The use of angiotensin-converting enzyme inhibitors vs. angiotensin receptor blockers and cognitive decline in Alzheimer’s disease: the importance of blood-brain barrier penetration and APOE ε4 carrier status

Abstract

Background The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition. Methods Participants in the National Alzheimer’s Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer’s disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised – Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein ( APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers. Results Among 1689 participants with AD, ARB use ( n \u2009=\u2009578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28\u2009years compared with ACE-I use ( n \u2009=\u20091111) [RR\u2009=\u20091.094, p \u2009=\u20090.0327]; specifically, users of BBB-crossing ARBs (RR\u2009=\u20091.25, p \u2009=\u20090.002), BBB-crossing ACE-Is (RR\u2009=\u20091.16, p \u2009=\u20090.010), and non-BBB-crossing ARBs (RR\u2009=\u20091.20, p \u2009=\u20090.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR\u2009=\u20091.196, p \u2009=\u20090.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR\u2009=\u20091.200, p \u2009=\u20090.003), but not in carriers (RR\u2009=\u20091.003, p \u2009=\u20090.957). ARB use was also associated with better performance over time on the TMT-A ( B \xa0=\u20092.023\u2009s, p \u2009=\u20090.0004) and the DSST ( B \u2009=\u20090.573 symbols, p \u2009=\u20090.0485), and these differences were significant among APOE ε4 non-carriers ( B \u2009=\u20094.066\u2009s, p \u2009=\u20090.0004; and B \u2009=\u20090.982 symbols, p \u2009=\u20090.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers. Conclusions Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.