Association of Endogenous Erythropoietin Levels and Iron Status With Cognitive Functioning in the General Population

Abstract

BackgroundEmerging data suggest that erythropoietin (EPO) promotes neural plasticity and that iron homeostasis is needed to maintain normal physiological brain function. Cognitive functioning could therefore be influenced by endogenous EPO levels and disturbances in iron status.ObjectiveTo determine whether endogenous EPO levels and disturbances in iron status are associated with alterations in cognitive functioning in the general population.Materials and MethodsCommunity-dwelling individuals from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a general population-based cohort in Groningen, Netherlands, were surveyed between 2003 and 2006. Additionally, endogenous EPO levels and iron status, consisting of serum iron, transferrin, ferritin, and transferrin saturation were analyzed. Cognitive function was assessed by scores on the Ruff Figural Fluency Test (RFFT), as a reflection of executive function, and the Visual Association Test (VAT), as a reflection of associative memory.ResultsAmong 851 participants (57% males; mean age 60 ± 13 years), higher endogenous EPO levels were independently associated with an improved cognitive function, reflected by RFFT scores (ß = 0.09, P = 0.008). In multivariable backward linear regression analysis, EPO levels were among the most important modifiable determinants of RFFT scores (ß = 0.09, P = 0.002), but not of VAT scores. Of the iron status parameters, only serum ferritin levels were inversely associated with cognitive function, reflected by VAT scores, in multivariable logistic regression analysis (odds ratio, 0.77; 95% confidence interval 0.63–0.95; P = 0.02 for high performance on VAT, i.e., ≥11 points). No association between iron status parameters and RFFT scores was identified.ConclusionThe findings suggest that endogenous EPO levels and serum ferritin levels are associated with specific cognitive functioning tests in the general population. Higher EPO levels are associated with better RFFT scores, implying better executive function. Serum ferritin levels, but not other iron status parameters, were inversely associated with high performance on the VAT score, implying a reduced ability to create new memories and recall recent past. Further research is warranted to unravel underlying mechanisms and possible benefits of therapeutic interventions.

Learning induces EPO/EPOr expression in memory relevant brain areas, whereas exogenously applied EPO promotes remote memory consolidation

“…Consistent with our data, it has been shown that the expression of EPO and its receptor vary in different brain regions, and that the exogenous administration of EPO may contribute to improve oxidative metabolism and synaptic transmission capacities, in addition to produce improvements in various hippocampal‐dependent behavioral tests and short‐term spatial memory (Jacobs et al., 2021). Recent data suggest that higher endogenous EPO levels are associated with better scores on specific tests of cognitive functioning in the general human population (Ayerdem et al., 2022).…”

“…This leads to increased oxygen consumption, which might activate the mechanisms that physiologically produce greater expression of EPO. EPO, together with other agents of neural plasticity, can also produce changes related to memory, although it has not been shown that this is directly due to hypoxia‐inducible factor 1 (Chin et al., 2000; Ayerdem et al., 2022). Spatial learning during the place recognition test can naturally generate a higher oxygen demand in activated neurons, which increases the expression of EPO and EPOr in a physiological way.…”