Abstracts
TAR DNA-binding protein 43 (TDP43) is a focus of research in late-onset dementias. TDP43 pathology in the brain was initially identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and later in Alzheimer disease (AD), other neurodegenerative diseases and ageing. Limbic-predominant age-related TDP43 encephalopathy (LATE), recognized as a clinical entity in 2019, is characterized by amnestic dementia resembling AD dementia and occurring most commonly in adults over 80 years of age. Neuropathological findings in LATE, referred to as LATE neuropathological change (LATE-NC), consist of neuronal and glial cytoplasmic TDP43 localized predominantly in limbic areas with or without coexisting hippocampal sclerosis and/or AD neuropathological change and without frontotemporal lobar degeneration or amyotrophic lateral sclerosis pathology. LATE-NC is frequently associated with one or more coexisting pathologies, mainly AD neuropathological change. The focus of this Review is the pathology, genetic risk factors and nature of the cognitive impairments and dementia in pure LATE-NC and in LATE-NC associated with coexisting pathologies. As the clinical and cognitive profile of LATE is currently not easily distinguishable from AD dementia, it is important to develop biomarkers to aid in the diagnosis of this condition in the clinic. The pathogenesis of LATE-NC should be a focus of future research to form the basis for the development of preventive and therapeutic strategies.
Key points
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In the two decades since the localization of TAR DNA-binding protein (TDP43) pathology in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, much information has become available regarding the tissue localization of TDP43 pathology in Alzheimer disease (AD) and other neurodegenerative disorders as well as in ageing.
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Characterization of limbic-predominant age-related TDP43 encephalopathy (LATE, the clinical disease) and LATE neuropathological change (LATE-NC) is a relatively recent development and its importance lies in the finding that LATE-NC is a common pathology underlying amnestic dementia, especially in individuals aged 80 years or more.
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LATE-NC can coexist with a variety of clinical and pathological conditions.
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As the clinical and cognitive profile of LATE is not yet easily distinguishable from AD dementia, it is important to develop biomarkers to aid in the diagnosis of this condition in the clinic.
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Future research needs to focus on the pathogenesis of LATE-NC to form the basis for the development of preventive and therapeutic strategies.
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Acknowledgements
The authors thank the participants of the Rush Memory and Aging Project, the Religious Orders Study, the Minority Aging Research Study, and the African American Core for making this research possible. The authors thank the late John Q. Trojanowski (Professor of Geriatric Medicine and Gerontology in the Department of Pathology and Laboratory Medicine, University of Pennsylvania) for encouragement and help at the initiation of these studies and for thought-provoking discussions. The authors also thank all the staff of Rush Alzheimer’s Disease Center. The authors’ work is supported by the NIH National Institute on Aging (R01AG042210, R01AG067482, R01AG017917, P30AG010161, P30AG072975, RF1AG022018).
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Nag, S., Schneider, J.A. Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases. Nat Rev Neurol 19, 525–541 (2023). https://doi.org/10.1038/s41582-023-00846-7
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DOI: https://doi.org/10.1038/s41582-023-00846-7
