ACE Inhibitors and Alzheimer's Disease Progression
ACE Inhibitors and Alzheimer's Disease Progression
The Réseau sur la Maladie d'Alzheimer Français (REAL.FR) cohort is a 4-year prospective multicenter cohort study of 686 individuals with AD recruited in 16 specialized memory clinics in France between April 2000 and October 2002. A detailed protocol has been published elsewhere. Briefly, the study examined ambulatory community-dwelling individuals diagnosed with probable AD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria and who were considered to have mild to moderately severe AD according to Mini-Mental State Examination (MMSE) score. To be included, individuals needed to have the support of an informal caregiver. At inclusion, each individual underwent a complete investigation including brain computed tomography (CT). Individuals with severe dementia (MMSE score <10) or a life expectancy of less than 12 months were excluded. The follow-up of this cohort included biannual evaluations of participants using a standardized protocol.
This study received ethical approval from the Advisory Committee for the Protection of Persons participating in Biomedical Research. Written informed consent was obtained from all participants or guardians of participants.
A memory expert physician conducted inclusion and semiannual clinical assessments, which included a neurogeriatric evaluation. Information was gathered from the caregiver.
Assessment of Cognitive Function Cognitive decline was assessed using the MMSE score obtained at baseline and every 6 months by a trained neuropsychologist. This scale is robust and appropriate in evaluating clinically meaningful cognitive decline.
Antihypertensive Drugs Information on use of drugs was obtained twice a year throughout the study. A trained nurse ascertained medication use through examination of medical prescriptions. Analytical variables were created for use of ACE-Is, beta-blockers, calcium-channel blockers, thiazides, and central and peripheral alpha-blockers. Continuous users included participants who had reported use of ACE-Is at each twice-yearly follow-up visit and participants with missing data for drug use at one or more follow-up visits who had reported use of ACE-Is at all other visits. Intermittent users included those who discontinued ACE-I drugs during the study or those who started taking ACE-Is at any follow-up visit. Continuous or intermittent users of other drugs were defined as those who reported use of beta-blockers, calcium-channel blockers, thiazides, or alpha-blockers but not ACE-Is at one or more follow-up visits. For the present analyses, first, 70 participants receiving angiotensin II receptor blockers (ARBs) were excluded from analyses to examine the "pure" effect of ACE-Is on cognition. In a second step, these 70 participants were also included in the analysis.
Assessment of Covariates The following covariates were considered in the present analyses to be potentially confounding:
Sociodemographic characteristics: age, sex, education (≤primary school vs ≥secondary school).
Clinical conditions: Information on comorbidities (chronic obstructive pulmonary disease (asthma, chronic bronchitis, pulmonary emphysema), sensory impairment (moderate or severe hearing or visual loss), gastrointestinal disease, renal failure, genital or urinary disease, musculoskeletal disease, endocrine disease, alcoholism, and cancer) was collected at baseline and at every 6-month visit. The number of comorbidities was categorized as zero, one, and two or more 2 clinical conditions.
Therapy: AD treatment was recorded according to the Anatomical Therapeutic Chemical coding system. Disability measured according to the activity of daily living scale. This index ranks capacity to perform six functional tasks: bathing, dressing, toileting, transferring, continence, and feeding. Each item is graded on level of dependence. A total score of 6 indicates full function, and 0 indicates severe disability.
Behavioral and psychiatric symptoms (delusions, hallucinations, agitation or aggression, dysphoria or depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behavior, and nighttime and appetite disturbances) were measured using the Neuropsychiatric Inventory.
Vascular diseases and cardiovascular risk factors (CVRFs): baseline cardiovascular disease (heart failure, angina pectoris, myocardial infarction, atrial fibrillation) and history of diabetes mellitus, hypertension, and hypercholesterolemia were reported based on information including self- and proxy reports, reports from the primary care physician, present and past medical treatments, review of medical records, and medical signs and symptoms. The presence of CVRF was considered independently of the other comorbidities because of its association with ACE-I treatment and because CVRFs are well-known risk factors for developing dementia. Participants were judged to be hypertensive at baseline on the basis of self-report or if they had baseline systolic blood pressure of 140 mmHg or greater or diastolic blood pressure of 90 mmHg or greater. Blood pressure was measured at each follow-up visit according to a standardized protocol. Hypertension during follow-up was defined as systolic blood pressure of 140 mmHg or greater or diastolic blood pressure of 90 mmHg or greater. Participants were instructed to take all their drugs (antihypertensive and others) as usual the day of the clinic visit, so reported blood pressure, obtained at approximately the same hour (in the morning) for all participants was assumed to be with treatment.
