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Cited by 203Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchIntracerebral and Subarachnoid Hemorrhage Research

The development and convergence of co-pathologies in Alzheimer’s disease

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Robinson, John L, Richardson, Hayley, Xie, Sharon X, Suh, EunRan, Van Deerlin, Vivianna M, Alfaro, Brian, Loh, Nicholas, Porras-Paniagua, Matias +5 more·2021·Brain
DOI 10.1093/brain/awaa438PMC PMC8041349
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Abstract

Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer’s disease, but their prevalence and severity dramatically increase in Alzheimer’s disease. To investigate how plaques, tangles, age and apolipoprotein E ε4 (APOE ε4) interact with co-pathologies in Alzheimer’s disease, we analysed 522 participants ≥50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer’s disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38–1.94, P < 0.01), LATE-NC (1.48, 1.16–1.88, P < 0.01), and Lewy bodies (1.45, 1.15–1.83, P < 0.01), but APOE ε4 only associated with CAA (4.80, 2.16–10.68, P < 0.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15–1.46, P < 0.01), while Lewy bodies associated with younger ages (0.90, 0.81–1.00, P = 0.04), and APOE ε4 only associated with CAA (2.36, 1.52–3.65, P < 0.01). A longer disease course only associated with LATE-NC (1.06, 1.01–1.11, P = 0.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50–3.30, P < 0.01), LATE-NC (5.24, 3.11–8.83, P < 0.01), and Lewy bodies (2.41, 1.51–3.84, P < 0.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77–9.28, P < 0.01), LATE-NC (5.54, 2.33–13.15, P < 0.01), and Lewy bodies (4.76, 2.07–10.95, P < 0.01). Increased amyloid phase associated with CAA (2.27, 1.07–4.80, P = 0.03) and Lewy bodies (6.09, 1.66–22.33, P = 0.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer’s disease dementia. CAA interacted with plaques and tangles especially in APOE ε4 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.

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  • APOEε4 carriage has been independently associated with increased odds and severity of Lewy body pathology and TDP-43 pathology and with the presence of TDP-43-related hippocampal sclerosis in the scenario of a primary neuropathological diagnosis of Alzheimer disease.

    “Specifically, APOEε4 carriage has been independently associated with increased odds and severity of Lewy body pathology49,62 and TDP-43 pathology59,63,64 and with the presence of TDP-43-related hippocampal sclerosis63 in the scenario of a primary neuropathological diagnosis of AD.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [59]

    The ‘Co-pathology prevalence varies by age, APOE allele and dementia status’ section states that APOE ε4 was associated with cerebral amyloid angiopathy but not with any other co-pathology. Table 4 likewise shows no significant APOE ε4 association with LATE-NC (TDP-43 pathology) or Lewy body stage, contrary to the claimed increased odds and severity. The cited passages do not establish the separate hippocampal-sclerosis association. (LLM, conf=0.89)

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Authors
Robinson, J. L., Richardson, H., Xie, S. X., Suh, E., Van Deerlin, V. M., Alfaro, B., Loh, N., Porras-Paniagua, M., Nirschl, J. J., Wolk, D., Lee, V. M. Y., Lee, E. B., & Trojanowski, J. Q.
Affiliations
  • University of Pennsylvania (US)
  • Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA
Corresponding author
Trojanowski, John Q
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2021-01-15
Volume
144
Issue
3
Pages
953-962
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awaa438
PMC
PMC8041349
OpenAlex
W3124898533
Cited by
203
References
2
Citations by year
2026: 38 · 2025: 51 · 2024: 37 · 2023: 34 · 2022: 32 · 2021: 10 · 2012: 1
FWCI
11.58
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Brain (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • NIA (P30 AG019610, P30 AG013846, P30 AG062428-01, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P30 AG062421-01, P30 AG062422-01, P50 AG005138, P30 AG008051, P30 AG013854)
  • NIH (U01 AG016976)
  • US National Institutes of Health (P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P30 AG062429-01, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG053760, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P30 AG049638, P50 AG005136, P30 AG062715-01, P50 AG005681, P50 AG047270, AG062418, AG17586, AG010124)
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 › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
Alzheimer's disease, co-pathology, cerebral amyloid angiopathy, limbic-predominant age-related TDP-43 encephalopathy, Lewy bodies, APOE ε4, age, clinical course, Braak stages, dementia, amygdala, hippocampus, brainstem
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Retrospective Studies, Comorbidity, Cerebral Amyloid Angiopathy, Lewy Body Disease, TDP-43 Proteinopathies

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