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

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 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.

Keywords: Alzheimer's disease; TAR DNA‐binding protein 43; dementia; hippocampus; limbic‐predominant age‐related TDP‐43 encephalopathy; magnetic resonance imaging; medial temporal lobe; neurodegeneration; neurofibrillary tangle pathology.

FIGURE 1

A historical overview of the neuropathological criteria and milestones and human biomarker milestones. References: Neuropathological criteria & milestones: Blue: Mid‐80s—identification of Aβ & tau as core proteins in plaques and tangles, , , , ; 1985—Khachaturian criteria of AD pathology; 1991—Braak staging of neurofibrillary tangles; 1991—CERAD criteria; 1997—NIA‐R criteria for the neuropathological diagnosis of AD; 2002—Thal phases of Aβ deposition; 2012—NIA‐AA criteria of “AD neuropathological changes”. Green: 2006—Identification of TDP‐43 in FTLD & ALS, ; 2007—identification of TDP‐43 in patients with AD; 2019—Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). Human biomarker milestones: 1980—first publication of FDG PET in AD; 1988—first publication of in vivo MRI‐based atrophy in AD; 1995—first publication of Aβ & tau measures in CSF, ; 2004—first publication of Aβ PET; 2013—first publication of tau PET; Late 2010s—blood‐based biomarker development. Aβ, amyloid beta; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose; FTLD, frontotemporal lobar degeneration; MRI, magnetic resonance imaging; NIA‐AA, National Institute on Aging – Alzheimer's Association; NIA‐R, National Institutes on Aging and Reagan International Working Group; PET, positron emission tomography; TDP, TAR DNA‐binding protein.

FIGURE 2

Overview of the medial temporal lobe and its subregions. A, Medial view of the medial temporal lobe in the left hemisphere. B, Superior view of the medial temporal lobe. C, Cross‐section of the medial temporal lobe. BA, Brodmann area; CA, cornu ammonis.

FIGURE 3

The staging of NFT and TDP‐43 pathology in the MTL, and the association between NFT and TDP‐43 stages. A, Staging of NFT pathology according to Braak & Braak—note that only stages I–III are depicted. B, Staging of TDP‐43 pathology in LATE‐NC according to Nelson et al., Note that a small portion of cases deviates from this staging scheme. C, A demonstration of the positive association between the TDP‐43 stage and the NFT stage based on Table 5 from Nelson et al., using data from 3803 participants from 13 different community‐ and population‐based autopsy cohorts. ERC, entorhinal cortex; LATE‐NC, limbic‐predominant age‐related TDP‐43 encephalopathy; MTL, medial temporal lobe; NFT, neurofibrillary tangle; TDP, TAR DNA‐binding protein.

FIGURE 4

Alternate hypotheses regarding the interplay between tau NFTs and TDP‐43 pathology and the potential synergism and timing of both pathologies on downstream MTL atrophy and memory decline. A, Different potential factors contributing to MTL atrophy and memory decline, with tau NFTs and TDP‐43 highlighted. B, The potential interplay between tau NFTs and TDP‐43 pathology, with a potentiating effect of tau NFTs on TDP‐43 (depicted under 1) and a potentiating effect of TDP‐43 pathology on tau NFTs (depicted under 2). C, The potential additive (1) or synergistic (2) effect of NFTs and TDP‐43 pathologies on downstream MTL atrophy. D, Three hypotheses regarding the timing of the effect of tau NFTs and TDP‐43 pathology on MTL atrophy and memory decline, with an early effect of tau NFTs and a late TDP‐43 pathology depicted under 1, an early effect of TDP‐43 and a late effect of tau NFTs depicted under 2, and a similar timing for both pathologies depicted under 3. Aβ, amyloid beta; CVD, cerebrovascular disease; MTL, medial temporal lobe; NFT, neurofibrillary tangle; TDP, TAR DNA‐binding protein.