Adaptive immune changes associate with clinical progression of Alzheimer’s disease

Lynn van Olst; Alwin Kamermans; Sem Halters; Susanne M.A. van der Pol; Ernesto Rodriguez; Inge M.W. Verberk; Sanne G.S. Verberk; Danielle W.R. Wessels; Carla Rodriguez-Mogeda; Jan Verhoeff; Dorine Wouters; Jan Van den Bossche; Juan J. Garcia-Vallejo; Afina W. Lemstra; Maarten E. Witte; Wiesje M. van der Flier; Charlotte E. Teunissen; Helga E. de Vries

doi:10.1186/s13024-024-00726-8

Adaptive immune changes associate with clinical progression of Alzheimer’s disease

Lynn van Olst^*, Alwin Kamermans, Sem Halters, Susanne M.A. van der Pol, Ernesto Rodriguez, Inge M.W. Verberk, Sanne G.S. Verberk, Danielle W.R. Wessels, Carla Rodriguez-Mogeda, Jan Verhoeff, Dorine Wouters, Jan Van den Bossche, Juan J. Garcia-Vallejo, Afina W. Lemstra, Maarten E. Witte, Wiesje M. van der Flier, Charlotte E. Teunissen, Helga E. de Vries

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Background: Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods: We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results: We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1⁺ CD57⁺ CD8⁺ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions: Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.

Original language	English (US)
Article number	38
Journal	Molecular neurodegeneration
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s13024-024-00726-8
State	Published - Dec 2024

Funding

Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. NanoString funded the NanoString sample analyses with their nCounter Metabolic Pathways panel. Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434), and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CET and WMF are recipients of ABOARD, which is a public\u2013private partnership receiving funding from ZonMW (#73305095007) and Health\u2009~\u2009Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. Research programs of WMF have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health\u223CHolland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Biogen MA Inc, Boehringer Ingelheim, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. The chair of WMF is supported by the Pasman stichting. This work was further funded by Horizon 2020 (686009) and by Alzheimer Nederland; Call for Biomedical Research 2021 (WE.03\u20132021-02) to HEV.

Keywords

Adaptive immunity
Alzheimer’s disease
APOE
Neuroinflammation
T cells
TEMRA cells

ASJC Scopus subject areas

Molecular Biology
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1186/s13024-024-00726-8

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van Olst, L., Kamermans, A., Halters, S., van der Pol, S. M. A., Rodriguez, E., Verberk, I. M. W., Verberk, S. G. S., Wessels, D. W. R., Rodriguez-Mogeda, C., Verhoeff, J., Wouters, D., Van den Bossche, J., Garcia-Vallejo, J. J., Lemstra, A. W., Witte, M. E., van der Flier, W. M., Teunissen, C. E., & de Vries, H. E. (2024). Adaptive immune changes associate with clinical progression of Alzheimer’s disease. Molecular neurodegeneration, 19(1), Article 38. https://doi.org/10.1186/s13024-024-00726-8

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title = "Adaptive immune changes associate with clinical progression of Alzheimer{\textquoteright}s disease",

abstract = "Background: Alzheimer{\textquoteright}s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods: We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results: We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions: Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.",

keywords = "Adaptive immunity, Alzheimer{\textquoteright}s disease, APOE, Neuroinflammation, T cells, TEMRA cells",

author = "{van Olst}, Lynn and Alwin Kamermans and Sem Halters and {van der Pol}, {Susanne M.A.} and Ernesto Rodriguez and Verberk, {Inge M.W.} and Verberk, {Sanne G.S.} and Wessels, {Danielle W.R.} and Carla Rodriguez-Mogeda and Jan Verhoeff and Dorine Wouters and {Van den Bossche}, Jan and Garcia-Vallejo, {Juan J.} and Lemstra, {Afina W.} and Witte, {Maarten E.} and {van der Flier}, {Wiesje M.} and Teunissen, {Charlotte E.} and {de Vries}, {Helga E.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s13024-024-00726-8",

language = "English (US)",

volume = "19",

journal = "Molecular neurodegeneration",

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van Olst, L, Kamermans, A, Halters, S, van der Pol, SMA, Rodriguez, E, Verberk, IMW, Verberk, SGS, Wessels, DWR, Rodriguez-Mogeda, C, Verhoeff, J, Wouters, D, Van den Bossche, J, Garcia-Vallejo, JJ, Lemstra, AW, Witte, ME, van der Flier, WM, Teunissen, CE & de Vries, HE 2024, 'Adaptive immune changes associate with clinical progression of Alzheimer’s disease', Molecular neurodegeneration, vol. 19, no. 1, 38. https://doi.org/10.1186/s13024-024-00726-8

TY - JOUR

T1 - Adaptive immune changes associate with clinical progression of Alzheimer’s disease

AU - van Olst, Lynn

AU - Kamermans, Alwin

AU - Halters, Sem

AU - van der Pol, Susanne M.A.

AU - Rodriguez, Ernesto

AU - Verberk, Inge M.W.

AU - Verberk, Sanne G.S.

AU - Wessels, Danielle W.R.

AU - Rodriguez-Mogeda, Carla

AU - Verhoeff, Jan

AU - Wouters, Dorine

AU - Van den Bossche, Jan

AU - Garcia-Vallejo, Juan J.

AU - Lemstra, Afina W.

AU - Witte, Maarten E.

AU - van der Flier, Wiesje M.

AU - Teunissen, Charlotte E.

AU - de Vries, Helga E.

PY - 2024/12

Y1 - 2024/12

N2 - Background: Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods: We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results: We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions: Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.

AB - Background: Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods: We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results: We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions: Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.

KW - Adaptive immunity

KW - Alzheimer’s disease

KW - APOE

KW - Neuroinflammation

KW - T cells

KW - TEMRA cells

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DO - 10.1186/s13024-024-00726-8

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AN - SCOPUS:85191351548

SN - 1750-1326

VL - 19

JO - Molecular neurodegeneration

JF - Molecular neurodegeneration

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ER -

Adaptive immune changes associate with clinical progression of Alzheimer’s disease

Abstract

Funding

Keywords

ASJC Scopus subject areas

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