Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated
Open accessAbstract
Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.
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The APOEε4 allele correlates with the presence of Alzheimer disease neuropathological changes in people with a primary neuropathological diagnosis of amyotrophic lateral sclerosis, neocortical Lewy body disease, primary tauopathies including Pick's disease, progressive supranuclear palsy and corticobasal degeneration and multiple system atrophy.
“Converse to the APOEε4-associated increased likelihood of comorbid proteinopathies in people with AD, the APOEε4 allele also correlates with the presence of AD neuropathological changes in people with a primary neuropathological diagnosis of amyotrophic lateral sclerosis, neocortical Lewy body disease (LBD), primary tauopathies including Pick’s disease, progressive supranuclear palsy (PSP) and”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [65]
The Results section reports an APOE ε4 association with co-pathology in ALS and neocortical Lewy body disease, and notes that co-pathology cases in corticobasal degeneration, progressive supranuclear palsy and multiple system atrophy included ε4 carriers. It does not establish that ε4 correlates specifically with Alzheimer disease neuropathological changes in every listed diagnosis; Table 3 says all Pick’s disease cases with co-pathologies were ε4-negative. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured50-60% of Alzheimer's-type dementia is estimated to be attributable to copathologies including α-synucleinopathy, vascular pathology, non-Alzheimer's disease tauopathies, and TDP-43 pathology.
“50–60% of Alzheimer’s-type dementia (dementia defined clinically as Alzheimer’s disease) is estimated to be attributable to these copathologies.40,42–45”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [40]
A positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity.
“Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity.”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [40]
Pure Alzheimer's disease pathology is the exception rather than the rule, found in 3-30% of neuropathological series of people with dementia of the Alzheimer type, depending on age.
“Pure Alzheimer’s disease pathology is the exception rather than the rule (found in 3–30% of neuropathological series of people with dementia of the Alzheimer type, depending on age40) at post-mortem examination.”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [40]
Alzheimer's disease can be associated with other brain pathologies, including α-synucleinopathy, vascular pathology, non-Alzheimer's disease tauopathies, and TDP-43 pathology.
“Alzheimer’s disease can be associated with other brain pathologies, including α-synucleinopathy,56 vascular pathology, non-Alzheimer’s disease tauopathies, and TDP-43 pathology.40,42–44”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [40]
The positivity of both amyloid and tau biomarkers is required because an amnestic phenotype with only amyloid positivity is not specific to Alzheimer's disease and is seen in other neurodegenerative diseases with amyloid copathology or in patients with cerebral amyloid angiopathy and amnestic vascular cognitive impairment.
“The positivity of both amyloid and tau biomarkers is required because an amnestic phenotype with only amyloid positivity is not specific to Alzheimer’s disease and is seen in other neurodegenerative diseases with amyloid copathology (including LATE and dementia with Lewy bodies1,40,41,100) or in patients with cerebral amyloid angiopathy and amnestic vascular cognitive impairment101 (appendix p 2).”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [40]
Alzheimer-type lesions are frequently observed as copathology in post-mortem examination of people who had other neurodegenerative diseases.
“Alternatively, lesions of the Alzheimer type are frequently observed as copathology in post-mortem examination of people who had other neurodegenerative diseases.40,41,94,96”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [40]
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Bettencourt, C., Skene, N., Bandres‐Ciga, S., Anderson, E., Winchester, L. M., Foote, I. F., Schwartzentruber, J., Botia, J. A., Nalls, M., Singleton, A., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13427 · Cited by 30 · see citing works
Concurrent tau pathologies in frontotemporal lobar degeneration with TDP‐43 pathology
Koga, S., Zhou, X., Murakami, A., Fernandez De Castro, C., Baker, M. C., Rademakers, R., & Dickson, D. W. (2022) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12778 · Cited by 30 · see citing works
CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology
Cousins, K. A. Q., Arezoumandan, S., Shellikeri, S., Ohm, D., Shaw, L. M., Grossman, M., Wolk, D., McMillan, C. T., Chen-Plotkin, A., Lee, E., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000201202 · Cited by 25 · see citing works
Self-citationDaneshvar, D. H., Nowinski, C. J., Abdolmohammadi, B., Luster, C. B., Uretsky, M., Martin, B. M., Palmisano, J. N., Weuve, J., McClean, M. D., Cherry, J. D., et al. (2026) · BMJ · doi:10.1136/bmj-2026-100418 · Cited by 17 · see citing works
- Authors
- Robinson, J. L., Lee, E. B., Xie, S. X., Rennert, L., Suh, E., Bredenberg, C., Caswell, C., Van Deerlin, V. M., Yan, N., Yousef, A., Hurtig, H. I., Siderowf, A., Grossman, M., McMillan, C. T., Miller, B., Duda, J. E., Irwin, D. J., Wolk, D., Elman, L., McCluskey, L., Chen-Plotkin, A., Weintraub, D., Arnold, S. E., Brettschneider, J., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- Penn Alzheimer’s Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- University of California, San Francisco (US)
- Philadelphia VA Medical Center (US)
- Harvard University (US)
- cts CaritasKlinikum Saarbrücken (DE)
- Corresponding author
- Trojanowski, John Q
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-06-05
- Volume
- 141
- Issue
- 7
- Pages
- 2181-2193
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6022546
- OpenAlex
- W2806938337
- Cited by
- 729
- References
- 36
- Citations by year
- 2026: 68 · 2025: 124 · 2024: 109 · 2023: 99 · 2022: 93 · 2021: 78 · 2020: 80 · 2019: 65 · 2018: 11 · 2012: 1
- FWCI
- 40.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (P30 AG10124, PO1 AG17586, P50 NS053488)
- Karen Cohen Segal
- Eleanor Margaret Kurtz Endowed Fund
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- neurodegenerative diseases, co-pathology, proteinopathies, tau protein, amyloid-beta, alpha-synuclein, TDP-43, APOE ε4, Lewy body disease, progressive supranuclear palsy, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Pick's disease
- MeSH terms
- Aged, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Inclusion Bodies, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Supranuclear Palsy, Progressive, Prevalence, Lewy Bodies, tau Proteins, Multiple System Atrophy, Neurodegenerative Diseases, Pick Disease of the Brain, Lewy Body Disease, Tauopathies, alpha-Synuclein, Apolipoprotein E4, TDP-43 Proteinopathies
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