciences, University of Deusto, Bilbo, Bizkaia, Spain
Advanced Neurology 2024, 3(2), 2603
Submitted: 1 January 2024 | Accepted: 15 March 2024 | Published: 23 May 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Alzheimer’s disease (AD) is the main cause of neurodegenerative cognitive impairment leading to dementia. It is characterized by progressively worsening cognitive impairment with a predominant amnestic involvement. However, it is not the sole neurodegenerative disease presenting such symptoms, particularly prevalent among the elderly in our society. Recently, limbic-predominant age-related TDP-43 encephalopathy (LATE) has been identified. The diagnosis of LATE in living individuals is very complex due to the lack of universally applicable diagnostic criteria and reliable biomarkers. Nonetheless, its relevance is not diminished, as up to 20% of cases diagnosed with AD, especially in individuals over 80 years old, are actually due to LATE, and over 50% of AD cases have associated LATE copathology. This narrative review aims to address several aspects related to LATE, including identifying its typical clinical features, gaining a better understanding of its pathogenesis in pure cases and those associated with other neurodegenerative diseases, advancements in diagnostic tools for detecting LATE during life, its anatomopathological definition and staging, and potential advances in treatment. In the current era of potentially disease-modifying anti-amyloid treatments for AD, understanding both pure LATE and its co-pathology with AD is of particular relevance.

Cognitive impairment
Alzheimer’s disease
  1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013;80(19):1778-1783. doi: 10.1212/WNL.0b013e31828726f5


  1. Garre-Olmo J. Epidemiology of Alzheimer’s disease and other dementias. Rev Neurol. 2018;66(11):377-386. doi: 10.33588/rn.6611.2017519


  1. Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report. Brain. 2019;142(6):1503-1527. doi: 10.1093/brain/awz099


  1. Harrison WT, Lusk JB, Liu B, et al. Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old. Acta Neuropathol. 2021;142(5):917-919. doi: 10.1007/s00401-021-02360-w


  1. Butler Pagnotti RM, Pudumjee SB, Cross CL, Miller JB. Cognitive and clinical characteristics of patients with limbic-predominant age-related TDP-43 encephalopathy. Neurology. 2023;100(19):e2027-e2035. doi: 10.1212/WNL.0000000000207159


  1. Nelson PT, Brayne C, Flanagan ME, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol. 2022;144(1):27-44. doi: 10.1007/s00401-022-02444-1


  1. Nichols E, Merrick R, Hay SI, et al. The prevalence, correlation, and co-occurrence of neuropathology in old age: Harmonisation of 12 measures across six community-based autopsy studies of dementia. Lancet Healthy Longev. 2023;4(3):e115-e125. doi: 10.1016/S2666-7568(23)00019-3


  1. Duong MT, Wolk DA. Limbic-predominant age-related TDP-43 encephalopathy: LATE-breaking updates in clinicopathologic features and biomarkers. Curr Neurol Neurosci Rep. 2022;22(11):689-698. doi: 10.1007/s11910-022-01232-4


  1. Wang SHJ, Guo Y, Ervin JF, Lusk JB, Luo S. Neuropathological associations of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) differ between the oldest-old and younger-old. Acta Neuropathol. 2022;144(1):45-57. doi: 10.1007/s00401-022-02432-5


  1. Boyle PA, Wang T, Yu L, et al. To what degree is late life cognitive decline driven by age-related neuropathologies? Brain. 2021;144(7):2166-2175. doi: 10.1093/brain/awab092


  1. Nelson PT. LATE neuropathologic changes with little or no Alzheimer disease is common and is associated with cognitive impairment but not frontotemporal dementia. J Neuropathol Exp Neurol. 2021;80(7):649-651. doi: 10.1093/jnen/nlab050


  1. Kapasi A, Yu L, Boyle PA, Barnes LL, Bennett DA, Schneider JA. Limbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging. Neurology. 2020;95(14):e1951-e1962. doi: 10.1212/WNL.0000000000010454


  1. Huang W, Zhou Y, Tu L, et al. TDP-43: From Alzheimer’s disease to limbic-predominant age-related TDP-43 encephalopathy. Front Mol Neurosci. 2020;13:26. doi: 10.3389/fnmol.2020.00026


  1. Nag S, Barnes LL, Yu L, Wilson RS, Bennett DA, Schneider JA. Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents. Neurology. 2020;95(15):e2056-e2064. doi: 10.1212/WNL.0000000000010602


  1. Sajjadi SA, Bukhari S, Scambray KA, et al. Impact and risk factors of limbic predominant age-related TDP-43 encephalopathy neuropathologic change in an oldest-old cohort. Neurology. 2023;100(2):e203-e210. doi: 10.1212/WNL.0000000000201345


  1. Agrawal S, Yu L, Kapasi A, et al. Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and microvascular pathologies in community-dwelling older persons. Brain Pathol. 2021;31(3):e12939. doi: 10.1111/bpa.12939


  1. Agrawal S, Yu L, Nag S, et al. The association of Lewy bodies with limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer’s dementia in older persons. Acta Neuropathol Commun. 2021;9(1):156. doi: 10.1186/s40478-021-01260-0


