Elevated sulfides are associated with cognitive dysfunction and brain atrophy in Alzheimer's disease and related dementias

Emerging evidence indicates that vascular stress is an important contributor to the pathophysiology of Alzheimer's disease and related dementias (ADRD). Hydrogen sulfide (H2S) and its metabolites (acid-labile (e.g., iron-sulfur clusters) and bound (e.g., per-, poly-sulfides)) have been shown to regulate both vascular and neuronal homeostasis. We recently reported that elevated plasma sulfides were associated with cognitive dysfunction and microvascular disease in ADRD; here we extend our previous work to show associations between elevated sulfides and magnetic resonance-based metrics of brain atrophy and white matter integrity. Elevated bound sulfides were associated with decreased measures of gray matter volume, while increased acid labile sulfides were associated with measures of decreased white matter integrity and increased ventricular volume. These findings are consistent with a ‘toxic’ sulfide model of ADRD. Our results are consistent with a compensatory sulfide response to oxidative stress.