Discussion
This study leveraged genetic data to identify support for ACE in prevention of AD, with no strong evidence identified supporting effects of ACE on other neurodegenerative traits. While increased corticalACE expression associated with lower AD risk, there was no MR evidence supporting that genetically predicted SBP affects risk of AD.
From a mechanistic perspective, ACE has been shown to breakdown neurotoxic amyloid-beta isoform (Aβ42) to a less toxic form (Aβ40). Administration of a clinical dose of ACE inhibitor to human amyloid precursor protein transgenic mice was associated with increased brain amyloid deposition4. In humans, patients with AD have lower Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals4. Our current findings support that ACE protects against AD, although further work is required to investigate whether this is attributable to reduced amyloid aggregation or other unrelated mechanisms.
An observational study among 406 participants with mild-to-moderate AD demonstrated a reduction in cognitive decline for people receiving a centrally-acting ACE inhibitor (perindopril) compared to peripherally-acting ACE inhibitor18. Other studies have shown increased risk of incident dementia and disability associated with peripherally-acting ACE inhibitors compared to other anti-hypertensive medication19. Conflicting findings between genetic and observational studies could be explained by MR being less liable to environmental confounding and reverse causality20, due to the random allocation of genetic variants at conception.
Our current work is consistent with other genetic studies supporting a role of ACE in preventing AD and has several additional strengths. Firstly, obtaining association estimates from the MetaBrain consortium (n = 6,601 participants)10, we investigate corticalACE expression and AD risk. This dataset is significantly larger than the GTEx resource (n = 205) that has been utilised in previous work7. Secondly, we investigate whether SBP mediates the relationship between ACE and AD risk, and do not find evidence that supports this. Finally, we explore the associations of genetically proxied cortical ACE expression with other traits and do not find evidence to support that this association applies across other neurodegenerative traits.
This work also has several limitations. Clinical diagnosis of AD is challenging as there is significant overlap in symptoms with other forms of dementia, limiting the specificity of case definitions in GWAS. To explore for this, we also assessed several other neurocognitive traits. Given the absence of strong evidence of ACE effects for these outcomes, it seems likely that our findings are specific for AD risk, rather than a generic effect on dementia or cognition. As with all studies leveraging genetic data, there remains the possibility of biological pleiotropy introducing confounding. It is also not possible to extrapolate the magnitude of clinical effect or required drug exposure for ACE inhibitors to represent a real-world risk for AD. Factors such as the ability of an ACE inhibitor to cross the blood-brain-barrier may also shape AD risk and should be further studied. Furthermore, our work was based on data obtained from individuals of European genetic ancestry, and it is unclear whether these findings extend to other ethnic groups.
In summary, while ACE inhibitors have numerous indications and are the cornerstone of hypertension, chronic kidney disease and heart failure management, this study finds evidence for a beneficial effect of cerebral cortex ACE in preventing AD. It would be premature to alter current clinical practice based on this evidence, and rather these findings should encourage further research into the effect of ACE inhibitors on AD risk.