Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele

Abstract

Objective: The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD.

Methods: This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined.

Results: A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education.

Conclusion: The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.

Keywords: ACE inhibitor; Alzheimer disease; Apolipoprotein E4 allele (ApoE4); angiotensin converting enzyme (ACE).

FIGURE 1. Alzheimer disease among those with and without the ACE treatment in the absence and presence of ApoE4 allele

The percentages of AD were compared between different subgroups: in the absence of ApoE4 (ApoE4 −) or presence of ApoE4 (ApoE4 +) and further divided into no ACE inhibitor use (ACE inhibitor −) and ACE inhibitor use (ACE inhibitor +). Chi square (χ² test) was used to compare between any two subgroups or among the four subgroups. p values for the statistical significance between the two subgroups are shown. In the presence of ApoE4, those who were on an ACE inhibitor had a significantly higher number of AD cases than those who were not (χ² test: 28% versus 6%, DF = 1, χ² = 8.02, p = 0.01). Among all the elderly who were on ACE inhibitors, ApoE4 carriers had more AD cases than the ApoE4 non-carriers (χ² test: 28% versus 10%, DF = 1, χ²= 6.21, p = 0.03)

FIGURE 2. Characterization of ACE activity in the serum samples

6-µL human serum was incubated with fluorogenic substrates specific for either ACE N-domain (A) or C-domain (B) at 37°C for 24 hours and the generated fluorescence were measured. The ApoE4 status and ACE inhibitor usage for each subgroup are illustrated. Mean ± SD of fluorescence with t test used to compare the differences between any two subgroups, DF = 1 and p values for the statistical significance are shown.