During follow-up, information on hospitalizations occurred during the past 6 months (and the cause for each event) was recorded.
To compare the baseline characteristics of the four groups, according to antihypertensive drug use, chi-square or Fisher exact (for expected values <5) tests for categorical variables, Fisher tests for quantitative variables with Gaussian (normal) distributions, and nonparametric tests (Kruskal-Wallis test) for quantitative variables without normal distributions were used. P-values were based on two-sided tests and were considered statistically significant if P < .05. To assess differences in 4-year change on the MMSE between the four groups, linear mixed-effects models with random intercept and random slope (to take into account the heterogeneity of baseline scores and individual slopes over time) were used. Time, time squared and time cubed were introduced as continuous variables in years to identify the best slope of MMSE over time. The advantage of this approach is that it used all available data and adjusted results on the basis of correlations between outcomes and predictor variables. Thus, it was possible to obtain unbiased estimates in the presence of missing data.
Two models of adjustment were used. Model 1 was an unadjusted model and included antihypertensive drug use, time, and the interaction term of antihypertensive drug use by time as fixed effects. Model 2 was adjusted including the same terms as Model 1 with the addition of potential confounders and their interaction with time. Confounding variables potentially influencing the rate of cognitive decline in individuals with AD were tested in univariate linear mixed-effects models with random intercept and random slope: number of comorbidities; history of hypertension, diabetes mellitus, and cardiovascular disease; hospitalizations for stroke or transient ischemic attack during follow-up; vascular brain lesions on CT at baseline; and AD-specific treatment over time. Only variables associated with rate of cognitive decline in univariate analyses (using P < .05 as cutoff for significance for slope, intercept, or both) were considered in the adjusted models. These covariates were age, sex (and its interaction with time), and education. The presence of hypertension at baseline and at each biannual visit during 4-year follow-up (and its interaction with time) was also added as an adjustment variable in Model 2. Age was modeled using categories (<75, 75–80, 81–84, ≥85) to avoid the log-linear relationship between age as a continuous variable and the linear mixed function. The effect of any use of ACE-Is (n = 118) was also compared with no use of ACE-Is (n = 498) over the 4 years of the study. In secondary analyses, the 70 participants receiving ARBs were included in Model 2. Statistical analyses were performed using SAS 9.3 software (SAS Institute, Inc., Cary, NC).
Methods
Study Design and Participants
The Réseau sur la Maladie d'Alzheimer Français (REAL.FR) cohort is a 4-year prospective multicenter cohort study of 686 individuals with AD recruited in 16 specialized memory clinics in France between April 2000 and October 2002. A detailed protocol has been published elsewhere. Briefly, the study examined ambulatory community-dwelling individuals diagnosed with probable AD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria and who were considered to have mild to moderately severe AD according to Mini-Mental State Examination (MMSE) score. To be included, individuals needed to have the support of an informal caregiver. At inclusion, each individual underwent a complete investigation including brain computed tomography (CT). Individuals with severe dementia (MMSE score <10) or a life expectancy of less than 12 months were excluded. The follow-up of this cohort included biannual evaluations of participants using a standardized protocol.
This study received ethical approval from the Advisory Committee for the Protection of Persons participating in Biomedical Research. Written informed consent was obtained from all participants or guardians of participants.
Data Collection
A memory expert physician conducted inclusion and semiannual clinical assessments, which included a neurogeriatric evaluation. Information was gathered from the caregiver.
Assessment of Cognitive Function Cognitive decline was assessed using the MMSE score obtained at baseline and every 6 months by a trained neuropsychologist. This scale is robust and appropriate in evaluating clinically meaningful cognitive decline.
Antihypertensive Drugs Information on use of drugs was obtained twice a year throughout the study. A trained nurse ascertained medication use through examination of medical prescriptions. Analytical variables were created for use of ACE-Is, beta-blockers, calcium-channel blockers, thiazides, and central and peripheral alpha-blockers. Continuous users included participants who had reported use of ACE-Is at each twice-yearly follow-up visit and participants with missing data for drug use at one or more follow-up visits who had reported use of ACE-Is at all other visits. Intermittent users included those who discontinued ACE-I drugs during the study or those who started taking ACE-Is at any follow-up visit. Continuous or intermittent users of other drugs were defined as those who reported use of beta-blockers, calcium-channel blockers, thiazides, or alpha-blockers but not ACE-Is at one or more follow-up visits. For the present analyses, first, 70 participants receiving angiotensin II receptor blockers (ARBs) were excluded from analyses to examine the "pure" effect of ACE-Is on cognition. In a second step, these 70 participants were also included in the analysis.
