Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men

Article type: Research Article

Authors: Bartzokis, George^{a; b; c; *} | Lu, Po H.^d | Tishler, Todd A.^{a; c} | Peters, Douglas G.^{a; c} | Kosenko, Anastasia^{a; c} | Barrall, Katherine A.^a | Finn, J. Paul^e | Villablanca, Pablo^e | Laub, Gerhard^f | Altshuler, Lori L.^{a; c} | Geschwind, Daniel H.^d | Mintz, Jim^g | Neely, Elizabeth^h | Connor, James R.^h

Affiliations: [a] Department of Psychiatry and Biobehavioral Sciences and Semel Institute, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [b] Laboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, UCLA, Los Angeles, CA, USA | [c] Greater Los Angeles VA Healthcare System, West Los Angeles, CA, USA | [d] Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [e] Department of Radiology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [f] Siemens Medical Solutions, Los Angeles, CA, USA | [g] University of Texas Health Science Center at San Antonio, Department of Epidemiology and Biostatistics, San Antonio, TX, USA | [h] Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA

Correspondence: [*] Correspondence to: George Bartzokis, M.D., 300 UCLA Medical Plaza, Suite 2200, Los Angeles, CA 90095-6968, USA. Tel.: +1 310 206 3207; Fax: +1 310 268 3266; E-mail: [email protected].

Note: [] Handling Associate Editor: Christopher Exley

Abstract: Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p = 0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.

Keywords: Alpha synuclein, amyloid, basal ganglia, chelation, dementia, diet, free radicals, gene, gray matter, iron, Lewy body, metal, myelin, oligodendrocytes, prevention, risk, tau, treatment

DOI: 10.3233/JAD-2010-1368

Journal: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 333-341, 2010