The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity.
Objective:
To test the association of essential metals with APOE genotype.
Methods:
We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype.
Results:
Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC.
Conclusion:
These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.
BushAI (2013) The metal theory of Alzheimer’s disease. J Alzheimers Dis33(Suppl 1), S277–281.
2.
ZubčićK, RadovanovićV, VlainićJ, HofPR, OršolićN, ŠimićG, Jazvinšćak JembrekM (2020) PI3K/Akt and ERK1/2 signalling are involved in quercetin-mediated neuroprotection against copper-induced injury. Oxid Med Cell Longev2020, 9834742.
3.
ZubčićK, HofPR, ŠimićG, Jazvinšćak JembrekM (2020) The role of copper in tau-related pathology in Alzheimer’s disease. Front Mol Neurosci13, 572308.
4.
BuG (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: Pathways, pathogenesis and therapy. Nat Rev Neurosci10, 333–344.
5.
StrittmatterWJ, SaundersAM, SchmechelD, Pericak-VanceM, EnghildJ, SalvesenGS, RosesAD (1993) Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A90, 1977–1981.
6.
SaundersAM, StrittmatterWJ, SchmechelD, George-HyslopPH, Pericak-VanceMA, JooSH, RosiBL, GusellaJF, Crapper-MacLachlanDR, AlbertsMJ (1993) Association of apolipoprotein E allele ɛ4 with late-onset familial and sporadic Alzheimer’s disease. Neurology43, 1467–1472.
7.
MahleyRW, RallSC (2000) Apolipoprotein E: Far more than a lipid transport protein. Annu Rev Genomics Hum Genet1, 507–537.
8.
StrittmatterWJ (2012) Medicine. Old drug, new hope for Alzheimer’s disease. Science335, 1447–1448.
XuH, FinkelsteinDI, AdlardPA (2014) Interactions of metals and apolipoprotein E in Alzheimer’s disease. Front Aging Neurosci6, 121.
11.
MiyataM, SmithJD (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides. Nat Genet14, 55–61.
12.
SquittiR, BressiF, PasqualettiP, BonominiC, GhidoniR, BinettiG, CassettaE, MoffaF, VentrigliaM, VernieriF, RossiniPM (2009) Longitudinal prognostic value of serum ‘free’ copper in patients with Alzheimer disease. Neurology72, 50–55.
13.
GonzálezC, MartínT, CachoJ, BreñasMT, ArroyoT, García-BerrocalB, NavajoJA, González-BuitragoJM (1999) Serum zinc, copper, insulin and lipids in Alzheimer’s disease epsilon 4 apolipoprotein E allele carriers. Eur J Clin Invest29, 637–642.
14.
JiangL, ZhongJ, DouX, ChengC, HuangZ, SunX (2015) Effects of ApoE on intracellular calcium levels and apoptosis of neurons after mechanical injury. Neuroscience301, 375–383.
15.
KagererSM, van BergenJMG, LiX, QuevencoFC, GietlAF, StuderS, TreyerV, MeyerR, KaufmannPA, NitschRM, van ZijlPCM, HockC, UnschuldPG (2020) APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults. Alzheimers Dement (Amst)12, e12002.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCR, KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
18.
BobanM, MalojčićB, MimicaN, VukovićS, ZrilićI, HofPR, ŠimićG (2012) The reliability and validity of the mini-mental state examination in the elderly Croatian population. Dement Geriatr Cogn Disord33, 385–392.
19.
MillerSA, DykesDD, PoleskyHF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res16, 1215.
20.
SquittiR, LupoiD, PasqualettiP, Dal FornoG, VernieriF, ChiovendaP, RossiL, CortesiM, CassettaE, RossiniPM (2002) Elevation of serum copper levels in Alzheimer’s disease. Neurology59, 1153–1161.
21.
SquittiR, VentrigliaM, BarbatiG, CassettaE, FerreriF, Dal FornoG, RamiresS, ZappasodiF, RossiniPM (2007) ‘Free’ copper in serum of Alzheimer’s disease patients correlates with markers of liver function. J Neural Transm114, 1589–1594.
22.
ZappasodiF, SalustriC, BabiloniC, CassettaE, Del PercioC, ErcolaniM, RossiniPM, SquittiR (2008) An observational study on the influence of the APOE-ɛ4 allele on the correlation between ‘free’ copper toxicosis and EEG activity in Alzheimer’s disease. Brain Res1215, 183–189.
23.
JoDW, LerenTP, YangZY, ChungYH, TaylorJM, PaikYK (1995) Characterization of an upstream regulatory element of the human apolipoprotein E gene, and purification of its binding protein from the human placenta. J Biochem117, 915–922.
24.
LitwinT, GromadzkaG, CzłonkowskaA (2012) Wilson’s disease: Does iron metabolism impact phenotypic presentation?Liver Int32, 869–870.
25.
BurkheadJL,
GrayLW,
LutsenkoS (2011) Systems biology approach to Wilson’s disease. BioMetals24, 455–466.
26.
MoirRD, AtwoodCS, RomanoDM, LauransMH, HuangX, BushAI, SmithJD, TanziRE (1999) Differential effects of apolipoprotein E isoforms on metal-induced aggregation of Aβ using physiological concentrations. Biochemistry38, 4595–4603.
27.
OhSB, KimJA, ParkS, LeeJ-Y (2020) Associative interactions among zinc, apolipoprotein E, and amyloid-β in the amyloid pathology. Int J Mol Sci21, 802.
28.
LeeJY, ChoE, KimTY, KimDK, PalmiterRD, VolitakisI, KimJS, BushAI, KohJY (2010) Apolipoprotein E ablation decreases synaptic vesicular zinc in the brain. BioMetals23, 1085–1095.
GreiciusMD, SrivastavaG, ReissAL, MenonV (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: Evidence from functional MRI. Proc Natl Acad Sci U S A101, 4637–4642.
32.
ŠimićG, BabićM, BorovečkiF, HofPR (2014) Early failure of the default-mode network and the pathogenesis of Alzheimer’s disease. CNS Neurosci Ther20, 692–698.
33.
LiangL, YuanY, WeiY, YuB, MaiW, DuanG, NongX, LiC, SuJ, ZhaoL, ZhangZ, DengD (2021) Reccurent and concurrent patterns of regional BOLD dynamics and functional connectivity dynamics in cognitive decline. Alzheimers Res Ther13, 28.
34.
Van BergenJMG, LiX, HuaJ, SchreinerSJ, SteiningerSC, QuevencoFC, WyssM, GietlAF, TreyerV, LehSE, BuckF, NitschRM, PruessmannKP, Van ZijlPCM, HockC, UnschuldPG (2016) Colocalization of cerebral iron with amyloid beta in mild cognitive impairment. Sci Rep6, 35514.
35.
AytonS, FauxNG, BushAI, WeinerMW, AisenP, PetersenR, JackCR, JagustW, TrojanowkiJQ, TogaAW, et al. (2015) Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun6, 6760.
36.
AytonS, FauxNG, BushAI (2017) Association of cerebrospinal fluid ferritin level with preclinical cognitive decline in APOE-ɛ4 carriers. JAMA Neurol74, 122–125.
37.
TisatoV, ZulianiG, ViglianoM, LongoG, FranchiniE, SecchieroP, ZauliG, ParaboschiEM, SinghAV, SerinoML, OrtolaniB, ZurloA, BosiC, GrecoA, SeripaD, AsseltaR, GemmatiD (2018) Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases. PLoS One13, e0193867.
38.
XuH, PerreauVM, DentKA, BushAI, FinkelsteinDI, AdlardPA (2016) Iron regulates apolipoprotein E expression and secretion in neurons and astrocytes. J Alzheimers Dis51, 471–487.
39.
AytonS, WangY, DioufI, SchneiderJA, BrockmanJ, MorrisMC, BushAI (2020) Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry25, 2932–2941.
40.
SouzaLAC, TrebakF, KumarV, SatouR, KehoePG, YangW, WhartonW, EarleyYF (2020) Elevated cerebrospinal fluid sodium in hypertensive human subjects with a family history of Alzheimer’s disease. Physiol Genomics52, 133–142.
HaegerA, CosteA, Lerman-RabraitC, LagardeJ, SchulzJB, VignaudA, SarazinM, BottlaenderM, ReetzK, RomanzettiS, BoumezbeurF (2020) Quantitative sodium imaging using ultra-high field magnetic resonance imaging in patients with Alzheimer’s disease. Alzheimers Dement16, e042107.
43.
VitvitskyVM, GargSK, KeepRF, AlbinRL, BanerjeeR (2012) Na+ and K+ ion imbalances in Alzheimer’s disease. Biochim Biophys Acta1822, 1671–1681.
44.
