Endothelial Cells are Heterogeneous in Different Brain Regions and are Dramatically Altered in Alzheimer's Disease

Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer's disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 AD and non-AD donors each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex and primary visual cortex. Analysis of 51,586 endothelial cell nuclei revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimer's brain endothelial cell nuclei were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid beta plaques and cerebral amyloid angiopathy. This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain. ### Competing Interest Statement MEW, AW, GL, TK, RVT, KB, and EHK are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. BTH has received research funding from AbbVie as part of a collaboration agreement with The General Hospital Corporation, d/b/a Massachusetts General Hospital. BTH has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a SAB or is a consultant for AbbVie, Avrobio, Axon, Biogen, BMS Cell Signaling, Genentech, Ionis, Novartis, Seer, Takeda, the US Dept of Justice, Vigil, and Voyager. His laboratory is supported by Sponsored research agreements with AbbVie, F Prime, and research grants from the National Institutes of Health, Cure Alzheimer's Fund, Tau Consortium, and the JPB Foundation. AB, ZL, ASP, SD, and RB work on the AbbVie-Hyman Collaboration and hove no other competing interests to disclose.