  1. Paganini-Hill A, Montine TJ, Bukhari SA, Corrada MM, Kawas CH, Sajjadi SA. LATE and potential estrogen-related risk factors collected 30 years earlier: The 90+ study. J Neuropathol Exp Neurol. 2023;82(2):120-126. doi: 10.1093/jnen/nlac119


  1. Dugan AJ, Nelson PT, Katsumata Y, et al. Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: A retrospective genetic association study. Acta Neuropathol Commun. 2021;9(1):152. doi: 10.1186/s40478-021-01250-2


  1. Cykowski MD, Arumanayagam AS, Powell SZ, et al. Patterns of amygdala region pathology in LATE-NC: Subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies. Acta Neuropathol. 2022;143(5):531-545. doi: 10.1007/s00401-022-02416-5


  1. Zhang L, Chen Y, Liu M, Wang Y, Peng G. TDP-43 and limbic-predominant age-related TDP-43 encephalopathy. Front Aging Neurosci. 2019;11:376. doi: 10.3389/fnagi.2019.00376


  1. Wu X, Peng C, Nelson PT, Cheng Q. Random forest-integrated analysis in AD and LATE brain transcriptome-wide data to identify disease-specific gene expression. PLoS One. 2021;16(9):e0256648. doi: 10.1371/journal.pone.0256648


  1. Katsumata Y, Fardo DW, Shade LMP, Nelson PT. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry. J Neuropathol Exp Neurol. 2023;82(9):760-768. doi: 10.1093/jnen/nlad059


  1. Feng T, Lacrampe A, Hu F. Physiological and pathological functions of TMEM106B: A gene associated with brain aging and multiple brain disorders. Acta Neuropathol. 2021;141(3):327-339. doi: 10.1007/s00401-020-02246-3


  1. Prater KE, Latimer CS, Jayadev S. Glial TDP-43 and TDP- 43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes. Glia. 2022;70(2):239-255. doi: 10.1002/glia.24096


  1. Nag S, Schneider JA. Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases. Nat Rev Neurol. 2023;19(9):525-541. doi: 10.1038/s41582-023-00846-7


  1. Nelson PT, Lee EB, Cykowski MD, et al. LATE-NC staging in routine neuropathologic diagnosis: An update. Acta Neuropathol. 2023;145(2):159-173. doi: 10.1007/s00401-022-02524-2


  1. Maioli H, Mittenzwei R, Shofer JB, et al. Performance of a condensed protocol to assess limbic-predominant age-related TDP-43 encephalopathy neuropathologic change. J Neuropathol Exp Neurol. 2023;82(7):611-619. doi: 10.1093/jnen/nlad035


  1. Besser LM, Teylan MA, Nelson PT. Limbic predominant age-related TDP-43 encephalopathy (LATE): Clinical and neuropathological associations. J Neuropathol Exp Neurol. 2020;79(3):305-313. doi: 10.1093/jnen/nlz126


  1. Robinson JL, Porta S, Garrett FG, et al. Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration. Brain. 2020;143(9):2844-2857. doi: 10.1093/brain/awaa219


  1. Katsumata Y, Abner EL, Karanth S, et al. Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy. Acta Neuropathol. 2020;140(5):659-674. doi: 10.1007/s00401-020-02211-0


  1. Murakami A, Koga S, Sekiya H, et al. Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology. Brain Pathol. 2022;32(6):e13100. doi: 10.1111/bpa.13100


  1. Hiya S, Maldonado-Díaz C, Walker JM, Richardson TE. Cognitive symptoms progress with limbic-predominant age-related TDP-43 encephalopathy stage and co-occurrence with Alzheimer disease. J Neuropathol Exp Neurol. 2023;83(1):2-10. doi: 10.1093/jnen/nlad098


  1. Gauthreaux KM, Teylan MA, Katsumata Y, et al. Limbic-predominant age-related TDP-43 encephalopathy: Medical and pathologic factors associated with comorbid hippocampal sclerosis. Neurology. 2022;98(14):e1422-e1433. doi: 10.1212/WNL.0000000000200001


  1. Gauthreaux K, Mock C, Teylan MA, et al. Symptomatic profile and cognitive performance in autopsy-confirmed limbic-predominant age-related TDP-43 encephalopathy with comorbid Alzheimer disease. J Neuropathol Exp Neurol. 2022;81(12):975-987. doi: 10.1093/jnen/nlac093


  1. Young AL, Vogel JW, Robinson JL, et al. Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies. Brain. 2023;146(7):2975-2988. doi: 10.1093/brain/awad145


  1. Tomé SO, Tsaka G, Ronisz A, et al. TDP-43 pathology is associated with increased tau burdens and seeding. Mol Neurodegener. 2023;18(1):71. doi: 10.1186/s13024-023-00653-0



  1. Latimer CS, Liachko NF. Tau and TDP-43 synergy: A novel therapeutic target for sporadic late-onset Alzheimer’s disease. GeroScience. 2021;43(4):1627-1634. doi: 10.1007/s11357-021-00407-0


