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.