. 2025 Feb;21(2):e14487.

doi: 10.1002/alz.14487. Epub 2024 Dec 31.

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Timothy E Richardson¹, Miranda E Orr^{2

3}, Timothy C Orr², Susan K Rohde^{1

4

5

6

7}, Alexander J Ehrenberg^{8

9

10}, Emma L Thorn^{1

11}, Thomas D Christie^{1

11}, Victoria Flores-Almazan^{1

11}, Robina Afzal^{1

11}, Claudia De Sanctis^{1

11}, Carolina Maldonado-Díaz¹, Satomi Hiya¹, Leyla Canbeldek¹, Lakshmi Shree Kulumani Mahadevan¹, Cheyanne Slocum¹, Jorge Samanamud¹, Kevin Clare¹, Nicholas Scibetta¹, Raquel T Yokoda¹², Daniel Koenigsberg^{1

11

13

14

15

16}, Gabriel A Marx^{1

11

13

14

15

16

17}, Justin Kauffman^{1

11

13

14

15

16}, Adam Goldstein^{1

11}, Enna Selmanovic^{13

16}, Eleanor Drummond¹⁸, Thomas Wisniewski^{19

20

21}, Charles L White 3rd²², Alison M Goate^{13

15

23}, John F Crary^{1

11

13

14

15

16}, Kurt Farrell^{1

11

13

14

15

16}, Michael L Alosco^{24

25}, Jesse Mez^{24

25}, Ann C McKee^{24

25

26

27}, Thor D Stein^{24

25

26

27}, Kevin F Bieniek^{28

29}, Tiffany F Kautz²⁹, Elena V Daoud²², Jamie M Walker^{1

11

13

29}

Affiliations

¹ Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
³ St. Louis VA Medical Center, St. Louis, Missouri, USA.
⁴ Department of Pathology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Human Genetics, Genomics of Neurodegenerative Diseases and Aging, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷ Department of Neurology, Alzheimer Center Amsterdam, Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁸ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
⁹ Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
¹⁰ Innovative Genomics Institute, University of California, Berkeley, California, USA.
¹¹ Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
¹³ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Brain & Mind Center and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
¹⁹ Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Department of Psychiatry, New York University Grossman School of Medicine, New York, New York, USA.
²¹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
²² Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
²³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁴ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
²⁵ Boston University Alzheimer's Disease Research Center and BU CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
²⁶ VA Boston Healthcare System, Boston, Massachusetts, USA.
²⁷ VA Bedford Healthcare System, Bedford, Massachusetts, USA.
²⁸ Department of Pathology & Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
²⁹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

PMID: 39737785
PMCID: PMC11848160
DOI: 10.1002/alz.14487

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Timothy E Richardson et al. Alzheimers Dement. 2025 Feb.

. 2025 Feb;21(2):e14487.

doi: 10.1002/alz.14487. Epub 2024 Dec 31.

Authors

Affiliations

¹ Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
³ St. Louis VA Medical Center, St. Louis, Missouri, USA.
⁴ Department of Pathology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Human Genetics, Genomics of Neurodegenerative Diseases and Aging, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷ Department of Neurology, Alzheimer Center Amsterdam, Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁸ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
⁹ Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
¹⁰ Innovative Genomics Institute, University of California, Berkeley, California, USA.
¹¹ Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
¹³ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁶ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Brain & Mind Center and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
¹⁹ Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Department of Psychiatry, New York University Grossman School of Medicine, New York, New York, USA.
²¹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
²² Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
²³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁴ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
²⁵ Boston University Alzheimer's Disease Research Center and BU CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
²⁶ VA Boston Healthcare System, Boston, Massachusetts, USA.
²⁷ VA Bedford Healthcare System, Bedford, Massachusetts, USA.
²⁸ Department of Pathology & Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
²⁹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

PMID: 39737785
PMCID: PMC11848160
DOI: 10.1002/alz.14487

Abstract

Introduction: Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition.

Methods: We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5).

Results: There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders.

Discussion: These results suggest that there are subregion-specific proteomic differences among the neurons of these disorders, which appear to be influenced to a large degree by the presence of hippocampal Aβ. These proteomic differences may play a role in the differing hippocampal p-tau distribution and pathogenesis of these disorders.

Highlights: Alzheimer's disease neuropathologic change (ADNC), possible primary age-related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) can be differentiated based on the proteomic composition of their neurofibrillary tangle (NFT)- and non-NFT-bearing neurons. The proteome of these NFT- and non-NFT-bearing neurons is largely correlated with the presence or absence of amyloid beta (Aβ). Neurons in CTE and definite PART (Aβ-independent pathologies) share numerous proteomic similarities that distinguish them from ADNC and possible PART (Aβ-positive pathologies).

Keywords: Alzheimer's disease neuropathologic change; aging; autophagy; chronic traumatic encephalopathy; cognitive reserve; neurodegeneration; oxidative stress; primary age‐related tauopathy; resilience; resistance; synapse loss; synapses; tauopathy.

PubMed Disclaimer

Conflict of interest statement

Preliminary results of the data presented in this paper have been published in abstract form for the 2024 Alzheimer's Disease/Parkinson's Disease (AD/PD) conference. The authors declare that they have no competing interests, conflicts of interest, or other relevant disclosures. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Representative paired phosphorylated tau (p‐tau; AT8) immunohistochemical stains and immunofluorescent stains demonstrating p‐tau and amyloid beta (Aβ) pathology in overview hippocampal sections, the entorhinal cortex, CA1 subregion, CA2 subregion, and CA4 subregion in representative cases of Alzheimer's disease neuropathologic change (ADNC), definite primary age‐related tauopathy (PART), and chronic traumatic encephalopathy (CTE). Overview panel scalebars = 2 mm, subregion panel scalebars = 100 µm.

**FIGURE 2**
Principal component analysis (PCA) of (A‐B) neurofibrillary tangle (NFT)–bearing neurons, (C‐D) non–NFT‐bearing neurons, and (E‐F) all neurons in cases of Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE).

**FIGURE 3**
Correlation analysis examining (A) the relationship between the level of each quantified protein and the presence of each neurodegenerative pathology (ADNC, possible PART, definite PART, and CTE) as well as (B) the relationship between the level of protein expression and the presence of Aβ (only significant interactions displayed). Aβ, amyloid beta; ADNC, Alzheimer's disease neuropathologic change; CTE, chronic traumatic encephalopathy; PART, possible primary age‐related tauopathy.

**FIGURE 4**
Significant differences in levels of phosphorylated tau (p‐tau) epitopes in neurofibrillary tangle (NFT)‐bearing neurons and non–NFT‐bearing neurons (and their immediate microenvironments) between subjects with Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) in each hippocampal subregion evaluated. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001.

**FIGURE 5**
Significant differences in protein levels in neurofibrillary tangle (NFT)‐bearing neurons (and their immediate microenvironments) between subjects with Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) in each hippocampal subregion evaluated. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001.

**FIGURE 6**
Differences in protein levels in non‐neurofibrillary tangle (NFT)‐bearing neurons (and their immediate microenvironments) between subjects with Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) in each hippocampal subregion evaluated. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001.

See this image and copyright information in PMC

References

1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:63‐75. - PubMed
1. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021;397:1577‐1590. - PMC - PubMed
1. Collaborators GBDDF . Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7:e105‐e25. - PMC - PubMed
1. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community‐dwelling older persons. Neurology. 2007;69:2197‐2204. - PubMed
1. White LR, Edland SD, Hemmy LS, et al. Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu‐Asia Aging Studies. Neurology. 2016;86:1000‐1008. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Affiliations

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous