Key result
Cortical ACE expression linked to lower Alzheimer disease risk independent of blood pressure.
Why the study?
Previous observational studies showed conflicting associations between ACE inhibitors and Alzheimer disease risk, and it is unclear if cerebral ACE's protective effect is mediated through blood pressure or extends to other neurodegenerative diseases.
Does cortical ACE expression affect the risk of Alzheimer disease and other neurodegenerative diseases in people of European ancestry?
Observational
Does cortical ACE expression affect the risk of Alzheimer disease and other neurodegenerative diseases in people of European ancestry?
Genetic evidence suggests that higher cerebral ACE expression protects against Alzheimer disease, raising questions about the cognitive safety of therapeutic ACE inhibition.
Cerebral ACE expression may protect against AD independent of BP; leaves open whether ACE inhibition raises Alzheimer risk.
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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Ryan et al. (2022) conducted an observational in Alzheimer disease. Cortical ACE expression was evaluated on Alzheimer disease risk. Cortical ACE expression was genetically associated with a protective effect against Alzheimer disease risk in people of European ancestry, an effect not mediated by blood pressure.
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