No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Lupton, Michelle K.; Benyamin, Beben; Proitsi, Petroula; Nyholt, Dale R.; Ferreira, Manuel; Montgomery, Grant W.; Heath, Andrew C.; Madden, Pamela A. F.; Medland, Sarah E.; Gordon, Scott D.; Lovestone, Simon; Tsolaki, Magda; Kłoszewska, Iwona; Mecocci, Patrizia; Vellas, Bruno; Powell, John; Bush, Ashley I.; Wright, Margaret J.; Martin, Nicholas G.; Whitfield, John B.

doi:10.3233/jad-170027

Cited by 11 publications

(10 citation statements)

References 48 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, the two genders belonging to the AD subgroup showed completely overlapped iron levels (78.73±29.11 μg/dL and 78.78±31.56 μg/dL in males and females respectively; P = 0.495). Peripheral iron dyshomeostasis does not necessarily cause neurodegeneration or reflect brain iron deposit causing no genetic connection with neurodegeneration [ 70 ], and the common iron SNPs usually investigated are not considered strong determinants of iron accumulation [ 71 , 72 ]. On the contrary, APOE 4-allele has been widely confirmed as key determinant of brain iron deposit in dementia also contributing to cognitive decline [ 73 – 77 ].…”

Section: Resultsmentioning

confidence: 99%

“…In line with this, APP is crucial also for MS being upregulated in damaged axons and emerging as a promising therapeutic target [ 101 ]. Finally, a recent study evaluating results summarized from GWAS meta-analyses on circulating iron levels and common variants affecting iron homeostasis on AD risk did not identify any genetic relationship ascribing to peripheral iron a no causal role in initiation of AD, rather suggesting ferritin as leader mechanism by which APOE 4 is considered a risk factor for AD [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases

et al. 2018

View full text Add to dashboard Cite

Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer’s disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Pichler et al [ 37 ] used MR with three SNP instruments to find that increased iron reduces the risk of Parkinson’s disease and implying that there may well be a causal association in other similar diseases. However, Lupton et al [ 38 ] used genetic determinants of the serum iron measures transferrin and ferritin in a reanalysis of large-scale GWAS data but found no association with AD. One possible explanation for this apparent discrepancy is the use of MCH in the present study, reportedly a more reliable measure of haemoglobin not influenced by sample storage conditions or cell counter methods [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

BackgroundStudies 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.MethodsTwo 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.ResultsBoth 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.ConclusionsLower 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.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0556-z) contains supplementary material, which is available to authorized users.

show abstract

“…Polygenic risk score (PRS): PRS-no APOE was constructed from genome-wide SNP array data by summing the number of risk alleles weighted by the effect size (log odds ratio) as previously described (Lupton et al, 2017). Risk alleles were identified from the largest AD GWAS meta-analysis available at the start of the study, performed by the IGAP consortium (Lambert et al, 2013) (see Supplementary methods section 2 for details of the IGAP discovery sample).…”

Section: Methodsmentioning

confidence: 99%

A prospective cohort study of prodromal Alzheimer’s disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA)

Lupton

Robinson

Adam

et al. 2020

Preprint

View full text Add to dashboard Cite

This prospective cohort study, Prospective Imaging Study of Ageing: "Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting mid-life Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling nearly 3,000 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for lifestyle monitoring, detailed neurocognitive testing, blood sample donation, plus functional, structural and molecular neuroimaging. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

show abstract

No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Cited by 11 publications

References 48 publications

Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases

Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases

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

A prospective cohort study of prodromal Alzheimer’s disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA)

Contact Info

Product

Resources

About