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

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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
Pages (from-to)	1263-1278
Number of pages	16
Journal	Nature Aging
Volume	4
Issue number	9
DOIs	https://doi.org/10.1038/s43587-024-00682-4
State	Published - Sep 2024
Externally published	Yes

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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, 4(9), 1263-1278. https://doi.org/10.1038/s43587-024-00682-4

@article{b26c6079a3b146299e467663e2b2149a,

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.",

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",

month = sep,

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

language = "English",

volume = "4",

pages = "1263--1278",

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, vol. 4, no. 9, pp. 1263-1278. 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 - 2024/9

Y1 - 2024/9

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.

UR - http://www.scopus.com/inward/record.url?scp=85201229797&partnerID=8YFLogxK

U2 - 10.1038/s43587-024-00682-4

DO - 10.1038/s43587-024-00682-4

M3 - Article

AN - SCOPUS:85201229797

SN - 2662-8465

VL - 4

SP - 1263

EP - 1278

JO - Nature Aging

JF - Nature Aging

IS - 9

ER -

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

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