@article{e6b9722b67284c3baca4efe886689f9f,
title = "Retinal imaging demonstrates reduced capillary density in clinically unimpaired apoe ε4 gene carriers",
abstract = "Introduction: Apolipoprotein E (APOE) ε4, the strongest non-Mendelian genetic risk factor for Alzheimer{\textquoteright}s disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE ε4 effects on human central nervous system capillaries. Methods: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype–phenotype associations. Results: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature. Discussion: These results suggest that APOE ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.",
keywords = "Alzheimer{\textquoteright}s disease, Apolipoprotein E ε4, Capillary rarefaction, Preclinical biomarker, Preclinical disease, Vascular contributions to Alzheimer{\textquoteright}s disease",
author = "Elahi, {Fanny M.} and Ashimatey, {Senyo B.} and Bennett, {Daniel J.} and Walters, {Samantha M.} and Joie, {Renaud La} and Xuejuan Jiang and Amy Wolf and Yann Cobigo and Staffaroni, {Adam M.} and Rosen, {Howie J.} and Miller, {Bruce L.} and Rabinovici, {Gil D.} and Kramer, {Joel H.} and Green, {Ari J.} and Kashani, {Amir H.}",
note = "Funding Information: We would like to thank patients and their families whose help and participation made this work possible. We also thank the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), for sample storage, which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA). We thank Dr. William Jagust for conducting PiB scans. Additionally, we thank contributors who collected samples used in this study, in addition to Drs. Eliana Marisa Ramos and Giovanni Coppola and Ms. Anna Karydas for assistance in obtaining genotypes, as well as the funding sources mentioned below for grants that have supported our work. Funding Information: The authors have no conflicts of interest to disclose with respect to the content presented in this manuscript. A.H.K. and F.M.E. note that they have received equipment from Carl Zeiss Meditec Inc in support of this study. In addition, A.H.K. has received grants, honoraria, and financial support from Carl Zeiss Meditec. G.D.R. receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, and Life Molecular Imaging. G.D.R. has also received honoraria as a consultant for Axon Neurosciences, Eisai, and Merck, and speaking honoraria from GE Healthcare. Funding Information: This study was supported by the following grants: Larry L. Hill-blom start-up (2019A012SUP) and American Academy of Neurology fellowship to F.M.E.; UH2NS100614, UH3NS100614, R01EY030564, and unrestricted funding from Research to Prevent Blindness to the USC Department of Ophthalmology to A.H.K.; That Man May See and Hellman family funding to A.J.G., UH2NS100608, UH3NS100608, and Larry L. Hillblom Network Grant (2014-A-004-NET) to J.H.K.; NIH-NIA ADRC (P50 AG023501) and PPG (P01AG019724) to B.L.M., R01 (AG045611) to G.D.R., R01(s) (AG032289, AG048234), an Alzheimer{\textquoteright}s Association fellowship (AARF-16-443577) to R.L.J., and Larry L. Hillblom fellowship grant (2018-A-025-FEL) and NIH-NIA (K23AG061253) to A.M.S. Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer{\textquoteright}s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer{\textquoteright}s Association.",
year = "2021",
doi = "10.1002/dad2.12181",
language = "English (US)",
volume = "13",
journal = "Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring",
issn = "2352-8729",
publisher = "John Wiley and Sons Inc.",
number = "1",
}