Blood Protein PlGF Predicts Cognitive Decline Years Before Symptoms Appear

Cerebrovascular disease is among the most prevalent contributors to cognitive aging and dementia, yet current imaging biomarkers like white matter hyperintensities (WMHs) primarily reflect end-stage tissue damage rather than early upstream pathology. This gap limits opportunities for prevention and early intervention, motivating the search for more sensitive fluid biomarkers that capture cerebrovascular risk before irreversible injury occurs.

This study examined plasma placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, as a potential susceptibility biomarker for cognitive and white matter decline. PlGF is hypothesized to promote vascular permeability and endothelial inflammation, mechanisms that may contribute to white matter injury and downstream cognitive impairment. While prior cross-sectional studies linked PlGF to WMH burden and worse cognitive status in heterogeneous clinical cohorts, no longitudinal data existed in cognitively healthy older adults.

The UCSF BrANCH cohort provided 272 functionally intact older adults (CDR=0 at baseline; mean age 71.6 years) who underwent baseline blood draws for plasma PlGF measured via Meso Scale Discovery (MSD) assay, along with longitudinal neuropsychological testing and neuroimaging. Participants were followed for an average of 6.1 years with approximately five cognitive visits. A replication subset of 110 participants had banked plasma re-assayed using the NULISAseq platform to evaluate cross-platform reliability. Linear mixed-effects models tested whether baseline PlGF predicted trajectories of memory, executive function, processing speed, spatial cognition, WMH volume, gray matter volume, fractional anisotropy (FA), and mean diffusivity (MD).

Higher baseline PlGF was significantly associated with steeper longitudinal declines in memory and processing speed across both biomarker platforms, providing robust cross-validation. At baseline, elevated PlGF also correlated with greater WMH volume and lower global FA, indicating existing white matter damage. However, PlGF did not predict the rate of change in white matter metrics over time, nor did it associate with gray matter volume trajectories, suggesting its cognitive effects may operate through mechanisms beyond ongoing structural white matter accumulation—or that white matter progression occurs over longer timescales than captured.

These findings position PlGF as a promising upstream, susceptibility-phase biomarker of vascular-related cognitive decline that is detectable in peripheral blood before clinical impairment manifests. The replication across two independent assay platforms substantially strengthens the translational potential of these findings. The authors propose that PlGF-related endothelial dysfunction may represent an earlier, more modifiable stage of the cerebrovascular disease pathway than WMHs alone, offering a potential target for risk stratification and preventive intervention in aging.