TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia
Open accessAbstract
Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP ) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer's disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer's-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer's-type dementia. Data came from 946 older adults with ( n = 398) and without dementia ( n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer's disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer's-type dementia formerly labelled 'pure pathologic diagnosis of Alzheimer's disease' was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer's-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer's disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer's disease and TDP-43 pathologies were associated with higher odds of clinical Alzheimer's-type dementia (odds ratio = 6.73, 95% confidence interval = 4.18, 10.85) than pathologic Alzheimer's disease alone (odds ratio = 4.62, 95% confidence interval = 2.84, 7.52). In models examining TDP-43 stage, a dose-response relationship with clinical Alzheimer's-type dementia was observed, and a significant association was observed starting at stage 2, extension beyond the amygdala. In this large sample from almost 1000 community participants, we observed that TDP-43 proteinopathy was very common, frequently mixed with pathological Alzheimer's disease, and associated with a higher likelihood of the clinical expression of clinical Alzheimer's-type dementia but only when extended beyond the amygdala.
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Research has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have brain changes of another cause of dementia.
“research has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have the brain changes of another cause of dementia”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [224]
The section on pathologic diagnosis by clinical dementia status reports that 322 of 398 people with clinical Alzheimer’s-type dementia had pathologically confirmed Alzheimer’s disease, leaving about 19% without that diagnosis—within the claimed 15%–30% range. It does not establish that this group had no Alzheimer’s brain changes or that all instead had changes attributable to another cause of dementia. The paper also emphasizes that Alzheimer’s pathology commonly co-occurs with other pathologies. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTDP43 and α-synuclein proteinopathies, micro infarcts, hippocampal sclerosis, and argyrophilic grains can occur alone, or more frequently, along with AD pathologic changes.
“TDP43 and α-synuclein proteinopathies, micro infarcts, hippocampal sclerosis, and argyrophilic grains can occur alone, or more frequently, along with AD pathologic changes [162,163]; however, validated biomarkers are not presently available for them.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [163]
The Distribution section reports TDP-43 as the only measured pathology in 4.2% of participants and more commonly alongside other pathologies; the Results also describe Alzheimer’s pathology mixed with infarcts, Lewy bodies, or hippocampal sclerosis. The paper does not establish the same alone-versus-more-frequently-with-Alzheimer’s pattern for every item listed. Argyrophilic grains appear only in a reference title, not in the paper’s findings. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrevalence estimates of dementia due to Alzheimer's disease based on Alzheimer's brain changes as well as overt clinical dementia symptoms are likely to be lower than the 6.9 million figure reported.
“Prevalence estimates of dementia due to Alzheimer's disease based on Alzheimer's brain changes, as well as overt clinical dementia symptoms, are likely to be lower than the 6.9 million figure reported here.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [243]
In the Results section on TDP-43 by clinical dementia status (page unavailable), the paper reports that over 80% of participants with clinical Alzheimer’s-type dementia had a pathologic Alzheimer’s diagnosis. This supports the expectation that requiring both clinical symptoms and Alzheimer’s brain changes would yield a lower count than a clinical-only estimate. The paper does not calculate a population prevalence estimate or compare one with the citing document’s 6.9 million figure. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBoth autopsy studies and clinical trials have found that 15% to 30% of individuals who meet the criteria for clinical Alzheimer's dementia based on symptoms did not have Alzheimer's-related brain changes.
“Both autopsy studies and clinical trials have found that 15% to 30% of individuals who meet the criteria for clinical Alzheimer's dementia based on symptoms did not have Alzheimer's‐related brain changes.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [243]
In the Results section on clinical Alzheimer’s dementia status (page unavailable), 322 of 398 clinically diagnosed subjects had pathologically confirmed Alzheimer’s disease, leaving about 19% without a pathologic diagnosis—within the claimed range. But the paper defines absence of that diagnosis to include low-likelihood Alzheimer’s pathology, so it does not establish that those subjects had no Alzheimer’s-related brain changes. The cited evidence comes from an autopsy cohort, not clinical trials. (LLM, conf=0.88)
Experimental — accuracy not yet measuredResearch has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have the brain changes of another cause of dementia.
“research has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have the brain changes of another cause of dementia”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [243]
In the section on pathology by clinical dementia status (page unavailable), 322 of 398 people with clinical Alzheimer’s-type dementia had pathologically confirmed Alzheimer’s disease; the remaining 76, about 19%, fall within the claimed 15%–30% range. The paper does not establish that all 76 instead had the brain changes of another cause of dementia. Its findings about mixed pathologies largely concern people who also had Alzheimer’s pathology. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The 4-stage classification of TDP-43 distribution was based on previous studies.
“In this study, we used a 4-stages classification of TDP-43 distribution based on previous studies [30,42]”
From Sex differences in Alzheimer’s disease and common neuropathologies of aging (2018) · cites this paper as [30]
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- Authors
- James, B. D., Wilson, R. S., Boyle, P. A., Trojanowski, J. Q., Bennett, D. A., & Schneider, J. A.
- Affiliations
- Rush University Medical Center (US)
- University of Pennsylvania (US)
- Corresponding author
- James, Bryan D.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-09-30
- Volume
- 139
- Issue
- 11
- Pages
- 2983-2993
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5091047
- OpenAlex
- W2525541800
- Cited by
- 407
- References
- 60
- Citations by year
- 2026: 36 · 2025: 37 · 2024: 38 · 2023: 47 · 2022: 41 · 2021: 40 · 2020: 70 · 2019: 38 · 2018: 39 · 2017: 19 · 2015: 1
- FWCI
- 28.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Alzheimer's Association (P30AG10161)
- Eli Lilly and Company
- Avid Radiopharmaceuticals
- National Institute on Aging (R01AG017917, R01AG042210, K01AG050823, P30AG010124, P01AG017586, R01AG015819, P30AG010161, RF1AG015819, R01AG034374)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- TDP-43 proteinopathy, TARDBP, Alzheimer's disease pathology, mixed pathology, cytoplasmic inclusions, amygdala, hippocampus, neocortex, Lewy bodies, hippocampal sclerosis, arteriolosclerosis, infarction, cognitive impairment, older adults, community-dwelling
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Brain, DNA-Binding Proteins, Female, Humans, Male, Psychiatric Status Rating Scales, Cohort Studies, Brain Infarction, Arteriolosclerosis, TDP-43 Proteinopathies, Independent Living
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