High and Low Hemoglobin Tied to Long-Term Dementia Risk

Megan Brooks

August 06, 2019

Abnormal hemoglobin levels — both low and high — are associated with an increased risk of developing subsequent dementia, new research shows.

The latest results from the Rotterdam Study — a large, longitudinal population-based study — show individuals with anemia were 41% more likely to develop Alzheimer's disease (AD) and 34% more likely to develop any dementia type compared with individuals without anemia. The investigators also found that those with high hemoglobin were also at greater risk of developing dementia.

"Low hemoglobin levels, including anemia, could directly lead to neuronal damage due to reduced oxygen delivery, or via concomitant vascular or metabolic changes, for example changes in binding to amyloid-beta-42, which is an important marker of Alzheimer pathology," study investigator Frank J. Wolters, PhD, Department of Epidemiology and Neurology, Erasmus Medical Center, Rotterdam, the Netherlands, told Medscape Medical News.

"High levels of hemoglobin and hematocrit increase the risk of stroke, and may as such contribute to the development of dementia. However, various other diseases can give rise to erythrocytosis and these might contribute to dementia via other ways, even though our results remained unchanged after excluding individuals with these other common causes of erythrocytosis," he added.

The study was published online July 31 in Neurology.

Implications for Brain Health

Serum hemoglobin was measured in 12,305 participants (mean age, 64 years; 58% women). A total of 1520 people developed dementia during a mean follow-up of 12 years, 1194 of whom had AD.

The results showed a U-shaped association between hemoglobin levels and dementia (P = .005), such that both low and high hemoglobin levels were associated with increased dementia risk.

The hazard ratio was 1.29 (95% confidence interval [CI], 1.09 - 1.52) for the lowest vs middle quintile and 1.20 (95% CI, 1.00 - 1.44) for the highest vs middle quintile.

The overall prevalence of anemia was 6.1%, and anemia was associated with a 34% increased risk of dementia (HR, 1.34; 95% CI, 11% - 62%) and 41% increased for AD (HR, 1.41; 95% CI, 15% - 74%).

The researchers also studied imaging markers of vascular brain disease, structural connectivity and cerebral perfusion in a subset of 5319 participants without dementia underwent brain MRI.

Similar to dementia risk, volume of white matter hyperintensities (P = .03) and structural connectivity (in particular for mean diffusivity, P < .0001) were worse in both the lower and upper ranges of hemoglobin levels. Mean diffusivity was also higher, indicating worse structural connectivity, in individuals with anemia than in those without.

Cerebral microbleeds were more common in the presence of anemia and hemoglobin levels inversely correlated to cerebral perfusion (P < .0001).

"Given the potential implications for the burden of dementia globally, studies are needed to identify biological substrates, potentially focusing around disturbances in structural brain connectivity and cerebral blood flow regulation," write Wolters and colleagues.

"Anemia is often under diagnosed and under treated, which may have detrimental implications for brain health," Wolters told Medscape Medical News. "However, before we can use these findings to recommend interventions, it is important that additional studies are done to establish whether hemoglobin is in fact the culprit, or that, for example, concomitant vascular or metabolic changes lead to increased dementia risk," he added.

Confirmatory Findings

Commenting on the findings for Medscape Medical News, Steven T. DeKosky, MD, the Aerts-Cosper Professor of Alzheimer's Research at the University of Florida College of Medicine and a fellow of the American Academy of Neurology, said the study is "interesting and a strong confirmation of what we have known for a while. However, these are much longer-term data and a larger set of variables that aid in trying to determine possible mechanisms of action and eliminate others, such as diseases that drive hematocrit up or down."

The study is also "noteworthy," said DeKosky, "because it is a very large population, followed for a long time, with a lot of careful thought about what possible confounders or medical factors might cause some of the findings."

Also commenting for Medscape Medical News, Ashley I. Bush, MBBS, PhD, director of the Melbourne Dementia Research Centre and professor of psychiatry and neuroscience at University of Melbourne, Australia, said the study is "very interesting and the results are consistent with findings we published in a cross-sectional study of the Australia Imaging Biomarker and Lifestyle (AIBL) study. It is exciting to see the phenomena we picked up a few years ago being reflected in another important cohort."

Results to date, said Bush, "support the likelihood that Alzheimer's disease impacts on hemoglobin formation peripherally, and that hematological changes impact of Alzheimer's disease and the risk of dementia."

"Clinically, the current finding underscore the importance of not using iron-supplements for treating anemia in older patients where there is no clear evidence of iron deficiency. There is growing concern that higher brain iron levels are associated with more aggressive disease in both AD and Parkinson's disease," said Bush.

"We do not know whether nutritional iron levels are associated with either diseases, but the current paper highlights the need for a better understanding of the mobilization of nutritional iron and the formation of hemoglobin in the risk for these diseases," he added.

The study was supported by the Netherlands Cardiovascular Research Initiative, Erasmus Medical Centre, Erasmus University Rotterdam, Netherlands Organization for Scientific Research, Netherlands Organization for Health Research and Development, Research Institute for Diseases in the Elderly, Netherlands Genomic Initiative, Dutch Ministry of Education, Culture and Science, Dutch Ministry of Health, Welfare and Sports, European Commission, Municipality of Rotterdam, Netherlands Consortium for Healthy Aging and Dutch Heart Foundation. Wolters, DeKosky, and Bush have disclosed no relevant financial relationships.

Neurology. Published online July 31, 2019. Abstract

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