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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  = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use ( n  = 1111) [RR = 1.094,  p  = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25,  p  = 0.002), BBB-crossing ACE-Is (RR = 1.16,  p  = 0.010), and non-BBB-crossing ARBs (RR = 1.20,  p  = 0.005) 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 = 1.196,  p  = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200,  p  = 0.003), but not in carriers (RR = 1.003,  p  = 0.957). ARB use was also associated with better performance over time on the TMT-A ( B  = 2.023 s,  p  = 0.0004) and the DSST ( B  = 0.573 symbols,  p  = 0.0485), and these differences were significant among  APOE  ε4 non-carriers ( B  = 4.066 s,  p  = 0.0004; and  B  = 0.982 symbols,  p  = 0.0230; 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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13195-021-00778-8.

alzheimer's research and therapy

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