Michael Ouk1,2, Che-Yuan Wu1,2, Jennifer S Rabin2,3,4,5, Aaron Jackson1, Jodi D Edwards6,7,8, Joel Ramirez2,9, Mario Masellis2,4, Richard H Swartz2,4,9, Nathan Herrmann2,10, Krista L Lanctôt1,2,10,11, Sandra E Black2,7,9,11, Walter Swardfager12,13,14,15. 1. Department of Pharmacology & Toxicology Room 4207, University of Toronto, Medical Sciences Building 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. 2. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. 3. Harquail Centre for Neuromodulation, Sunnybrook Research Institute, Toronto, M4N 3M5, Canada. 4. Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. 5. Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada. 6. University of Ottawa Heart Institute, University of Ottawa, Ottawa, ON, Canada. 7. School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada. 8. ICES, Ottawa, ON, Canada. 9. Canadian Partnership for Stroke Recovery, Toronto, ON, Canada. 10. Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. 11. KITE UHN Toronto Rehabilitation Institute, Toronto, ON, Canada. 12. Department of Pharmacology & Toxicology Room 4207, University of Toronto, Medical Sciences Building 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. w.swardfager@utoronto.ca. 13. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. w.swardfager@utoronto.ca. 14. Canadian Partnership for Stroke Recovery, Toronto, ON, Canada. w.swardfager@utoronto.ca. 15. KITE UHN Toronto Rehabilitation Institute, Toronto, ON, Canada. w.swardfager@utoronto.ca.
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 = 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.
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.
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