Fitting TDP-43 into the APOE ε4 and neurodegeneration story

Josephs, Keith A.

doi:10.1016/s1474-4422(18)30288-6

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…Interestingly, APOE 4 carrier status did not have an effect on hippocampal volumes or rate of HA in cognitively intact individuals [16] suggesting that the presence of the APOE 4 allele is not a strong determinant of neurodegeneration in this population. Moreover, it has been reported that the 4 allele is a possible risk factor of TDP-43 [61][62][63]. Therefore, given that the studies that reported the effect of APOE 4 on rate were purely clinical and did not include an autopsy cohort [16,17], it is possible that TDP-43 or tau were confounders of the associations with hippocampal neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes

Buciuc

Wennberg

Weigand

et al. 2020

JAD

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Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer's disease (AD), but whether the association is modified by other factors is unknown. Objective: To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E (APOE) 4, Lewy bodies (LBs), amyloid-␤ (A␤), or Braak neurofibrillary tangle (NFT) stage. Methods: In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (A␤-positive) that had completed antemortem head MRI, we investigated how age, gender, APOE 4, presence of LBs, A␤, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models. Results: Older age, female gender, APOE 4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOE 4 carriers (p = 0.04). Conclusion: Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another.

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Section: Discussionmentioning

confidence: 99%

Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes

Buciuc

Wennberg

Weigand

et al. 2020

JAD

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“…It was later shown to be present in 17-74% of brains of aged individuals and those with Alzheimer's disease [1,3,4,9,12,14,29,35,56]. Today, TDP-43 has become important to our understanding of age-related cognitive impairment and Alzheimer's disease [15,21]. TDP-43 has been shown to be associated with the presence of dementia, more severe cognitive impairment in general at death and overtime, and loss of episodic memory even after accounting for other pathologies that have also been linked to these clinical features [5,[24][25][26]57].…”

mentioning

confidence: 99%

“…TDP-43 has also been shown to be associated with smaller hippocampal volumes and faster rates of hippocampal atrophy in aging and Alzheimer's disease [17,24,26]. TDP-43 has also been linked to the apolipoprotein epsilon e4 allele (APOE ε4) [15,53,58] and the transmembrane protein 106B (TMEM106B) [46] in aging and Alzheimer's disease.…”

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confidence: 99%

Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

et al. 2019

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TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B & GRN variants), imaging and clinical data between types, and compared imaging between types and a group of TDP-43 negative cases (n=309). Two-hundred forty-one cases were classified as TDP type-α (n=131, 54%) or TDP typeβ (n=110, 46%). Type-α cases were older than type-β at death (median 89 years vs 87; p=0.02). Hippocampal sclerosis was present in 78 type-α cases (60%) and 16 (15%) type-β cases (p<0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type-β cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and CA1 region of the hippocampus (84% TDP-43 stages 1-3) (p<0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs 24%/49%/27%; p=0.01).Type-α cases had smaller amygdala (−10.6% [−17.6%, −3.5%]; p=0.003) and hippocampal (−14.4% [−21.6%, −7.3%]; p<0.001) volumes on MRI at death compared to type-β cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43

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Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer’s disease neuropathologic changes and cognitive decline

Chang,

Ling,

Redding-Ochoa

et al. 2023

Acta Neuropathol

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Fitting TDP-43 into the APOE ε4 and neurodegeneration story

Cited by 3 publications

References 10 publications

Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes

Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes

Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer’s disease neuropathologic changes and cognitive decline

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