title: Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulation.
abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.
authors.affiliation: Health Promotion and Prevention of Noncommunicable Diseases Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Ângela C
authors.initials: ÂC
authors.lastname: Crespo
authors.affiliation: Human Genetics Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva
authors.affiliation: Health Promotion and Prevention of Noncommunicable Diseases Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal; Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Marques
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Erica
authors.initials: E
authors.lastname: Marcelino
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Maruta
authors.affiliation: Neurology Department, Hospital Prof. Dr Fernando Fonseca, E.P.E., Amadora, Portugal.
authors.forename: Sónia
authors.initials: S
authors.lastname: Costa
authors.affiliation: Neurology Department, Hospital Prof. Dr Fernando Fonseca, E.P.E., Amadora, Portugal.
authors.forename: Angela
authors.initials: A
authors.lastname: Timóteo
authors.affiliation: Health Promotion and Prevention of Noncommunicable Diseases Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal.
authors.forename: Arminda
authors.initials: A
authors.lastname: Vilares
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Frederico Simões
authors.initials: FS
authors.lastname: Couto
authors.affiliation: Human Genetics Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Faustino
authors.affiliation: Hospital Magalhães Lemos, Porto, Portugal.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Correia
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Verdelho
authors.affiliation: Center for Predictive and Preventive Genetics, Instituto de Biologia Molecular e Celular, Porto, Portugal.
authors.forename: Graça
authors.initials: G
authors.lastname: Porto
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Guerreiro
authors.affiliation: Neurology Department, Hospital Prof. Dr Fernando Fonseca, E.P.E., Amadora, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Herrero
authors.affiliation: Neurology Department, Hospital Prof. Dr Fernando Fonseca, E.P.E., Amadora, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Costa
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Mendonça
authors.affiliation: Health Promotion and Prevention of Noncommunicable Diseases Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal; Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Luciana
authors.initials: L
authors.lastname: Costa
authors.affiliation: Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal; Instituto Gulbenkian de Ciência, Oeiras, Portugal. Electronic address: mcmartins@igc.gulbenkian.pt.
authors.forename: Madalena
authors.initials: M
authors.lastname: Martins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics*; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000097:blood / Q000235:genetics; D005260:Female; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D011990:Receptors, Transferrin / Q000097:blood / Q000235:genetics; D012306:Risk; D000098742:Ferroportin
chemical_list: D015703:Antigens, CD; D001057:Apolipoproteins E; C068126:CD71 antigen; D027682:Cation Transport Proteins; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D000098742:Ferroportin; D007501:Iron; D035941:Iron Regulatory Protein 1
keywords: Alzheimer's disease; Biochemical markers; Gene expression; Genetics; Iron metabolism; Quantitative trait loci (QTL)