ArticleAlzheimer's research & therapy2026
Genome-wide investigation of synthetic rescue interactions in Alzheimer's disease implicates glial lipid and sterol metabolism.
Article in Alzheimer's research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors.
Funding
Abstract
backgroundSynthetic 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.
methodsUsing 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.
resultsAmong 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.
conclusionsOur 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.
Indexed as
Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.