Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Cell-based polygenic risk scores predict clinical progression and prioritize network-based therapeutic targets in Alzheimer's disease.
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Sahelijo Nathan, Rajagopalan Priya, Qian Lu, Rahman Rufuto, Goldstein Daniel, Thomopoulos Sophia I, Bennett David A, Farrer Lindsay A, Stein Thor D, Shen Li, Huang Heng, Nho Kwangsik, Saykin Andrew J, Davatzikos Christos, Thompson Paul M, Tcw Julia, Jun Gyungah R
Аннотация
BACKGROUND: Late-onset Alzheimer's disease (AD) exhibits substantial biological heterogeneity. We developed a framework linking cell-type-specific polygenic risk profiles to precision medicine in AD.
METHODS: Cell-based polygenic risk scores (cbPRSs) derived from single-nucleus RNA-seq co-expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph-based PageRank algorithm and candidate drugs were validated in human-induced pluripotent stem cell (hiPSC)-derived astrocytes.
RESULTS: Cell-based PRS analysis identified two genetic risk axes independent of network cell-type labels: an apolipoprotein E (APOE)-concentrated axis (Ast-M2/Oli-M45) and an APOE-independent axis (Ast-M10/Oli-M50), which predicted accelerated progression to AD (hazard ratio: 1.25-2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High-risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the APOE-containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced APOE and complement C4 gene expression in hiPSC-derived astrocytes.
DISCUSSION: By integrating cell-based genetic risk with network-level target prioritization, this framework enables robust patient stratification and experimental target validation.
METHODS: Cell-based polygenic risk scores (cbPRSs) derived from single-nucleus RNA-seq co-expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph-based PageRank algorithm and candidate drugs were validated in human-induced pluripotent stem cell (hiPSC)-derived astrocytes.
RESULTS: Cell-based PRS analysis identified two genetic risk axes independent of network cell-type labels: an apolipoprotein E (APOE)-concentrated axis (Ast-M2/Oli-M45) and an APOE-independent axis (Ast-M10/Oli-M50), which predicted accelerated progression to AD (hazard ratio: 1.25-2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High-risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the APOE-containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced APOE and complement C4 gene expression in hiPSC-derived astrocytes.
DISCUSSION: By integrating cell-based genetic risk with network-level target prioritization, this framework enables robust patient stratification and experimental target validation.