Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker of Alzheimer’s disease (AD), with higher blood GFAP levels linked to faster cognitive decline, particularly among individuals with high brain amyloid burden. However, few studies have examined brain GFAP expression to clarify if peripheral associations reflect brain changes. This study aimed to correlate region-specific GFAP mRNA expression (n = 917) and protein abundance (n=386) with diverse neuropathological measures at autopsy in the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and to characterize the interaction between brain GFAP and brain amyloid burden on downstream outcomes. We assessed GFAP gene expression in the dorsolateral prefrontal cortex, caudate nucleus, and posterior cingulate cortex with respect to core AD pathology (amyloid-β and tau), cerebrovascular (microinfarcts, macroinfarcts, and cerebral amyloid angiopathy [CAA]), proteinopathic (TDP-43, Lewy bodies), and cognitive outcomes. These associations were further examined at the protein level using tandem-mass tag proteomic measurements from the dorsolateral prefrontal cortex. We also assessed GFAP interactions with AD neuropathology on downstream outcomes. Cortical GFAP gene and protein expression were significantly upregulated in participants with a neuropathologically confirmed AD diagnosis at autopsy (all P_FDR < 3.5e−4), but not in individuals positive for tau pathology and negative for amyloid pathology (all P_FDR > 0.05). Higher cortical GFAP levels were associated with increased amyloid pathology, CAA pathology, and faster cognitive decline (all P_FDR < 3.3e−3). GFAP’s associations with phosphorylated tau burden and cognition were influenced by amyloid burden, being most pronounced among amyloid-positive individuals, confirming previous in vivo biomarker observations. No associations were observed between GFAP gene expression and outcomes in the caudate nucleus. Our results support previous biomarker findings and suggest that higher brain GFAP levels are associated with higher brain amyloid burden and faster cognitive decline among amyloid-positive individuals.

血浆神经胶质纤维酸性蛋白 （GFAP） 是阿尔茨海默病 （AD） 的一种新兴生物标志物，较高的血液 GFAP 水平与更快的认知能力下降有关，尤其是在脑淀粉样蛋白负荷高的个体中。然而，很少有研究检查大脑 GFAP 表达以阐明外周关联是否反映了大脑变化。本研究旨在将区域特异性 GFAP mRNA 表达 （n = 917） 和蛋白质丰度 （n=386） 与宗教秩序研究和匆忙记忆与衰老项目 （ROS/MAP） 中尸检时的各种神经病理学指标相关联，并表征脑 GFAP 和脑淀粉样蛋白负荷之间的相互作用对下游结果的影响。我们评估了背外侧前额叶皮层、尾状核和后扣带皮层中 GFAP 基因在核心 AD 病理学 （淀粉样蛋白-β 和 tau）、脑血管 （微梗死、大梗死和脑淀粉样血管病 [CAA]）、蛋白质病 （TDP-43，路易体） 和认知结局方面的表达。使用来自背外侧前额叶皮层的串联质量标签蛋白质组学测量在蛋白质水平上进一步检查了这些关联。我们还评估了 GFAP 与 AD 神经病理学对下游结局的相互作用。在尸检时经神经病理学证实为 AD 的参与者中，皮质 GFAP 基因和蛋白表达显著上调 （均 P_FDR < 3.5e−4），但在 tau 病理阳性和淀粉样蛋白病理阴性的个体中未上调 （均 P_FDR > 0.05）。较高的皮质 GFAP 水平与淀粉样蛋白病理学、CAA 病理学和更快的认知能力下降相关 （均 P_FDR < 3.3e-3）。 GFAP 与磷酸化 tau 负荷和认知的关联受淀粉样蛋白负荷的影响，在淀粉样蛋白阳性个体中最为明显，证实了先前的体内生物标志物观察。未观察到 GFAP 基因表达与尾状核结局之间的关联。我们的结果支持以前的生物标志物发现，并表明较高的大脑 GFAP 水平与淀粉样蛋白阳性个体较高的脑淀粉样蛋白负荷和更快的认知能力下降有关。