University of Oulu

Ryan, D. K., Karhunen, V., Su, B., Traylor, M., Richardson, T. G., Burgess, S., Tzoulaki, I., & Gill, D. (2022). Genetic evidence for protective effects of angiotensin-converting enzyme against alzheimer disease but not other neurodegenerative diseases in european populations. Neurology Genetics, 8(5), e200014.

Genetic evidence for protective effects of angiotensin-converting enzyme against alzheimer disease but not other neurodegenerative diseases in European populations

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Author: Ryan, David K.1,2,3; Karhunen, Ville4,5,6,; Su, Bowen4;
Organizations: 1Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George’s University Hospitals NHS Foundation Trust
2Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George’s, University of London
3Centre for Clinical Pharmacology and Therapeutics, University College London
4Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom
5Research Unit of Mathematical Sciences, University of Oulu
6Center for Life Course Health Research, University of Oulu, Finland
7Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London
8The Barts Heart Centre and NIHR Barts Biomedical Research Centre-Barts Health NHS Trust, The William Harvey Research Institute, Queen Mary University London
9Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford
10Medical Research Council Integrative Epidemiology Unit, University of Bristol
11Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health
12Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
13Department of Hygiene and Epidemiology, University of Ioannina, Greece
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.4 MB)
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Language: English
Published: Wolters Kluwer, 2022
Publish Date: 2023-03-10


Background and objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases.

Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm.

Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits.

Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.

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Series: Neurology. Genetics
ISSN: 2376-7839
ISSN-E: 2376-7839
ISSN-L: 2376-7839
Volume: 8
Issue: 5
Article number: e200014
DOI: 10.1212/NXG.0000000000200014
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3111 Biomedicine
Funding: S. Burgess is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). This research was funded by United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and was supported by the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014).
Copyright information: © 2022 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution Licence 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.