MohanD, YapKH, ReidpathD, SohYC, McGrattanA, StephanBCM, RobinsonL, ChaiyakunaprukN, SiervoM, PaseM (2020) Link between dietary sodium intake, cognitive function, and dementia risk in middle-aged and older adults: A systematic review. J Alzheimers Dis76, 1347–1373.
45.
LawMR, FrostCD, WaldNJ (1991) By how much does dietary salt reduction lower blood pressure? III - Analysis of data from trials of salt reduction. Br Med J302, 819–824.
46.
YusufPS, HawkenS, ÔunpuuS, DansT, AvezumA, LanasF, McQueenM, BudajA, PaisP, VarigosJ, LishengL (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet364, 937–952.
47.
O’DonnellMJ, DenisX, LiuL, ZhangH, ChinSL, Rao-MelaciniP, RangarajanS, IslamS, PaisP, McQueenMJ, MondoC, DamascenoA, Lopez-JaramilloP, HankeyGJ, DansAL, YusoffK, TruelsenT, DienerHC, SaccoRL, RyglewiczD, CzlonkowskaA, WeimarC, WangX, YusufS (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): A case-control study. Lancet376, 112–123.
48.
AttemsJ, JellingerKA (2014) The overlap between vascular disease and Alzheimer’s disease - lessons from pathology. BMC Med12, 206.
49.
ŠimićG, ŠpanićE, Langer HorvatL, HofPR (2019) Blood-brain barrier and innate immunity in the pathogenesis of Alzheimer’s disease. Prog Mol Biol Transl Sci168, 99–145.
50.
PenlandJG (1994) Dietary boron, brain function, and cognitive performance. In Environmental Health Perspectives Public Health Services, US Dept of Health and Human Services, pp. 65-72.
51.
PenlandJG (1998) The importance of boron nutrition for brain and psychological function. Biol Trace Elem Res66, 299–317.
52.
PizzornoL (2015) Nothing boring about boron. Integr Med14, 35–48.
HartmannH, EckertA, FörstlH, MüllerWE (1994) Similar age-related changes of free intracellular calcium in lymphocytes and central neurons: Effects of Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci243, 218–223.
57.
WangXS, GruensteinE (1997) Rapid elevation of neuronal cytoplasmic calcium by apolipoprotein E peptide. J Cell Physiol173, 73–83.
58.
MüllerW, MeskeV, BerlinK, ScharnaglH, MärzW, OhmTG (1998) Apolipoprotein E isoforms increase intracellular Ca2 + differentially through a ω-agatoxin IVa-sensitive Ca2 +-channel. Brain Pathol8, 641–653.
59.
VeinbergsI, EversonA, SagaraY, MasliahE (2002) Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis. J Neurosci Res67, 379–387.
60.
Larramona-ArcasR, González-AriasC, PereaG, GutiérrezA, VitoricaJ, García-BarreraT, Gómez-ArizaJL, Pascua-MaestroR, GanforninaMD, KaraE, HudryE, Martinez-VicenteM, VilaM, GaleaE, MasgrauR (2020) Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice. Mol Neurodegener15, 1–23.
BardgettME, SchultheisPJ, McGillDL, RichmondRE, WaggeJR (2005) Magnesium deficiency impairs fear conditioning in mice. Brain Res1038, 100–106.
63.
CherbuinN, KumarR, SachdevPS, AnsteyKJ (2014) Dietary mineral intake and risk of mild cognitive impairment: The PATH through life project. Front Aging Neurosci6, 4.
64.
GlickJ (1990) Use of magnesium in the management of dementias. Med Sci Res18, 831–833.
65.
OzturkS, CillierAE (2006) Magnesium supplementation in the treatment of dementia patients. Med Hypotheses67, 1223–1225.
66.
AndrásiE, IgazS, MolnárZ, MakóS (2000) Disturbances of magnesium concentrations in various brain areas in Alzheimer’s disease. Magnes Res13, 189–196.
67.
VuralH, DemirinH, KaraY, ErenI, DelibasN (2010) Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer’s disease. J Trace Elem Med Biol24, 169–173.
68.
ZhuX, BorensteinAR, ZhengY, ZhangW, SeidnerDL, NessR, MurffHJ, LiB, ShrubsoleMJ, YuC, HouL, DaiQ (2020) Ca:Mg ratio, APOE cytosine modifications, and cognitive function: Results from a randomized trial. J Alzheimers Dis75, 85–98.
