Journal Article

Red blood cell indices and anaemia as causative factors for cognitive function deficits and for Alzheimer’s disease

Nevado-Holgado, Alejo J., Winchester, Laura M., Lovestone, Simon, Powell, John

2018

Overview

Background Studies have shown that low haemoglobin and anaemia are associated with poor cognition, and anaemia is known to be associated with Alzheimer’s disease (AD), but the mechanism of this risk is unknown. Here, we first seek to confirm the association between cognition and anaemia and secondly, in order to further understand the mechanism of this association, to estimate the direction of causation using Mendelian randomisation. Methods Two independent cohorts were used in this analysis: AddNeuroMed, a longitudinal study of 738 subjects including AD and age-matched controls with blood cell measures, cognitive assessments and gene expression data from blood; and UK Biobank, a study of 502,649 healthy participants, aged 40–69 years with cognitive test measures and blood cell indices at baseline. General linear models were calculated using cognitive function as the outcome with correction for age, sex and education. In UK Biobank, SNPs with known blood cell measure associations were analysed with Mendelian randomisation to estimate direction of causality. In AddNeuroMed, gene expression data was used in pathway enrichment analysis to identify associations reflecting biological function. Results Both sample sets evidence a reproducible association between cognitive performance and mean corpuscular haemoglobin (MCH), a measure of average mass of haemoglobin per red blood cell. Furthermore, in the AddNeuroMed cohort, where longitudinal samples were available, we showed a greater decline in red blood cell indices for AD patients when compared to controls ( p values between 0.05 and 10 −6 ). In the UK Biobank cohort, we found lower haemoglobin in participants with reduced cognitive function. There was a significant association for MCH and red blood cell distribution width (RDW, a measure of cell volume variability) compared to four cognitive function tests including reaction time and reasoning ( p  < 0.0001). Using Mendelian randomisation, we then showed a significant effect of MCH on the verbal–numeric and numeric traits, implying that anaemia has causative effect on cognitive performance. Conclusions Lower haemoglobin levels in blood are associated to poor cognitive function and AD. We have used UK Biobank SNP data to determine the relationship between cognitive testing and haemoglobin measures and suggest that haemoglobin level and therefore anaemia does have a primary causal impact on cognitive performance.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Alzheimer Disease - blood / Alzheimer Disease - physiopathology / Alzheimer's disease / Anaemia / Anemia / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Blood / Blood cells / Cancer Research / Case-Control Studies / Causality / Cell size / Cognition & reasoning / Cognitive ability / Cognitive Dysfunction - blood / Cognitive Dysfunction - physiopathology / Cognitive function / Cohort Studies / Dementia / Disease / Disease Neurogenomics / Erythrocyte Indices / Erythrocytes / Female / Gene expression / Gene Expression Regulation / Genetic aspects / Genomes / Hemoglobin / Hemoglobins - metabolism / Human Genetics / Humans / Iron / Male / Medical imaging / Medicine/Public Health / Mendelian randomisation / Metabolomics / Middle Aged / Quantitative Trait, Heritable / Single-nucleotide polymorphism / Social isolation / Studies / Systems Biology