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Role of tau versus TDP-43 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease

Wisse, Laura E M LU orcid ; Wuestefeld, Anika LU orcid ; Murray, Melissa E ; Jagust, William and La Joie, Renaud (2025) In Alzheimer's & dementia : the journal of the Alzheimer's Association 21(2).
Abstract

Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA-binding protein 43 (TDP-43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP-43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP-43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP-43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research... (More)

Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA-binding protein 43 (TDP-43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP-43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP-43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP-43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP-43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic-predominant age-related TDP-43 encephalopathy and pinpointing of the optimal timing for testing anti-tau and anti-TDP-43 treatments in trials. HIGHLIGHTS: Both tau and TAR DNA-binding protein 43 (TDP-43) pathology contribute to medial temporal lobe atrophy. There is a positive association between tau and TDP-43 and potentially a synergism. It is unclear if tau and TDP-43 have an additive or synergistic effect on atrophy. The relative timing of the tau and TDP-43 effects on atrophy remains unclear. Clarifying the interplay between tau and TDP-43 will help improve magnetic resonance imaging biomarkers.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Alzheimer Disease/pathology, tau Proteins/metabolism, Atrophy/pathology, DNA-Binding Proteins/metabolism, Temporal Lobe/pathology, Aging/pathology, Hippocampus/pathology
in
Alzheimer's & dementia : the journal of the Alzheimer's Association
volume
21
issue
2
article number
e14582
publisher
Wiley
external identifiers
  • pmid:39985478
ISSN
1552-5279
DOI
10.1002/alz.14582
language
English
LU publication?
yes
additional info
© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
id
96d9dc82-7a08-48d9-93b7-167ca7eee8a0
date added to LUP
2025-02-28 07:38:20
date last changed
2025-04-04 14:54:09
@article{96d9dc82-7a08-48d9-93b7-167ca7eee8a0,
  abstract     = {{<p>Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA-binding protein 43 (TDP-43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP-43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP-43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP-43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP-43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic-predominant age-related TDP-43 encephalopathy and pinpointing of the optimal timing for testing anti-tau and anti-TDP-43 treatments in trials. HIGHLIGHTS: Both tau and TAR DNA-binding protein 43 (TDP-43) pathology contribute to medial temporal lobe atrophy. There is a positive association between tau and TDP-43 and potentially a synergism. It is unclear if tau and TDP-43 have an additive or synergistic effect on atrophy. The relative timing of the tau and TDP-43 effects on atrophy remains unclear. Clarifying the interplay between tau and TDP-43 will help improve magnetic resonance imaging biomarkers.</p>}},
  author       = {{Wisse, Laura E M and Wuestefeld, Anika and Murray, Melissa E and Jagust, William and La Joie, Renaud}},
  issn         = {{1552-5279}},
  keywords     = {{Humans; Alzheimer Disease/pathology; tau Proteins/metabolism; Atrophy/pathology; DNA-Binding Proteins/metabolism; Temporal Lobe/pathology; Aging/pathology; Hippocampus/pathology}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's & dementia : the journal of the Alzheimer's Association}},
  title        = {{Role of tau versus TDP-43 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1002/alz.14582}},
  doi          = {{10.1002/alz.14582}},
  volume       = {{21}},
  year         = {{2025}},
}