In:
Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
Abstract:
Age‐associated dysfunction of the blood‐brain barrier results in increased non‐specific permeability of the barrier and “leakage” of blood proteins into the central nervous system (CNS). Over the past decade, fibrinogen, the blood coagulation factor, has been demonstrated to be necessary and sufficient for triggering brain dysfunction and degeneration in model systems and is now serving as a robust biomarker of pathological BBB leakage. Importantly, BBB leakage may be an early pathological feature of the aging brain, instigating the development of neurodegenerative disease pathologies. Method We used colorimetric enzyme‐linked immunosorbent and chemiluminescence immunoassays to quantify CSF concentrations of fibrinogen and A/T/N AD biomarkers in a cohort of 84 deeply phenotyped functionally normal older adults and built linear models to test the associations of fibrinogen (BBB leakage) with A/T/N biomarkers and cognition (processing speed). The “N” biomarkers included three synaptic proteins (neurogranin, SNAP25, and GAP43). We set significance at α=0.05. Result We found strong, significant associations of BBB leakage (CSF fibrinogen levels) with all three synaptic proteins, as well as tau and p‐tau. With respect to Aβ, we found a significant association of BBB leakage with Aβ 1‐40, which is the peptide most strongly associated with cerebral amyloid angiopathy, an aging and AD‐related microangiopathy of the CNS. Importantly, we also found a significant association with processing speed–a highly relevant cognitive measure for the aging brain. Conclusion In this work, we demonstrate associations between BBB leakage and levels of AD A/T/N biomarkers in the aging brain. Although correlation is not causation, prior mechanistic studies in mice have demonstrated that fibrinogen leakage into the CNS triggers and propagates degenerative brain pathologies, relevant to AD. This is the first in vivo translation and extension of these pathways to the aging brain. Our reported findings have implications for therapeutics, given great interest in development of therapies for BBB leakage in neurodegenerative disorders. This process may start early in the aging brain and therefore trials may consider the inclusion of preclinical disease stages.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2211627-8
detail.hit.zdb_id:
2201940-6
