Phillips Jared M, Schneider Julie A, Bennett David A, Crane Paul K, Risacher Shannon L, Saykin Andrew J, Dumitrescu Logan C, Hohman Timothy J
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Pac Symp Biocomput. 2025;30:488-503. doi: 10.1142/9789819807024_0035.
Alzheimer's disease (AD) is a polygenic disorder with a prolonged prodromal phase, complicating early diagnosis. Recent research indicates that increased astrocyte reactivity is associated with a higher risk of pathogenic tau accumulation, particularly in amyloid-positive individuals. However, few clinical tools are available to predict which individuals are likely to exhibit elevated astrocyte activation and, consequently, be susceptible to hyperphosphorylated tau-induced neurodegeneration. Polygenic risk scores (PRS) aggregate the effects of multiple genetic loci to provide a single, continuous metric representing an individual's genetic risk for a specific phenotype. We hypothesized that an astrocyte activation PRS could aid in the early detection of faster clinical decline. Therefore, we constructed an astrocyte activation PRS and assessed its predictive value for cognitive decline and AD biomarkers (i.e., cerebrospinal fluid [CSF] levels of Aβ1-42, total tau, and p-tau181) in a cohort of 791 elderly individuals. The astrocyte activation PRS showed significant main effects on cross-sectional memory (β = -0.07, p = 0.03) and longitudinal executive function (β = -0.01, p = 0.03). Additionally, the PRS interacted with amyloid positivity (p.intx = 0.02), whereby indicating that amyloid burden modifies the association between the PRS and annual rate of language decline. Furthermore, the PRS was negatively associated with CSF Aβ1-42 levels (β = -3.4, p = 0.07) and interacted with amyloid status, such that amyloid burden modifies the association between the PRS and CSF phosphorylated tau levels (p.intx = 0.08). These findings suggest that an astrocyte activation PRS could be a valuable tool for early disease risk prediction, potentially enabling intervention during the interval between pathogenic amyloid and tau accumulation.
阿尔茨海默病（AD）是一种具有漫长前驱期的多基因疾病，这使得早期诊断变得复杂。最近的研究表明，星形胶质细胞反应性增加与致病性tau蛋白积累风险较高相关，尤其是在淀粉样蛋白阳性个体中。然而，几乎没有临床工具可用于预测哪些个体可能表现出星形胶质细胞活化升高，进而易患高磷酸化tau蛋白诱导的神经变性。多基因风险评分（PRS）汇总多个基因位点的效应，以提供一个单一的连续指标，代表个体患特定表型的遗传风险。我们假设星形胶质细胞活化PRS有助于早期发现更快的临床衰退。因此，我们构建了一个星形胶质细胞活化PRS，并在791名老年人队列中评估了其对认知衰退和AD生物标志物（即脑脊液[CSF]中Aβ1-42、总tau蛋白和p-tau181水平）的预测价值。星形胶质细胞活化PRS对横断面记忆（β = -0.07，p = 0.03）和纵向执行功能（β = -0.01，p = 0.03）显示出显著的主效应。此外，PRS与淀粉样蛋白阳性存在相互作用（p.intx = 0.02），这表明淀粉样蛋白负荷会改变PRS与语言衰退年率之间的关联。此外，PRS与CSF Aβ1-42水平呈负相关（β = -3.4，p = 0.07），并与淀粉样蛋白状态相互作用，使得淀粉样蛋白负荷会改变PRS与CSF磷酸化tau蛋白水平之间的关联（p.intx = 0.08）。这些发现表明，星形胶质细胞活化PRS可能是早期疾病风险预测的有价值工具，有可能在致病性淀粉样蛋白和tau蛋白积累之间的间隔期进行干预。
