Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging

Meghan I. Short, Alison E. Fohner, Håvard K. Skjellegrind, Alexa Beiser, Mitzi M. Gonzales, Claudia L. Satizabal, Thomas R. Austin, W. T. Longstreth, Joshua C. Bis, Oscar Lopez, Kristian Hveem, Geir Selbæk, Martin G. Larson, Qiong Yang, Hugo J. Aparicio, Emer R. McGrath, Robert E. Gerszten, Charles S. Decarli, Bruce M. Psaty, Ramachandran S. VasanHabil Zare, Sudha Seshadri

Research output: Contribution to journalArticlepeer-review


Background: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. Objective: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. Methods: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up). Results: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. Conclusions: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

Original languageEnglish (US)
Pages (from-to)1767-1780
Number of pages14
JournalJournal of Alzheimer's Disease
Issue number4
StatePublished - Dec 6 2023


  • Alzheimer's disease
  • biomarkers
  • dementia
  • endophenotypes
  • magnetic resonance imaging
  • proteomics

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


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