Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related Dementias

痴呆症是一个重大的公共卫生问题，具有重大的个人、社会和经济负担，影响着全世界4700多万人，迄今尚无治愈方法。痴呆的主要类型包括阿尔茨海默病（AD）、路易体痴呆（LBD）和额颞叶痴呆（FTD），它们表现出不同且重叠的病理、神经和细胞特征，但其详细的分子特征仍未被表征。在这里，我们系统地分析了AD、LBD、FTD和健康衰老的分子特征，在单细胞水平上，跨越特征、个体、大脑区域、细胞类型、年龄、性别和疾病严重程度。我们使用遗传、表观基因组和转录谱，利用scRNA-seq和scATAC-seq在单细胞（sc）水平上生成了大约150万个全基因组图谱，这些图谱来自宗教秩序研究和记忆与衰老项目（ROS MAP）队列的768个死后大脑样本。我们在全基因组测序的遗传变异背景下分析所得数据集，并从丰富的纵向分析和认知评估中分析表型变异，使我们能够发现在AD和ADRD中起因果作用的基因，控制区，途径，细胞类型和大脑区域，以及它们如何在年龄，性别和性状中变化。由此产生的数据集将通过提供详细的治疗靶点和预测它们起作用的具体条件，帮助指导寻找新的治疗方法。

Dementia is a major public health problem with substantial personal, social, and financial burden, affecting more than 47 million people worldwide, with no cure to date. The major types of dementia include Alzheimer’s disease (AD), Lewy Body dementia (LBD), and frontotemporal dementia (FTD), which show distinct and overlapping pathological, neurological, and cellular signatures, but their detailed molecular signatures remain uncharacterized. Here, we systematically profile the molecular signatures of AD, LBD, FTD, and healthy aging, at the single-cell level, across traits, individuals, brain regions, cell types, age, sex, and disease severity. We use genetic, epigenomic, and transcriptional profiles, generating a total of ~1.5 million genome-wide maps at the single-cell (sc) level using scRNA-seq and scATAC-seq across 768 post-mortem brain samples from the Religious Order Study and Memory and Aging Project (ROS MAP) cohorts. We analyze the resulting datasets in the context of genetic variation from whole-genome sequencing, and phenotypic variation from rich longitudinal profiling and cognitive evaluations, enabling us to discover genes, control regions, pathways, cell types, and brain regions playing causal roles in AD and ADRD, and how they vary across age, sex, and traits. The resulting datasets will help guide the search for new therapeutics, by providing detailed therapeutic targets, and the specific conditions where they are predicted to act.