In nearly 900 older persons without dementia examined annually for up to 5 years, low and high hemoglobin levels were associated with incident AD. Our complementary finding that low and high hemoglobin levels were associated with the rate of cognitive decline in analyses that controlled for baseline level of cognition suggests that the association of hemoglobin with incident AD is not likely the result of diagnostic misclassification. The results point to the possibility of common pathophysiologic processes between hemoglobin abnormalities and brain dysfunction in elders.
A novel feature of this study is the ability to examine the effects of the entire range of hemoglobin levels on hazard of developing AD. To our knowledge, prior studies only examined clinically low hemoglobin levels (anemia) and found mixed results. A retrospective cohort study of persons over age 65 with anemia found no increased hazard for AD over 5 years of follow-up9
while a prospective study in an older Swedish cohort found that anemia was associated with a 2-fold increased hazard for developing AD over 3 years.10
Our work is consistent with the prior prospective cohort finding with anemia. The current study extends prior work in 2 important ways. First, by measuring the full range of hemoglobin, the current study found that each unit of hemoglobin lower and higher than 13.7 g/dL was nonlinearly associated with an increased risk of incident AD. Second, the current study found that there is also a nonlinear relationship between hemoglobin and the rate of cognitive decline, consistent with our prior cross-sectional data.8
As hemoglobin is frequently measured in current clinical practice, these results may have important translational consequences for identifying older persons at increased risk for developing AD and cognitive decline in our aging population.
The mechanisms linking hemoglobin levels to incident AD and cognitive decline are not understood. The association of hemoglobin levels and AD may be due to both being markers for frailty in older persons. Low hemoglobin level may be a marker for ischemia associated with cerebrovascular disease, hypoxia-associated changes in hypoxia inducible factor and erythropoietin levels, or oxidative stress–associated changes in heme regulation. Our finding that hemoglobin levels are associated with cognitive decline in other domains than episodic memory hints at a potential vascular cause. In older, community-dwelling persons, anemia has been associated with increased risk of white matter disease progression on neuroimaging.28
Second, chronic kidney disease (associated with low hemoglobin levels) could result in cerebral hypoxia. Initial studies mainly in animal models point to chronic kidney disease29
being associated with decreased production of hypoxia inducible factor, which may reduce erythropoietin production. As erythropoietin receptors have been localized in the brain30
and seem to have a neuroprotective effect in animal models of stroke or hypoxia,31,32
lower erythropoietin levels may increase the risk of neuronal degeneration in certain cognitive pathways. Finally, greater red cell fragility in conditions associated with lower hemoglobin levels may lead to brain astroglia having to process more heme molecules crossing the blood–brain barrier. Heme may upregulate the production of hemo-oxygenase-1 resulting in increased sterol dysregulation and oxidative stress damage, especially in individuals already with subclinical AD pathology.33
Our finding of high hemoglobin levels being associated with AD and cognitive decline warrant further investigation given the limited number of cases with clinically high hemoglobin levels. High hemoglobin levels may be associated with cognitive decline via ischemic and hypoxic mechanisms. Polycythemia vera has been associated with an increased risk of cerebral thrombosis.34
In limited studies, chronic obstructive pulmonary disease (associated with high hemoglobin levels) has been associated with cognitive decline in older persons35
and with decreased frontal and parietal lobe perfusion on brain imaging.36
Further studies are needed to determine the biologic basis for the association between hemoglobin, cognitive decline, and AD in elders.
Strengths of our study include detailed annual cognitive and clinical evaluations on a large, community-based cohort. We also were able to adjust for some important comorbidities associated with hemoglobin levels and AD. Our study has limitations. Although we were able to find an association between hemoglobin and incident AD, our study design limits our ability to determine whether hemoglobin alone causes AD or whether hemoglobin levels and AD may share a common cause. Also, due to the multiple risk factors that may be associated with both hemoglobin levels and AD, we were not able to adjust for other factors that may be associated with both items including but not limited to macronutrient and micronutrient deficiencies.
Our findings suggest that low hemoglobin levels may need to be considered as a potential contributing factor to the development of AD in older persons. Before tests of specific interventions in the elderly to correct hemoglobin abnormalities on reducing the hazard of developing AD are initiated, further confirmation of the relationship between hemoglobin and AD will be needed from other longitudinal cohort studies.