Associations of neurodegenerative proteins with brain iron deposition and cognition in cerebral small vessel disease: a quantitative susceptibility mapping and plasma biomarker study

Abstract INTRODUCTION Cerebral small vessel disease (CSVD) is a common neurological disorder with limited pathology on conventional magnetic resonance imaging. This study uses quantitative susceptibility mapping (QSM) to investigate links among brain iron, plasma neurodegenerative proteins, and cognition in CSVD. METHODS This study enrolled 319 CSVD patients, grouped into CSVD‐M and CSVD‐S. Plasma proteins were measured in 178 participants, with 80 being followed up after 2 years. QSM‐based voxel‐wise analysis assessed brain iron, CSVD severity, and protein correlations. A cross‐lagged panel model was used to analyze the temporal association between plasma protein levels and brain iron levels. RESULTS In CSVD‐S, elevated QSM values in the right Rolandic operculum/superior temporal gyrus negatively correlated with plasma Aβ42 and executive function. Aβ42 also negatively correlated with QSM in cortical regions, tied to episodic memory decline. Higher baseline Aβ40 predicted increased QSM in the left putamen at follow‐up. DISCUSSION Plasma Aβ42 and Aβ40 may drive brain iron deposition and cognitive impairment in CSVD, serving as potential early biomarkers for disease progression. Highlights QSM reveals brain iron links to Aβ42, cognition in CSVD. Plasma Aβ42 correlates with iron in motor and frontal areas. High Aβ40 predicts putamen iron increase in CSVD follow‐up. Iron deposition is tied to executive, memory deficits in CSVD.