Vascular plasticity and microglial mediators link blood‐brain barrier dysfunction to synaptic decline in cognitively typical aging independent of amyloid

TL;DR

This study shows that blood-brain barrier dysfunction, linked to fibrinogen levels, contributes to synaptic decline in aging without amyloid buildup.

Contribution

The study identifies thromboinflammatory pathways and vascular-immune mediators associated with synaptic decline in typical aging, independent of amyloid pathology.

Findings

Higher CSF fibrinogen is associated with elevated synaptic and neurodegenerative markers like pTau, GAP43, NRGN, and SNAP25.

Fourteen proteins mediate the link between fibrinogen and neurodegeneration, involving vascular plasticity and immune activation.

Vascular-specific mediators are reduced in amyloid-positive individuals, suggesting distinct mechanisms in amyloid aging.

Abstract

Cognitive decline frequently occurs during typical aging, yet the molecular mechanisms underlying this process remain poorly understood, especially in the absence of classical neuropathology such as amyloid. Vascular dysfunction and increased blood‐brain barrier (BBB) permeability have emerged as potential contributors. This study examined whether thromboinflammation, indicated by fibrinogen levels in cerebrospinal fluid (CSF), affects synaptic health and cognition in amyloid‐negative, typical aging.

We measured CSF fibrinogen and synaptic/neurodegenerative markers (pTau, GAP43, NRGN, and SNAP25) in cognitively normal older adults (N = 70). An unbiased proteomic screen (SomaScan 7k) was then performed to identify specific mediators linking fibrinogen to these markers, followed by validation in an independent cohort (N = 482). To assess potential interactions with amyloid pathology, we further examined these mediators in a separate group of amyloid‐positive older adults (N = 752).

Higher CSF fibrinogen was significantly associated with elevated pTau, GAP43, NRGN, and SNAP25, independent of amyloid status. Mediation analysis revealed 14 proteins that consistently linked fibrinogen to neurodegeneration, including factors regulating vascular plasticity and immune activation. Cell‐type mapping showed enrichment in endothelial cells, pericytes, and microglia. Results were validated in a large, independent typical aging cohort, confirming core pathways of fibrinogen‐mediated neurovascular dysfunction. In the amyloid‐positive cohort, vascular‐specific mediators were relatively reduced, indicating possibly altered molecular mechanisms in amyloid aging compared with typical aging.

These findings highlight a thromboinflammatory pathway underlying synaptic decline in typically aging older adults, driven by fibrinogen at the neurovascular interface. Targeting BBB integrity and its vascular‐immune signaling may offer therapeutic opportunities to preserve cognition in aging, even in the absence of amyloid pathology.

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