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. 2018 Jun 28;10(1):51.
doi: 10.1186/s13073-018-0556-z.

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

Laura M Winchester  1 , John Powell  2 , Simon Lovestone  3 , Alejo J Nevado-Holgado  3
Affiliations

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

Laura M Winchester et al. Genome Med. .

Abstract

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.

Keywords: Alzheimer’s disease; Anaemia; Cognitive function; Mendelian randomisation.

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Conflict of interest statement

Ethics approval and consent to participate

This research has been conducted using the UK Biobank Resource under Application Number 15181. UK Biobank has received ethics approval from the Research Ethics Committee (ref. 11/NW/0382). Full details for the AddNeuroMed study are available in the primary publications [17, 18]. The study conformed to the Declaration of Helsinki.

Consent for publication

Not applicable

Competing interests

The authors declare they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Cognitive tests have a significant effect on red blood cell measures. a There is a significant association between red blood cell measures and the reaction time, reasoning, numeric and prospective cognitive function tests. b Increased MCH and related indices have a positive effect on verbal–numeric reasoning, prospective and numeric memory (red squares). Reaction time is increased as haemoglobin decreases due to inverse nature of the reaction time test (blue squares). See Abbreviations for blood indices’ acronyms
Fig. 2
Fig. 2
MCH has a significant effect on the reasoning cognition in multiple MR analysis approaches. a Mendelian randomisation model used for analysis. b p values are significant (> 0.005) in multiple MR methods for the MCH measure (exposure) in the reasoning and numeric traits. Significance in more than one test method is important to rule out pleiotropy among instruments. c MCH instrument (SNP) causal estimates for the reasoning (outcome) show symmetry about 0 indicating a robust analysis (without pleiotropy). d MCH instrument causal estimates for the numeric trait. e Instrument causal estimates for the reasoning trait compared to RDW
Fig. 3
Fig. 3
Rate of change in red blood cells emphasises differences in AD case–control samples. a Rate of change per patient is not correlated with mean per patient. b The distribution of RBC is significantly decreased in AD compared to controls. c The distribution of MCV, a haemoglobin measure, is significantly decreased in AD patients. d RBC rate of change is significantly different for high and low MMSE scores
See this image and copyright information in PMC

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