Analysis of blood samples from 2,460 cognitively healthy adults revealed 52 proteins that predict cognitive decline over 15 years, with 34 linked to orientation problems and 18 to episodic memory loss. The proteins cluster around key aging mechanisms: extracellular matrix breakdown, immune dysfunction, cellular death pathways, and impaired cellular cleanup processes. This proteomics approach represents a significant advance in dementia prevention, moving beyond traditional cognitive tests to identify biological changes years before symptoms appear. The discovery that ten identified proteins are already being targeted by drugs in clinical trials creates immediate repurposing opportunities, potentially accelerating therapeutic development. Sex-specific patterns in the protein signatures suggest personalized approaches may be necessary. However, this preprint awaits peer review, and validation in diverse populations will be crucial before clinical application. The 15-year follow-up period and large sample size strengthen these findings, but the observational design cannot establish causation. If confirmed, these biomarkers could revolutionize early dementia screening and enable preventive interventions during the critical window when cognitive reserve remains intact.