Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline

Michael R. Duggan; Zhongsheng Peng; Pyry N. Sipilä; Joni V. Lindbohm; Jingsha Chen; Yifei Lu; Christos Davatzikos; Guray Erus; Timothy J. Hohman; Shea J. Andrews; Julián Candia; Toshiko Tanaka; Cassandra M. Joynes; Chelsea X. Alvarado; Mike A. Nalls; Jenifer Cordon; Gulzar N. Daya; Yang An; Alexandria Lewis; Abhay Moghekar; Priya Palta; Josef Coresh; Luigi Ferrucci; Mika Kivimäki; Keenan A. Walker

doi:10.1038/s43587-024-00682-4

Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline

Michael R. Duggan, Zhongsheng Peng, Pyry N. Sipilä, Joni V. Lindbohm, Jingsha Chen, Yifei Lu, Christos Davatzikos, Guray Erus, Timothy J. Hohman, Shea J. Andrews, Julián Candia, Toshiko Tanaka, Cassandra M. Joynes, Chelsea X. Alvarado, Mike A. Nalls, Jenifer Cordon, Gulzar N. Daya, Yang An, Alexandria Lewis, Abhay MoghekarPriya Palta, Josef Coresh, Luigi Ferrucci, Mika Kivimäki, Keenan A. Walker

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

Abstract

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ_42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

Original language	English
Journal	Nature Aging
ISSN	2662-8465
DOIs	https://doi.org/10.1038/s43587-024-00682-4
Publication status	Published - 2024
MoE publication type	A1 Journal article-refereed

Bibliographical note

Publisher Copyright:
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.

Fields of Science

3142 Public health care science, environmental and occupational health
1182 Biochemistry, cell and molecular biology
3112 Neurosciences

Access to Document

10.1038/s43587-024-00682-4

s43587-024-00682-4Final published version, 10.5 MBLicence: CC BY

Cite this

Duggan, M. R., Peng, Z., Sipilä, P. N., Lindbohm, J. V., Chen, J., Lu, Y., Davatzikos, C., Erus, G., Hohman, T. J., Andrews, S. J., Candia, J., Tanaka, T., Joynes, C. M., Alvarado, C. X., Nalls, M. A., Cordon, J., Daya, G. N., An, Y., Lewis, A., ... Walker, K. A. (2024). Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline. Nature Aging. https://doi.org/10.1038/s43587-024-00682-4

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title = "Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline",

abstract = "Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.",

keywords = "3142 Public health care science, environmental and occupational health, 1182 Biochemistry, cell and molecular biology, 3112 Neurosciences",

author = "Duggan, {Michael R.} and Zhongsheng Peng and Sipil{\"a}, {Pyry N.} and Lindbohm, {Joni V.} and Jingsha Chen and Yifei Lu and Christos Davatzikos and Guray Erus and Hohman, {Timothy J.} and Andrews, {Shea J.} and Juli{\'a}n Candia and Toshiko Tanaka and Joynes, {Cassandra M.} and Alvarado, {Chelsea X.} and Nalls, {Mike A.} and Jenifer Cordon and Daya, {Gulzar N.} and Yang An and Alexandria Lewis and Abhay Moghekar and Priya Palta and Josef Coresh and Luigi Ferrucci and Mika Kivim{\"a}ki and Walker, {Keenan A.}",

note = "Publisher Copyright: {\textcopyright} This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.",

year = "2024",

doi = "10.1038/s43587-024-00682-4",

language = "English",

journal = "Nature Aging",

issn = "2662-8465",

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Duggan, MR, Peng, Z, Sipilä, PN , Lindbohm, JV, Chen, J, Lu, Y, Davatzikos, C, Erus, G, Hohman, TJ, Andrews, SJ, Candia, J, Tanaka, T, Joynes, CM, Alvarado, CX, Nalls, MA, Cordon, J, Daya, GN, An, Y, Lewis, A, Moghekar, A, Palta, P, Coresh, J, Ferrucci, L, Kivimäki, M & Walker, KA 2024, 'Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline', Nature Aging. https://doi.org/10.1038/s43587-024-00682-4

TY - JOUR

T1 - Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline

AU - Duggan, Michael R.

AU - Peng, Zhongsheng

AU - Sipilä, Pyry N.

AU - Lindbohm, Joni V.

AU - Chen, Jingsha

AU - Lu, Yifei

AU - Davatzikos, Christos

AU - Erus, Guray

AU - Hohman, Timothy J.

AU - Andrews, Shea J.

AU - Candia, Julián

AU - Tanaka, Toshiko

AU - Joynes, Cassandra M.

AU - Alvarado, Chelsea X.

AU - Nalls, Mike A.

AU - Cordon, Jenifer

AU - Daya, Gulzar N.

AU - An, Yang

AU - Lewis, Alexandria

AU - Moghekar, Abhay

AU - Palta, Priya

AU - Coresh, Josef

AU - Ferrucci, Luigi

AU - Kivimäki, Mika

AU - Walker, Keenan A.

PY - 2024

Y1 - 2024

N2 - Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

AB - Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

KW - 3142 Public health care science, environmental and occupational health

KW - 1182 Biochemistry, cell and molecular biology

KW - 3112 Neurosciences

U2 - 10.1038/s43587-024-00682-4

DO - 10.1038/s43587-024-00682-4

M3 - Article

AN - SCOPUS:85201229797

SN - 2662-8465

JO - Nature Aging

JF - Nature Aging

ER -