|Summary||increased risk of Alzheimer's disease, consider reducing iron levels|
Carriers of the minor alleles for rs1049296 (C2) in the transferrin TF gene and rs1800562 (C282Y) in the HFE gene along with an APOE epsilon 4 genotype were reported to have a risk of late-onset Alzheimer's disease (AD) 37.5 times higher (OR is versus all others) than those without any of the minor alleles in the OPTIMA study (2004) (n=269 healthy eldery controls, n=191 cases with probable or definite AD and n=69 with MCI, 95% CI 2.2 to 638, p<0.0001). Of the 14 carriers in this study, 12 had AD and the other 2 had MCI. The synergy factor for carriers of the C2 and C282Y minor allele was 5.1. Those who only carried one of either C2 or C282Y were not found to have increased risk for AD in this study. However, the increased risk was only discovered in those of Northern European ancestry. [PMID 15060098]
A 2010 study also found that bi-carriers of the minor alleles of rs1049296 and rs1800562 in the combined sample were at increased risk of AD. ("using SFA (p= 0.0016, synergy factor =2.71) and adjusted SFA adjusting for age and presence of the APOE epsilon 4 allele (P=0.002,OR =2.4)") [PMID 20029940]. An estimate for the risk for bicarriers with APOE epsilon 4 (using the synergy factor approach) is OR(tricarriers)= 2 x 2.4 = 4.8. This risk is much less than the original study which found an OR for tricarriers of 37.5. The reason for the large difference in results is not presented. It is possible that specific lifestyle factors, statistical factors etc. could explain this difference. [PMID 20029940]
A 2012 study also replicated the synergy in bicarriers of rs1049296 and rs1800562 for risk of AD (" synergy factor, 1.75 (95% confidence interval, 1.1–2.8,p =0.02) in Northern Europeans. The synergy factor was 3.1 (1.4–6.9; 0.007) in subjects with the APOE4 allele.") [PMID 20817350]
In spite of the increased risk associated with this rare genoset, it should be noted that the underlying condition implicated by these findings - iron overload - is a treatable condition. If preventative action were taken to address the iron imbalance, it might be possible to reduce the risk of developing Alzheimer's disease for those with this genoset.