Proteogenomics captures a midlife biological state of Alzheimer's disease susceptibility
Alzheimer's disease (AD) develops over decades, but biological processes underlying susceptibility during midlife remain poorly understood. Using multimodal neuroimaging and plasma proteomics in UK Biobank participants, we identified circulating proteomic signatures of brain structure and organization. This 'neurostructural proteome' predicted future cognitive decline, incident dementia, and later-life AD pathology across independent cohorts spanning two decades of follow-up. Genetic and single-nucleus transcriptomic analyses demonstrated convergence of the neurostructural proteome and AD genetic architecture, highlighting enrichment in astrocyte, microglia, and endothelial pathways beyond the APOE region. Collectively, these findings identify a circulating neurostructural proteome detectable in midlife that captures molecular processes associated with future AD susceptibility and provide a framework for uncovering an early biological landscape of disease susceptibility that precedes conventional biomarkers and clinical onset.
Authors
- Andrew Perry (ORCID: https://orcid.org/0000-0003-3342-6158)
- Lifang Hou (ORCID: https://orcid.org/0000-0003-4877-0031)
- Ravi V. Shah (ORCID: https://orcid.org/0000-0002-4471-7156)
- Niranjana Shashikumar (ORCID: https://orcid.org/0009-0006-5627-8281)
- Elizabeth D. Hutchins (ORCID: https://orcid.org/0000-0003-2543-0798)
- Laura Anne Colangelo (ORCID: https://orcid.org/0000-0001-9322-705X)
- Eric H. Farber‐Eger (ORCID: https://orcid.org/0000-0003-0281-3796)
- Derek B. Archer (ORCID: https://orcid.org/0000-0001-8638-0785)
- Kendall R. Van Keuren‐Jensen (ORCID: https://orcid.org/0000-0001-8833-6323)
- Rebecca L. Sale
- Matthew Gregory Nayor (ORCID: https://orcid.org/0000-0002-6993-9396)
- Corey J. Bolton (ORCID: https://orcid.org/0000-0002-1715-5370)
- Antonina Risitano
- Carlos C Cruchaga (ORCID: https://orcid.org/0000-0002-0276-2899)
- Rowan Saloner (ORCID: https://orcid.org/0000-0002-1351-6183)
- Anshul Tiwari (ORCID: https://orcid.org/0000-0003-2647-8144)
- L. Taylor Davis (ORCID: https://orcid.org/0000-0003-2939-3875)
- Kristine S. Yaffe (ORCID: https://orcid.org/0000-0003-0919-3825)
- Quinn Stanton Wells (ORCID: https://orcid.org/0000-0003-3899-0313)
- Angela Lee Jefferson (ORCID: https://orcid.org/0000-0002-8245-0587)
- Xavier Bledsoe (ORCID: https://orcid.org/0000-0002-6091-9372)
- Kimberly R. Pechman (ORCID: https://orcid.org/0000-0003-0596-8064)
- Bennett A. Landman (ORCID: https://orcid.org/0000-0001-5733-2127)
- Kahraman Tanrıverdi (ORCID: https://orcid.org/0000-0002-1491-8803)
- Shilin Zhao (ORCID: https://orcid.org/0000-0002-3787-8111)
- Phillip Lin (ORCID: https://orcid.org/0009-0003-6988-0237)
- Amber L. Bahorik (ORCID: https://orcid.org/0000-0001-6333-3599)
- Quanhu Sheng (ORCID: https://orcid.org/0000-0001-8951-9295)
- Jane Freedman
- B. Lakshitha A. Perera (ORCID: https://orcid.org/0000-0003-3015-3529)
- Madeline Alexander
- Eric Gamazon
- Dandan Liu
- Siyuan Ma
- Yike Chen
- Hailey Adegboye
- Panpan Zhang
- Timothy Hohman
- Saumya Das
Institutions
- Boston University (US)
- Northwestern University (US)
- Translational Genomics Research Institute (US)
- University of California, San Francisco (US)
- Vanderbilt University (US)
- Washington University in St. Louis (US)
- Massachusetts General Hospital (US)
- Sunnybrook Research Institute (CA)
- UCSF Edward and Pearl Fein Memory and Aging Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-10-26
- DOI
- https://doi.org/10.64898/2026.10.22.26366029
- Primary Topic
- Dementia and Cognitive Impairment Research
- Type
- preprint
Funders
- Arizona Biomedical Research Commission