Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

中文翻译：

---

新的阿尔茨海默病风险基因决定了小胶质细胞对淀粉样蛋白-β 的反应，但不决定对 TAU 病理学的反应。


多基因风险评分发现，没有全基因组意义的遗传变异仍然会增加患阿尔茨海默病 (AD) 的遗传风险。阈下风险位点是否以及如何转化为相关疾病途径尚不清楚。我们在这里研究 AD 风险变异在两种小鼠模型转录反应中的参与：APPswe/PS1L166P 和 Thy-TAU22。一个独特的基因表达模块，高度富集 AD 风险基因，对 Aβ 而非 TAU 病理有特异性反应。我们在此模块中确定了 7 个已确定的 AD 风险基因（APOE、CLU、INPP5D、CD33、PLCG2、SPI1 和 FCER1G）和低于全基因组显着性阈值的 11 个 AD GWAS 基因（GPC2、TREML2、SYK、GRN、SLC2A5、SAMSN1） 、PYDC1、HEXB、RRBP1、LYN 和 BLNK），当暴露于 Aβ 时，它们的表达显着上调。单个小胶质细胞测序证实，Aβ（而非 TAU）病理学诱导小胶质细胞显着转录变化，包括活化小胶质细胞比例增加。我们得出的结论是，AD 的遗传风险在功能上转化为小胶质细胞通路对 Aβ 病理学的不同反应，将 AD 遗传风险置于淀粉样蛋白通路的下游，但位于 TAU 病理学的上游。