Using 5 years of longitudinal observational data and after adjusting for potential confounders (age, education, baseline cognition, any use of drug with definite central anti-cholinergic activities, history of depression, history of diabetes mellitus), this study showed that the continuous use of H2As by African Americans aged 65 and older who were cognitively intact at baseline was associated with greater risk of developing incident cognitive impairment (OR = 2.42, 95% CI = 1.17–5.04) than for H2A nonusers.
These findings are in agreement with recent longitudinal observational analyses of 2,082 community-dwelling older adults in North Carolina.13
The North Carolina study used cognitive decline as the outcome, determined as differences in the Short Portable Mental Status Questionnaire (SPMSQ) score measured over 7 years. In this study, the use of H2As was a risk factor for subsequent cognitive decline (risk ratio = 1.51, 95% CI = 0.93–2.47). These findings are also consistent with the results from the single clinical trial evaluating the efficacy of H2As (150-mg daily dose of nazitidine) in delaying the progression of cognitive decline in older adults with AD.14
Although this trial showed no positive effects of nazitidine on any of the clinical cognitive outcome measures over the 1-year study interval, there were some trends toward deleterious effects for nazitidine on patients' memory and language.14
Nevertheless, the findings of the current study are not consistent with the results from other longitudinal and cross-sectional studies.9,11,12
In 1995, one study compared H2A exposure in pairs of siblings with and without AD.9
Siblings who used H2As for a sustained time experienced a later onset of AD than those were not exposed to any.9
Analyses of the cross-sectional data from the Cache County Study indicated similar protective effects.11
However, neither longitudinal data from the same Cache county study nor cross-sectional data from the Rotterdam Study showed an association between H2A usage and incident AD.10,12
The reasons for the inconsistencies in results between studies are not readily apparent. Populations included in these studies were different (cognitively normal subjects vs subjects at high risk for dementia, African Americans vs other populations). The study design used (cross-sectional, prospective cohort, case–control) and the outcome criteria varied between studies (defining cognitive impairment based on a screening vs comprehensive neuropsychological assessment, using incident AD vs cognitive decline). The current study included cognitively normal subjects, had a prospective design, and used incident cognitive impairment defined according to a comprehensive neuropsychological assessment. The possible different effects for the various drugs of the H2A class may also explain these inconsistent findings, although the current study had a limited number of subjects to explore these various effects. Furthermore, there were differences in the method used to determine exposure to H2As (home-based review of the medication vs survey questionnaire) and the control for potential confounders in the analysis.
The mechanism responsible for the adverse cognitive effects associated with H2As is not clear. Suggested mechanisms include vitamin B12
deficiency associated with H2A use and the potential anticholinergic effect of some H2As. Certain H2As, such as ranitidine and cimetidine, have anti-cholinergic activities that lead to the development of delirium and other cognitive deficits.26–29
H2As use could result in vitamin B12
deficiency that leads to cognitive deficit. Stomach acidity is necessary for the removal of vitamin B12
from dietary protein sources before it can be absorbed, so it might be that H2A prevents the absorption of vitamin B12
Because the body contains enough vitamin B12
stores for 2 to 5 years, a full dose of a H2A for more than 2 years might lead to vitamin B12
In the current study, the incidence of cognitive impairment was significant only in those who used H2As continuously.
This study has a number of limitations. First, the ascertainment of medication use was based on up to three interviews during the 5 years. The study did not have data on the actual medication dispensed during the 5-year follow-up period; thus, continuous use was assumed, although medication use was recorded from direct observation of the medication containers in participants' homes or from active drug lists or was based on informants' reports. Second, the study had few participants who were exposed to H2As (203 in total). Despite the limited power of this study, there was a significant relationship between H2As and incident cognitive impairment. Third, the study population was entirely African American, so generalizability with non-African-American populations is limited. Fourth, the data did not include sufficient information to allow for dose analyses. Despite these limitations, the study had a strong longitudinal design with 5 years of follow-up that allowed for the evaluation of the effect of H2A use on the incidence (but not prevalence) of cognitive impairment in an understudied cohort of African Americans with no prevalence cases of cognitive impairment. In addition, data collection permitted adjustment for potential confounders that might explain the relationship between H2As and cognition.
In conclusion, this study suggests that long-term use of H2As is associated with cognitive impairment in elderly African Americans. Because a significant number of Americans are exposed to H2As every year, with approximately 16 million prescriptions in 2005,7
the association between H2As and cognitive impairment merits further study. This proposed study would need to measure incident cognitive impairment annually or biannually using a similar accurate methodology of the Indianapolis–Ibadan project and at the same time collect drug dispensing data to capture continuous exposure to certain medications instead of self-reporting at various time points.