The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease
Introduction
Various lines of evidence suggest that Alzheimer’s disease (AD) is not a single disease but a clinical syndrome due to different genetic and environmental factors leading to a relatively uniform clinical and histopathological appearance [35]. The recognised genetic factors include mutations of the genes encoding the amyloid precursor protein [14] and presenilin 1 and 2 [16], [31], which are responsible for a small proportion of familial and usually early-onset AD cases. A fourth gene encoding apolipoprotein E (APOE) is also implicated in the risk of developing the disease [4], [23], [29], [36]. However, although APOE-ϵ4 is a major risk factor for AD, it is neither necessary nor sufficient for the development of the disease and the presence of other genetic or acquired factors has been postulated.
In vitro and pathological observations have led to the hypothesis that iron may play a role in the pathogenesis of AD, possibly through free-radical production [33], [34]. The “iron hypothesis” is further supported by the presence of iron in amyloid plaques and neurofibrillary tangles [33], and the demonstration that iron facilitates the aggregation of β-amyloid peptide [7], [17] and increases β-amyloid toxicity [30]. Increased amounts of loosely bound iron have been detected in brain samples taken from AD patients [15]. The discovery of HFE [12], a protein that plays a key role in the regulation of body iron, and of HFE gene mutations causing genetic hemochromatosis has opened up new perspectives in the study of the relationship between iron and AD. The known function of HFE is to complex the transferrin receptor on the cell membrane and lowering its affinity for iron-bound transferrin [13]. Hemochromatosis is the most common inherited monogenic disorder in people of European descent. It is characterised by an inappropriately increased absorption of dietary iron that leads to excess iron deposition in various tissues and organs [24]; it is inherited as an autosomal recessive trait linked to the major histocompatibility complex on the short arm of chromosome 6. Although severe iron overload is typical of homozygous hemochromatosis, minor modifications of serum iron, transferrin-saturation and serum ferritin can also be observed in a fraction of heterozygotes, but very rarely they give rise to complications [6]. However, the mild modifications of iron status induced by heterozygous hemochromatosis can influence the severity and clinical evolution of heterogeneous conditions such as hepatitis [32], porphyria cutanea tarda [27] and cardiovascular disease [26]. Two common missense HFE gene mutations have been associated with hemochromatosis: a large proportion of patients with severe hemochromatosis are homozygous for the major C282Y mutation, which is very frequent in populations of Celtic ancestry but less frequent in Mediterranean countries [19]; the second common mutation is H63D, which has a less evident effect on iron status but an increased frequency on the chromosomes of hemochromatosis patients not bearing the C282Y [12]. The H63D mutation is thought to be more ancient than C282Y and has a high frequency in many populations [19]. Overall, 2–20% of individuals of European descent may have genetically determined mild or latent iron status alterations associated with C282Y, while a much larger proportion carry H63D [11].
A recent study reported an increased frequency of HFE mutations in male patients with familial AD and suggested that HFE mutations could be predisposing for familial AD in males APOE-ϵ4 negative [20]. The aim of the present study was to investigate whether HFE gene mutations are associated with an increased risk for sporadic AD, and to evaluate their influence on the age of disease onset.
Section snippets
Patients
Two hundred and six elderly subjects living in the urban area of Milan were recruited at the Day Hospital of the Department of Geriatrics of IRCCS Ospedale Maggiore (Milan, Italy), 107 of whom (35 males, 72 females: age 66–93 years, mean 80 ± 6 years) had a clinical diagnosis of sporadic late-onset (>60 years) Alzheimer’s disease. The diagnosis of AD was based on the NINCDS-ADRDA [18] and DSM IV criteria [1]. The results of routine laboratory tests for serum TSH, FT4, B12 vitamin and folates,
Results
The allelic frequencies of APOE and HFE alleles in the AD patients and controls are shown in Table 1. Five homozygotes and 41 heterozygotes for the APOE-ϵ4 allele were found among the AD patients, and two homozygotes and 15 heterozygotes among the controls. The HFE-C282Y mutation was found in the heterozygous state in four AD patients and four controls; given the low frequency of this mutation, it was not further analysed. The H63D allele was common in both patients and controls, being present
Discussion
The possible role of iron in the pathogenesis of some neurodegenerative disorders prompted us to evaluate hemochromatosis mutations in subjects with AD. To our knowledge this is the first study to examine the distribution of HFE mutations in sporadic late-onset AD typed for APOE, and to analyse the effect of HFE on the age of presentation. The principal HFE-C282Y hemochromatosis mutation is less frequent in Italy than in Northern Europe [8], and was poorly represented in our patient and control
Acknowledgements
Prof. Gemino Fiorelli and Prof. Silvia Fargion are thanked for advice and support. This work was supported by MURST (60% contributions and Progetto Speciale 1998 to M.S.), intramural funds from IRCCS Ospedale Maggiore to M.S. and C.V., and AGER Foundation, Milano.
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The roles of iron and HFE genotype in neurological diseases
2020, Molecular Aspects of MedicineCitation Excerpt :One consistent finding that has been replicated in multiple studies is the effect of H63D HFE variant on age of onset. Four studies have reported earlier age of AD onset for H63D HFE carriers compared to WT HFE patients (Alizadeh et al., 2009; Avila-Gomez et al., 2008; Combarros et al., 2003; Sampietro et al., 2001). Studies on animal models of Hfe gene modifications have to date not included the Hfe gene variants but transcriptome of the Hfe−/− mouse brain has been reported to show up to 9-fold decrease in the transcript levels of amyloid-β protein precursor, tau, apolipoprotein E, presenilin 1, and γ-secretase components (Johnstone et al., 2012).
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