Proteomic signatures of corona and herpes viral antibodies identify IGDCC4 as a mediator of neurodegeneration
Mechanisms underlying the dynamic relationships of viral infections and neurodegeneration warrant examination. Using a community-based cohort of older adults, the current study characterized the neurocognitive (cognitive functioning, brain volumes, Alzheimer's disease positron emission tomography, and plasma biomarkers) and plasma proteomic (7268 proteins) profiles of four common coronavirus and six herpesvirus antibody titers. Genetic inference techniques demonstrated the associations between viral antibody titers and neurocognitive outcomes may be attributed to altered expression in a subset of mechanistically relevant proteins in plasma. One of these proteins, IGDCC4 (immunoglobulin superfamily deleted in colorectal cancer subclass member 4), was related to 20-year dementia risk, cognitive functioning, and amyloid-β positivity using data from two independent cohorts, while its plasma and intrathecal abundance were causally implicated in dementia risk and clinically relevant brain atrophy. Our findings illuminate the biological basis by which host immune responses to viruses may affect neurocognitive outcomes in older adults and identify IGDCC4 as an important molecular mediator of neurodegeneration.
Authors
- Susan M. Resnick (ORCID: https://orcid.org/0000-0003-1115-7145)
- Yuhan Cui (ORCID: https://orcid.org/0000-0002-0017-0056)
- Timothy J. Hohman (ORCID: https://orcid.org/0000-0002-3377-7014)
- Nicholas James Ashton (ORCID: https://orcid.org/0000-0002-3579-8804)
- David Alan Bennett (ORCID: https://orcid.org/0000-0003-3689-554X)
- Ana W. Capuano (ORCID: https://orcid.org/0000-0002-3505-344X)
- Brion S. Maher (ORCID: https://orcid.org/0000-0001-9809-0064)
- Kaj Blennow (ORCID: https://orcid.org/0000-0002-1890-4193)
- Logan C. Dumitrescu (ORCID: https://orcid.org/0000-0002-9782-9944)
- Güray Erus (ORCID: https://orcid.org/0000-0001-6633-4861)
- Gabriela Gómez (ORCID: https://orcid.org/0000-0002-1761-0070)
- David Zweibaum (ORCID: https://orcid.org/0009-0006-7413-4038)
- Jingsha Chen
- Christos A. Davatzikos (ORCID: https://orcid.org/0000-0002-1025-8561)
- Rebecca F. Gottesman (ORCID: https://orcid.org/0000-0002-9504-1256)
- Przemysław Radosław Kac (ORCID: https://orcid.org/0000-0001-5083-0924)
- Josef Coresh (ORCID: https://orcid.org/0000-0002-4598-0669)
- Luigi Ferrucci (ORCID: https://orcid.org/0000-0002-6273-1613)
- Michael R. Duggan (ORCID: https://orcid.org/0000-0002-1029-4423)
- Thomas K. Karikari (ORCID: https://orcid.org/0000-0003-1422-4358)
- Qu Tian (ORCID: https://orcid.org/0000-0003-2706-1439)
- Julián Candia (ORCID: https://orcid.org/0000-0001-5793-8989)
- Abhay Moghekar (ORCID: https://orcid.org/0000-0001-9464-1551)
- Alexandria Lewis (ORCID: https://orcid.org/0000-0002-3812-8080)
- Keenan A. Walker (ORCID: https://orcid.org/0000-0002-5989-9853)
- Adam P. Spira (ORCID: https://orcid.org/0000-0003-1507-0995)
- Henrik Zetterberg (ORCID: https://orcid.org/0000-0003-3930-4354)
- Junhao Wen (ORCID: https://orcid.org/0000-0003-2077-3070)
- Murat Bilgel (ORCID: https://orcid.org/0000-0001-5042-7422)
- Robert H. Yolken (ORCID: https://orcid.org/0000-0001-9902-1554)
- Shuojia Yang
- Shannon M. Drouin (ORCID: https://orcid.org/0000-0001-8767-5884)
- Zhijian Yang (ORCID: https://orcid.org/0000-0002-7863-827X)
Institutions
- University of Science and Technology of China (CN)
- Rush University Medical Center (US)
- National Institutes of Health (US)
- University of Wisconsin–Madison (US)
- Johns Hopkins University (US)
- University of Pittsburgh (US)
- King's College London (GB)
- Anhui Medical University (CN)
- Johns Hopkins Medicine (US)
- Stavanger University Hospital (NO)
- Sahlgrenska University Hospital (SE)
- Stanley Foundation (US)
- Centre for Mental Health (GB)
- Sorbonne Université (FR)
- National Institute of Neurological Disorders and Stroke (US)
- UK Dementia Research Institute (GB)
- First Affiliated Hospital of Anhui Medical University (CN)
- National Institute on Aging (US)
- Center for Innovation (US)
- New York Genome Center (US)
- Artificial Intelligence in Medicine (Canada) (CA)
- University College London (GB)
- New York University (US)
- Columbia University (US)
- University of Pennsylvania (US)
- University of Gothenburg (SE)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1126/sciadv.adt7176
- Citations
- 5
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.89