CMV titer associations with cognition and the plasma proteome implicate FLT1 and neurovascular mechanisms as potential moderators.

Overview

1. Laboratory of Behavioral Neuroscience, National Institute On Aging, National Institutes of Health, NIH Biomedical Research Center Bg. RM. 04B316, 251 Bayview Blvd, Baltimore, MD 21224 USA
2. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
3. Stanley Laboratory of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD USA
4. Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA USA
5. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
6. Translational Gerontology Branch, National Institute On Aging, Baltimore, MD USA
7. Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA USA

Abstract

Immune processes play complex roles in Alzheimer’s disease and related dementias (ADRD), but it remains unclear whether host defenses against common microbes also contribute to ADRD, and what underlying mechanisms may account for these relationships. Using antibody and plasma proteomic data from the Monongahela-Youghiogheny Healthy Aging Team study (n = 1,003; mean age = 78.0 yrs; follow up 7.6 yrs), the present study detected accelerated decline across a variety of cognitive domains and altered plasma abundance of FLT1 (also known as Vascular Endothelial Growth Factor Receptor 1) among participants with elevated cytomegalovirus (CMV) titers. After analyses in the Baltimore Longitudinal Study of Aging (n = 323) and the UK Biobank (n = 956) revealed CMV titer associations with higher cross-sectional cognition and greater cognitive decline were moderated by plasma FLT1 abundance, we leveraged two-sample Mendelian Randomization to uncover causal roles for host immune responses to CMV, including limiting brain amyloidosis. Using multi-cohort proteomic signatures of CMV antibody levels and plasma FLT1, bioinformatic analyses suggested that host immune responses to CMV may impact neurologic health through alterations in lymphocytic immunoregulatory cascades, with circulating FLT1 abundance capturing the extent to which these effects may be transmitted across the blood–brain-barrier. In addition to detecting pleiotropic associations of CMV titers with neurocognitive outcomes, our findings highlight FLT1 as an important molecular moderator of these effects, and extend our understanding of the biological basis by which host immune responses to common microbes may contribute to ADRD.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-026-03800-8.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• figshare:32413852, at figshare; found in DataCite
• ukbiobank.ac.uk/enable-your-research/apply-for-access, at UK Biobank; found in “Data availability”

Data availability

MYHAT data used in the present study are available upon reasonable request. Requests can be made using the “Contact Us” link on the MYHAT public-facing website (https://www.dementia-epidemiology.pitt.edu/) and are subject to approval in accordance with data sharing policies at the University of Pittsburgh. All BLSA data generated in the present study are included in this article, available on reasonable request, or in an online public repository. BLSA proteomic data are available via the Alzheimer’s Disease Data Initiative (https://www.neuroproteome.org). Participants did not consent to unrestricted data sharing. Anonymized data not published within this article may be shared upon request from qualified investigators for purposes of replicating procedures and findings. Researchers who wish to use BLSA data (including proteomics) are encouraged to develop a pre-analysis plan that can be submitted for approval (https://blsa.nia.nih.gov/how-apply). Data, protocols, and other metadata of the UKB are available to the scientific community upon request in accordance with the UKB data sharing policy (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). No original code was developed for this study, and no custom code or mathematical algorithm was central to its conclusions. Analyses used publicly available R packages, including stats (4.4), tidyverse (2.0), nlme (3.1), and ggplot2 (3.5), with basic functions (e.g., lm, full_join, geom_point etc.,).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 15 MeSH terms, 2 funders, 89 references.

Cite

This paper

Duggan, M. R., Jacobsen, E., Yang, S., Zeng, X., Kandala, S., Joynes, C. M., Karikari, T. K., Nimgaonkar, V. L., Kamboh, M. I., Snitz, B. E., Ferrucci, L., Yolken, R., Ganguli, M., & Walker, K. A. (2026). CMV titer associations with cognition and the plasma proteome implicate FLT1 and neurovascular mechanisms as potential moderators. Journal of neuroinflammation, 23(1), 169. https://doi.org/10.1186/s12974-026-03800-8

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1038/s41467-026-72091-7 [code]

Coupled cross-sectional and longitudinal non-negative matrix factorization reveals dominant brain aging trajectories in 48,949 individuals.

Journal: Nature communications

In common: Alzheimer's / dementia, 3 references, author Michael R. Duggan

[2] doi:10.1002/trc2.70286 [code]

The proteomic and metabolomic signature of inherited chromosomally integrated HHV-6 and its role in all-cause dementia and mortality risk: The UK Biobank study.

Journal: Alzheimer's & dementia (New York, N. Y.)

In common: Alzheimer's / dementia, genetics / omics, 6 references

[3] doi:10.1038/s41398-026-04137-9 [code]

An integrative mendelian randomisation and drug mechanism framework for target prioritisation and therapeutic repurposing in major depression.

Journal: Translational psychiatry

In common: ukbiobank.ac.uk/enable-your-research/apply-for-access, genetics / omics, 4 references

[4] doi:10.34133/research.1298 [code]

Multisite Chronic Pain Reveals Neuro-Immune-Metabolic Dysregulation across Rheumatoid Arthritis and Depression.

Journal: Research (Washington, D.C.)

In common: ukbiobank.ac.uk/enable-your-research/apply-for-access, genetics / omics, 2 references

[5] doi:10.1038/s41467-026-71738-9 [code]

Genetic landscape of adult executive function reveals a cell-type-specific developmental origin.

Journal: Nature communications

In common: ukbiobank.ac.uk/enable-your-research/apply-for-access, genetics / omics, 2 references

[6] doi:10.1093/cercor/bhag105 [code]

The tangential growth of the human visual cortex and maternal smoking during pregnancy.

Journal: Cerebral cortex (New York, N.Y. : 1991)

In common: ukbiobank.ac.uk/enable-your-research/apply-for-access, 2 references

[7] doi:10.1371/journal.pmed.1004868 [code]

Plasma proteomic signatures of early retinal neurodegeneration in diabetes: A multi-cohort study.

Journal: PLoS medicine

In common: genetics / omics, 4 references

[8] doi:10.1038/s41467-026-70243-3 [code]

TYK2 mediates neuroinflammation in Alzheimer's disease brains with TDP-43 pathology.

Journal: Nature communications

In common: Alzheimer's / dementia, 4 references

[9] doi:10.1038/s41591-026-04492-6 [code]

The genetic architecture of fibromyalgia across 2.5 million individuals.

Journal: Nature medicine

In common: genetics / omics, 4 references

[10] doi:10.1038/s41467-026-76676-0 [code]

Determinants of functional burden pleiotropy and gene dosage responses across human traits.

Journal: Nature communications

In common: ukbiobank.ac.uk/enable-your-research/apply-for-access, genetics / omics, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.