Alzheimer’s, Dementia Risk Tied to Hemoglobin Levels

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Both low and high levels of hemoglobin were linked to an increased risk of dementia and Alzheimer’s disease, a population-based cohort study showed.

Over 12 years, anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease, reported M. Arfan Ikram, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, and colleagues.

Compared with mid-range hemoglobin levels, low and high levels both were associated with increased dementia risk, they wrote in Neurology. White matter structural connectivity, cerebral perfusion, and microbleeds also were tied to hemoglobin levels.

“This study establishes that deviations in hemoglobin levels relate to the development of dementia many years later, suggesting these could be involved in the early phase of the disease,” said co-author Frank Wolters, PhD, also of Erasmus Medical Center.

“Abnormal levels of hemoglobin, including anemia, are a very common finding,” Wolters told MedPage Today. “Several putative biological links to the development of dementia make it important to study hemoglobin as a potentially modifiable risk factor, as well as to understand the importance of, for example, oxygenation and iron metabolism, in the process leading to neurodegeneration.”

Prior studies have tied anemia to dementia but this research “looked at the whole range of hemoglobin level — not just the cutoff for low or anemia — and found an interesting U-shaped association with both low and high hemoglobin being associated with dementia risk and MRI changes,” noted Kristine Yaffe, MD, of the University of California San Francisco, who was not involved with the study.

The finding that white matter health and microbleeds were associated with anemia is novel, Yaffe told MedPage Today. “This supports the idea that the level of hemoglobin — which carries oxygen and also interacts with beta-amyloid protein — is an important risk for Alzheimer’s disease. It is often something that can be modified and knowing about its association with brain health is another reason to screen and treat.”

In this analysis, researchers looked at serum hemoglobin measurements of 12,305 people without dementia in the ongoing population-based Rotterdam Study, which was started in 1990, and determined their risk of dementia and Alzheimer’s disease until 2016. Mean age at baseline was 64.6 and 57.7% were women. In a subset of 5,267 participants who had brain MRI, the researchers assessed hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion.

Over a mean follow-up of 12.1 years, 1,520 people developed dementia, 1,194 of whom had Alzheimer’s disease. Of all incident dementia cases, 222 were preceded by a stroke.

The overall prevalence of anemia was 6.1%, which steeply increased with age in men, from 1.4% age <50 to 33.3% age >90. In women, anemia prevalence was higher in pre-menopausal ages, but lower than in men in old age. Anemia was associated with a 34% increased risk of dementia (95% CI 11%-62%) and 41% (15%-74%) of Alzheimer’s disease.

Hemoglobin levels and dementia risk showed a U-shaped association (P=0.005): compared with the middle quintile of hemoglobin levels, the lowest quintile had a HR of 1.29 (95% CI 1.09-1.52) and the highest quintile had a HR of 1.20 (95% CI 1.00-1.44).

On brain MRI, similar U-shaped associations were seen between hemoglobin and white matter hyperintensity volume (P=0.03) and structural connectivity (P<0.0001 for mean diffusivity), but not with cortical and lacunar infarcts. Low levels of hemoglobin, but not high levels, were associated with a higher prevalence of microbleeds. Hemoglobin levels were inversely correlated with cerebral perfusion (P<0.0001).

The worldwide prevalence of anemia is much higher than what was found in this study, the researchers pointed out. “With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia, especially as the prevalence of dementia is expected to increase threefold over the next decades, with the largest increases predicted in the countries where the anemia rate is the highest,” Ikram said in a statement.

And while this study shows associations only, not causality, “the link of hemoglobin to cerebral perfusion and white matter damage should encourage further study into hypoxia and white matter integrity as potential explanations for increased dementia risk,” Wolters noted.

The analysis had several limitations, the researchers reported. Residual confounding may have occurred, even though findings were adjusted for a wide range of potential confounders including chronic disease. Participants who had MRI were more educated and used lipid-lowering medication than others in the study. The Dutch population studied was predominantly of European descent and these findings may not apply to other ethnicities and geographic regions, they added.

Last Updated July 31, 2019

The study was supported by the Netherlands Cardiovascular Research Initiative, Erasmus Medical Centre, Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomic Initiative, the Dutch Ministry of Education, Culture and Science, the Dutch Ministry of Health, Welfare and Sports, the European Commission, the Municipality of Rotterdam, the Netherlands Consortium for Healthy Aging, and the Dutch Heart Foundation.

Ikram and co-authors disclosed no relevant relationships with industry.

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