Introduction
Alzheimer’s disease (AD) is a leading cause of morbidity worldwide and its prevalence is projected to increase in line with the aging global population1. Several pre-clinical and observational studies have implicated the role of central nervous system angiotensin converting enzyme (ACE) levels in the pathogenesis of AD. Cerebral ACE, and downstream product angiotensin II, are increased in patients with AD and promote neuroinflammatory cytokines, reduce acetylcholine release and attenuate cerebral blood flow – all factors implicated in the development of AD2. Animal models have shown that hypertensive rats treated with centrally acting ACE inhibitors (e.g. captopril, perindopril), but not hydralazine, have significantly lower age-related impairment in learning and memory, regardless of changes in blood pressure3. Observational data also supports the neuroprotective role of central-acting ACE-inhibitors compared to predominantly peripherally acting ACE-inhibitors2,4.
On the contrary, there is also some evidence that ACE may serve in preventing AD. For example, in vitro studies have supported that ACE degrades amyloid-β plaques, a pathological hallmark of AD5. Animal AD models with heterozygous deletion of the ACE gene demonstrated that a decrease in ACE levels promoted amyloid-β deposition and increased the number of apoptotic neurons4. At present, there is therefore uncertainty surrounding the role of ACE-inhibitors in the pathogenesis of AD.
Recent genetic evidence has identified the ACE gene as a locus of interest in the development of AD6. Bivariate GWAS and colocalisation studies suggest that the ACE gene may mediate an association between blood pressure traits and AD risk, with the allele associated with lower SBP also associated with higher AD risk. Tissue-specific expression has demonstrated that higher cerebellarACE expression has a positive association with AD risk7. By extension, this implicates a possible detrimental effect of centrally acting pharmacological ACE inhibition on AD risk. This is of direct clinical relevance as ACE inhibitors are one of the most commonly prescribed anti-hypertensive agents and are oftentimes commenced as a first-line medication in younger patients. Therefore, it is imperative to understand any potential long-term effect of ACE modulation on risk of later life neurodegenerative diseases.
To further explore the relationship between ACE and neurodegenerative diseases, we advance previous work by performing three-way colocalization analyses for ACE gene expression in the cortex, systolic blood pressure (SBP) and AD risk. This approach enables us to identify a genetic proxy for the effect of ACE inhibitors that cross the blood-brain barrier, and explore its association with risk of AD and other neurodegenerative diseases. Finally, we assess whether any association could be mediated by effects of SBP on AD risk. In this way, we elucidate the complex interplay between ACE and AD, and assess the potential effect of ACE-inhibition on neurodegenerative disease risk more widely.