Genome-wide investigation of synthetic rescue interactions in Alzheimer’s disease implicates glial lipid and sterol metabolism

Synthetic rescue (SR) interactions, where a disease-promoting alteration in one gene is compensated by a secondary alteration in another gene, remain largely unexplored in Alzheimer’s disease (AD). Here, we performed a genome-wide investigation of SR gene pairs that mitigate the genetic risk of AD. Using whole exome sequencing (WES) data from the Alzheimer’s Disease Sequencing Project (ADSP) participants (n = 9,895), we first identified AD risk genes by two complementary methods: Single-variant analysis and Gene-wise Variant Burden (GVB) analysis. We then performed a genome-wide log odds ratio comparison to identify candidate SR gene pairs and further prioritized them via Cox proportional hazards regression. Validation and single-cell analyses were performed in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Among the 37 candidate SR gene pairs, 27 pairs showing significant protective effects (HR < 1, FDR < 0.05) in Cox regression were prioritized. Notably, NR4A1, SULT2A1, AKR1C4, OR52H1, ARMC7, RBAK-RBAKDN, DMC1 for APOE, and LPP, ZNF510 for TREM2 reduced the hazard of AD onset by more than half. The prioritized SR pairs were validated in ROSMAP cohort using a synthetic rescue score (SRS) that quantifies the cumulative protective effect of rescuer genes against risk gene burden. We observed that SRS was significantly associated with delayed AD onset. In addition, SRS was significantly associated with better cognitive outcomes but not with neuropathological burden, suggesting that SR pairs may confer cognitive resilience. Functional enrichment and single cell analyses highlighted lipid and sterol metabolism in oligodendrocytes and astrocytes as a plausible biological mechanism of SR interactions in AD. Our study extends understanding of SR interactions in AD, implicating glial lipid and sterol metabolism as a key underlying mechanism and providing novel insights for therapeutic strategies beyond targeting AD risk loci.