Assessment of Covariates The following covariates were considered in the present analyses to be potentially confounding:
Sociodemographic characteristics: age, sex, education (≤primary school vs ≥secondary school).
Clinical conditions: Information on comorbidities (chronic obstructive pulmonary disease (asthma, chronic bronchitis, pulmonary emphysema), sensory impairment (moderate or severe hearing or visual loss), gastrointestinal disease, renal failure, genital or urinary disease, musculoskeletal disease, endocrine disease, alcoholism, and cancer) was collected at baseline and at every 6-month visit. The number of comorbidities was categorized as zero, one, and two or more 2 clinical conditions.
Therapy: AD treatment was recorded according to the Anatomical Therapeutic Chemical coding system. Disability measured according to the activity of daily living scale. This index ranks capacity to perform six functional tasks: bathing, dressing, toileting, transferring, continence, and feeding. Each item is graded on level of dependence. A total score of 6 indicates full function, and 0 indicates severe disability.
Behavioral and psychiatric symptoms (delusions, hallucinations, agitation or aggression, dysphoria or depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behavior, and nighttime and appetite disturbances) were measured using the Neuropsychiatric Inventory.
Vascular diseases and cardiovascular risk factors (CVRFs): baseline cardiovascular disease (heart failure, angina pectoris, myocardial infarction, atrial fibrillation) and history of diabetes mellitus, hypertension, and hypercholesterolemia were reported based on information including self- and proxy reports, reports from the primary care physician, present and past medical treatments, review of medical records, and medical signs and symptoms. The presence of CVRF was considered independently of the other comorbidities because of its association with ACE-I treatment and because CVRFs are well-known risk factors for developing dementia. Participants were judged to be hypertensive at baseline on the basis of self-report or if they had baseline systolic blood pressure of 140 mmHg or greater or diastolic blood pressure of 90 mmHg or greater. Blood pressure was measured at each follow-up visit according to a standardized protocol. Hypertension during follow-up was defined as systolic blood pressure of 140 mmHg or greater or diastolic blood pressure of 90 mmHg or greater. Participants were instructed to take all their drugs (antihypertensive and others) as usual the day of the clinic visit, so reported blood pressure, obtained at approximately the same hour (in the morning) for all participants was assumed to be with treatment.
During follow-up, information on hospitalizations occurred during the past 6 months (and the cause for each event) was recorded.
Statistical Analyses
To compare the baseline characteristics of the four groups, according to antihypertensive drug use, chi-square or Fisher exact (for expected values <5) tests for categorical variables, Fisher tests for quantitative variables with Gaussian (normal) distributions, and nonparametric tests (Kruskal-Wallis test) for quantitative variables without normal distributions were used. P-values were based on two-sided tests and were considered statistically significant if P < .05. To assess differences in 4-year change on the MMSE between the four groups, linear mixed-effects models with random intercept and random slope (to take into account the heterogeneity of baseline scores and individual slopes over time) were used. Time, time squared and time cubed were introduced as continuous variables in years to identify the best slope of MMSE over time. The advantage of this approach is that it used all available data and adjusted results on the basis of correlations between outcomes and predictor variables. Thus, it was possible to obtain unbiased estimates in the presence of missing data.
Two models of adjustment were used. Model 1 was an unadjusted model and included antihypertensive drug use, time, and the interaction term of antihypertensive drug use by time as fixed effects. Model 2 was adjusted including the same terms as Model 1 with the addition of potential confounders and their interaction with time. Confounding variables potentially influencing the rate of cognitive decline in individuals with AD were tested in univariate linear mixed-effects models with random intercept and random slope: number of comorbidities; history of hypertension, diabetes mellitus, and cardiovascular disease; hospitalizations for stroke or transient ischemic attack during follow-up; vascular brain lesions on CT at baseline; and AD-specific treatment over time. Only variables associated with rate of cognitive decline in univariate analyses (using P < .05 as cutoff for significance for slope, intercept, or both) were considered in the adjusted models. These covariates were age, sex (and its interaction with time), and education. The presence of hypertension at baseline and at each biannual visit during 4-year follow-up (and its interaction with time) was also added as an adjustment variable in Model 2. Age was modeled using categories (<75, 75–80, 81–84, ≥85) to avoid the log-linear relationship between age as a continuous variable and the linear mixed function. The effect of any use of ACE-Is (n = 118) was also compared with no use of ACE-Is (n = 498) over the 4 years of the study. In secondary analyses, the 70 participants receiving ARBs were included in Model 2. Statistical analyses were performed using SAS 9.3 software (SAS Institute, Inc., Cary, NC).