Ryan David K, Karhunen Ville, Su Bowen, Traylor Matthew, Richardson Tom G, Burgess Stephen, Tzoulaki Ioanna, Gill Dipender
Clinical Pharmacology Group (D.K.R., D.G.), Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust; Clinical Pharmacology and Therapeutics Section (D.K.R., D.G.), Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London; Centre for Clinical Pharmacology and Therapeutics (D.K.R.), University College London; Department of Epidemiology and Biostatistics (V.K., B.S., I.T., D.G.), School of Public Health, Imperial College London, United Kingdom; Research Unit of Mathematical Sciences (V.K.), University of Oulu; Center for Life Course Health Research (V.K.), University of Oulu, Finland; Clinical Pharmacology (M.T.), William Harvey Research Institute, Queen Mary University of London; The Barts Heart Centre and NIHR Barts Biomedical Research Centre-Barts Health NHS Trust (M.T.), The William Harvey Research Institute, Queen Mary University London; Novo Nordisk Research Centre Oxford (M.T., T.G.R., D.G.), Old Road Campus, Oxford; Medical Research Council Integrative Epidemiology Unit (T.G.R.), University of Bristol; Medical Research Council Biostatistics Unit (S.B., D.G.), Cambridge Institute of Public Health; Cardiovascular Epidemiology Unit (S.B.), Department of Public Health and Primary Care, University of Cambridge, United Kingdom; and Department of Hygiene and Epidemiology (I.T.), University of Ioannina, Greece.
Neurol Genet. 2022 Aug 29;8(5):e200014. doi: 10.1212/NXG.0000000000200014. eCollection 2022 Oct.
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.
We performed genetic colocalization investigating an effect of cortical expression on AD risk in people of European ancestry. We further investigated whether any effect of 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.
There was genetic evidence supporting a protective effect of cortical expression on AD risk in people of European ancestry. Although higher cortical 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 expression affected risk of other neurodegenerative traits.
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.
血管紧张素转换酶（ACE）抑制剂是一类常用于治疗心力衰竭、高血压和慢性肾病的处方药。然而，先前的观察性研究显示，ACE抑制剂与阿尔茨海默病风险之间的关联方向存在矛盾。遗传学证据支持脑ACE对阿尔茨海默病（AD）具有保护作用。然而，尚不清楚这种作用是否通过血压介导，以及是否扩展到其他神经退行性疾病。
我们进行了基因共定位研究，以调查欧洲血统人群中皮质表达对AD风险的影响。我们进一步研究了表达对AD风险的任何影响是否通过血压变化介导，以及在孟德尔随机化范式中，这种影响是否扩展到帕金森病、小血管疾病或认知功能。
有遗传学证据支持欧洲血统人群中皮质表达对AD风险具有保护作用。虽然较高的皮质表达与较高的血压相关，但没有强有力的证据支持其与AD的关联是通过血压介导的，也没有证据表明表达会影响其他神经退行性特征的风险。
遗传学证据支持脑ACE表达对欧洲血统人群的AD具有保护作用，但对其他神经退行性结局没有保护作用。需要进一步开展研究，以调查ACE的治疗性抑制是否会增加阿尔茨海默病的风险。
