The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

脑胆固醇代谢在阿尔茨海默病 (AD) 中的作用仍不清楚。由于血脑屏障 (BBB) 的不可渗透性，外周和脑胆固醇水平在很大程度上是独立的，这突出了研究脑胆固醇稳态在 AD 中的作用的重要性。我们首先使用巴尔的摩衰老纵向研究 (BLSA) 和宗教秩序研究 (ROS) 的两个脑尸检样本中的线性混合效应模型，测试了脑胆固醇生物合成和分解代谢的代谢物标记物是否在 AD 中发生了改变并与 AD 病理学相关联. 接下来，我们使用 ANOVA 测试在公开可用的脑组织转录组数据集中测试了脑胆固醇生物合成和分解代谢的遗传调节因子是否在 AD 中发生了改变。最后，使用区域大脑转录组数据，我们进行了基因组规模的代谢网络建模，以评估 AD 中胆固醇生物合成和分解代谢反应的变化。我们表明 AD 与胆固醇生物合成和分解代谢的普遍异常有关。使用来自帕金森病 (PD) 脑组织样本的转录组学数据，我们发现在 AD 中发现的基因表达改变在 PD 中没有观察到，这表明这些变化可能是 AD 特有的。我们的研究结果表明，胆固醇从头生物合成减少可能是对酶促胆固醇分解代谢受损和流出的反应，以维持 AD 中的脑胆固醇水平。这伴随着非酶促产生的细胞毒性氧化甾醇的积累。