Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Alzheimers Dement (Amst). 2021 Sep 27;13(1):e12240. doi: 10.1002/dad2.12240. eCollection 2021.


Introduction: This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.

Methods: Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).

Results: Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage.

Discussion: Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies.

Keywords: mediation; neurodegeneration; plasma proteomics; sex‐related difference; vascular damage.