Genetic evidence for protective effects of angiotensin converting enzyme against Alzheimer's disease but not other neurodegenerative diseases in European populations


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Authors
Gill, Dipender 
Abstract

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’s disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer’s 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’s 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’s disease.

Description

Abstract

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’s disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer’s 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’s 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’s disease.

Keywords
Alzheimer's disease, Cognitive aging, Cognitive Disorders/Dementia, Parkinson's disease with dementia, Vascular dementia
Journal Title
Neurology Genetics
Conference Name
Journal ISSN
2376-7839
Volume Title
Publisher
Lippincott, Williams & Wilkins
Sponsorship
Wellcome Trust and the Royal Society (204623/Z/16/Z); United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7); National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014);