Scavenger receptors associate with Alzheimer's pathology, cholesterol metabolism and synaptic dysfunction

This study investigated relationships between cerebrospinal fluid (CSF) scavenger receptors and early Alzheimer's disease (AD) pathology in cognitively unimpaired older adults at elevated familial risk, with complementary analyses in autopsied frontal cortex. In the PREVENT-AD cohort, CSF levels of the scavenger receptors MSR1, SCARB2, and SCARF2 were examined in relation to AD biomarkers and synaptic proteins. Complementary analyses, with the same scavenger receptors, used frontal cortex tissue from the Douglas-Bell Canada Brain Bank and targeted sterol/oxysterol mass spectrometry. Linear regression, longitudinal mixed-effects models, pathway enrichment, and mediation analyses were performed. Higher CSF concentrations of MSR1, SCARB2, and SCARF2 were strongly associated with synaptic markers (SNAP25, SYT1, GAP43), with SCARB2 showing the strongest relationships. Associations with Tau biomarkers (t-Tau and p-Tau181) were consistently stronger than those with Aβ species, and baseline receptor levels correlated with longitudinal increases in p-Tau181 over up to 12 years. In autopsied cortex, MSR1 was increased and SCARF2 decreased in AD, while APOB, MSR1 and SCARB2 were associated specific oxysterol levels. Proteomic enrichment linked APOB to vascular and extracellular matrix pathways, whereas scavenger receptor-associated proteins were enriched for synaptogenesis, myeloid activation, and MAPK/phosphorylation signaling. Mediation analyses showed by correlation that scavenger receptors, particularly SCARB2, partially or fully mediated numerous associations between Tau biomarkers and synaptic markers (SNAP25, SYT1 and GAP43). These findings identify MSR1, SCARB2, and SCARF2 as potential integrators of lipid, immune, and synaptic processes in early AD and highlight SCARB2 as a possible mediator of Tau-associated synaptic vulnerability, supporting further mechanistic and cell type-specific investigation.