  1. Leiby A-MC, Scambray KA, Nguyen HL, et al. Characterizing limbic-predominant age-related TDP-43 encephalopathy without Alzheimer’s disease and lewy body dementia in the oldest old: A case series. J Alzheimers Dis. 2023;96(1):113-124. doi: 10.3233/JAD-230238


  1. Ducharme S, Pijnenburg Y, Rohrer JD, Huey E, Finger E, Tatton N. Identifying and diagnosing TDP-43 neurodegenerative diseases in psychiatry. Am J Geriatr Psychiatry. 2024;32(1):98-113. doi: 10.1016/j.jagp.2023.08.017


  1. Liu KY, Reeves S, McAleese KE, et al. Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer’s disease. Brain. 2020;143(12):3842-3849. doi: 10.1093/brain/awaa315


  1. Koper MJ, Tomé SO, Gawor K, et al. LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease. Acta Neuropathol Commun. 2022;10(1):128. doi: 10.1186/s40478-022-01432-6


  1. Walker JM, Richardson TE. Cognitive resistance to and resilience against multiple comorbid neurodegenerative pathologies and the impact of APOE status. J Neuropathol Exp Neurol. 2023;82(2):110-119. doi: 10.1093/jnen/nlac115


  1. Uemura MT, Robinson JL, Cousins KAQ, et al. Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease. Acta Neuropathol. 2022;143(1):15-31. doi: 10.1007/s00401-021-02383-3


  1. Niedowicz DM, Katsumata Y, Nelson PT. In severe ADNC, hippocampi with comorbid LATE-NC and hippocampal sclerosis have substantially more astrocytosis than those with LATE-NC or hippocampal sclerosis alone. J Neuropathol Exp Neurol. 2023;82(12):987-994. doi: 10.1093/jnen/nlad085


  1. Teylan MA, Mock C, Gauthreaux K, et al. Differences in symptomatic presentation and cognitive performance among participants With LATE-NC compared to FTLD-TDP. J Neuropathol Exp Neurol. 2021;80(11):1024-1032. doi: 10.1093/jnen/nlab098


  1. Jeon YM, Kwon Y, Lee S, et al. Vitamin B12 reduces TDP- 43 toxicity by alleviating oxidative stress and mitochondrial dysfunction. Antioxidants (Basel). 2021;11(1):82. doi: 10.3390/antiox11010082


  1. Nilaver BI, Urbanski HF. Mechanisms underlying TDP-43 pathology and neurodegeneration: An updated mini-review. Front Aging Neurosci. 2023;15:1142617. doi: 10.3389/fnagi.2023.1142617


  1. Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ. The role of TDP-43 propagation in neurodegenerative diseases: Integrating insights from clinical and experimental studies. Exp Mol Med. 2020;52(10):1652-1662. doi: 10.1038/s12276-020-00513-7


  1. Jamerlan A, An SSA. The influence of Aβ-dependent and independent pathways on TDP-43 proteinopathy in Alzheimer’s disease: A possible connection to LATE-NC. Neurobiol Aging. 2020;95:161-167. doi: 10.1016/j.neurobiolaging.2020.06.020


  1. Tomé SO, Gawor K, Thal DR. LATE-NC in Alzheimer’s disease: Molecular aspects and synergies. Brain Pathol. 2023:e13213. doi: 10.1111/bpa.13213


  1. Corriveau-Lecavalier N, Botha H, Graff-Radford J, Switzer AR, Przybelski SA, Wiste HJ, et al. A limbic-predominant amnestic neurodegenerative syndrome associated with TDP-43 pathology. medRxiv 2023. doi: 10.1101/2023.11.19.23298314


  1. Oveisgharan S, Yu L, Agrawal S, et al. Relation of motor impairments to neuropathologic changes of limbic-predominant age-related TDP-43 encephalopathy in older adults. Neurology. 2023;101(15):e1542-e1553. doi: 10.1212/WNL.0000000000207726


  1. Winston CN, Sukreet S, Lynch H, et al. Evaluation of blood-based, extracellular vesicles as biomarkers for aging-related TDP-43 pathology. Alzheimers Dement (Amst). 2022;14(1):e12365. doi: 10.1002/dad2.12365


  1. Bauer CE, Zachariou V, Sudduth TL, et al. Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions. Alzheimers Dement (Amst). 2023;15(2):e12437. doi: 10.1002/dad2.12437


  1. Gal J, Vary C, Gartner CA, Jicha GA, Abner EL, Ortega YS, Choucair I, Wilcock DM, Nelson R, Nelson P, et al. Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC. Res Sq. 2023. doi: 10.21203/


  1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2022;388(1):9-21. doi: 10.1056/NEJMoa2212948


  1. Francois-Moutal L, Scott DD, Khanna M. Direct targeting of TDP-43, from small molecules to biologics: The therapeutic landscape. RSC Chem Biol. 2021;2(4):1158-1166. doi: 10.1039/d1cb00110h
Conflict of interest
The author declares that she has no competing interests.
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Advanced Neurology, Electronic ISSN: 2810-9619 Published by AccScience Publishing