In a cohort of community-dwelling older women, this study found a weak to moderate association between anemia and cognitive decline in the domains of verbal memory and executive function. After adjustment for demographic and disease variables, and as estimated by linear random effects models, anemia was associated with poorer baseline performance in executive function but not in immediate or delayed recall. By contrast, anemia was associated with a faster rate of decline over time in memory, but not in executive function.
Most studies demonstrating an association between anemia and cognitive impairment have done so in a clinical setting, specifically in patients with congestive heart failure (26
), chronic kidney disease (27
) and cancer (28
). Of those few studies that have examined the relationship between anemia and cognition in community-dwelling populations, most have been limited to a single index of global cognitive function (29
). To our knowledge, only one study has assessed the relationship between anemia and a specific domain of cognitive function in a community-based sample. In a cross-sectional study in the Women’s Health and Aging Study II, anemia was associated with executive function performance in the worst (as opposed to best) tertile of the TMTB (6
). Our work adds to the literature in that it is prospective with a lengthy follow-up (9 years), assesses multiple domains of cognitive functioning in a community-dwelling sample, and utilizes statistical methods that account for the heterogeneity of cognitive decline within this population.
Our results could suggest that the association between anemia and cognitive decline over time is differential by domain; in our study, anemia was associated with a faster rate of decline in memory, but not in executive function. We did find, however, a significant difference between women with and without anemia in baseline executive function. It could be, therefore, that anemia also acts as a modifier of the rate of decline in executive functioning, and that the observed discrepancies may be explained by the hierarchy of cognitive decline and the timing of the study window.
Declines in executive function precede those in memory by approximately 3 years in this cohort (12
). In our study, we observed this relationship for women without anemia; executive function began to decline at baseline while memory remained stable until year 3. However, women with anemia declined in memory during the first 3 years (). The established hierarchy of decline, coupled with the observed, significant difference in baseline executive function performance between women with and without anemia, could suggest that women with anemia had declined in executive function prior to the start of the study.
We hypothesize that the rate of decline in executive function in those without
anemia seems to be accelerated during years 1-3 (as compared to those with anemia) because, at the time of study entry, women with anemia had already declined and stabilized, perhaps due to floor effects, but those without anemia were just beginning to exhibit a normative, age-related decline. We were therefore able to detect the differences in baseline function, but not in rates of decline. The differential impact of anemia on the rate of decline in memory function was captured because, at study entry, normative decline in memory function had not yet accelerated. Although those with and without anemia began the study at approximately the same level of functioning, decline was accelerated in those with anemia during years 1-3. After year 3, normal memory decline began (12
), so that the impact of anemia on the rate of decline appeared to lessen.
This hypothesis is consistent with the observed negative correlation between random effects (i.e. the correlation between the random intercept and random slope for each participant) for the TMTB. Such a correlation could suggest that those with poorer baseline function (e.g. women with anemia) declined at a slower rate over time. Furthermore, this pattern of decline and stabilization is mirrored on the HVLT. Women with anemia declined at a significantly faster rate than women without anemia on the HVLT during years 1-3. After this time, women without anemia began to decline at a faster rate. Had we begun the study at year 3, we hypothesize that our results on the HVLT would have been similar to what we observed for the TMTB.
Within an observational context, our study yields evidence of a weak to moderate association between anemia and cognitive decline. We cannot discount, however, that our results could be due to non-causal factors, such as residual confounding or reverse causality. Although an attempt was made to adjust for comorbidity in our study, categorization of some variables could have resulted in residual confounding. Additionally, more refined measures of subclinical cardiovascular disease, such as magnetic resonance imaging (MRI) for the identification of potential silent infarcts in the brain, could help to alleviate the concern of residual confounding by cardiovascular disease. Additionally, our results could potentially be explained by reverse causation. For example, changes in cognition could lead to poorer eating habits; as one cause of anemia is nutritional deficiency in iron, folate or Vitamin B12, poor diet could then cause anemia. However, in our study, the majority of women had serum Vitamin B12 levels within the normal range at baseline (6
If our results represent a true causal relationship, the mechanism by which anemia acts on the brain to reduce cognitive function remains to be elucidated. Two hypotheses have been previously proposed. First, anemia leads to brain hypo-oxygenation and consequently to cognitive decline (10
). Second, aerobic capacity, a basic measure of physical functioning, mediates the relationship between low hemoglobin levels and decreased cognitive capacity (6
The current study is limited in that numbers of women with anemia were too small to permit any stratification by race. Forty-nine percent of women with anemia were non-white, as compared to 14% of women without anemia. WHO-defined anemia is more common in African Americans than whites, and has been shown to differentially predict mortality and mobility disability by race (30
). If possible, future studies should address potential differential effects of anemia on cognitive decline by race. Additionally, we were unable to stratify by anemia type (e.g. nutritional deficiency, anemia of chronic disease or unexplained anemia). Future studies incorporating information on anemia type may yield insight into potential mechanisms by which anemia may act to cause cognitive decline.
Anemia in this study was defined by baseline hemoglobin levels. Because prevalence of anemia increases with older age (8
), it is likely that measuring anemia at a single time point resulted in an underestimate of the risk of cognitive decline associated with anemia. In future studies, we will incorporate anemia as a time-dependent covariate.
In summary, our findings support the hypothesis that anemia may be a modifier of cognitive decline over time in multiple cognitive domains in a cohort of high-functioning older women. If this relationship is causal, it is possible that treatment of anemia could prevent or postpone cognitive decline and its associated sequelae. The association between anemia and cognitive decline was weak to moderate in this study. However, because of the high prevalence of cognitive decline in older adults, any intervention that could improve cognition, even modestly at the individual level, could have a large public health impact at the population level. Because little is known about how to prevent cognitive decline in older adults, future studies of anemia and cognitive decline are warranted. Our findings are relevant to the planning of such studies, as they may help inform decisions about which instruments should be used to measure cognition; anemia was associated with poorer cognitive function in the domains of immediate recall, delayed recall and executive function. Additionally, our results could suggest that, depending on the length of the study and the age of participants, future investigators may expect to see differential relationships between anemia and specific cognitive domains.