Generic placeholder image

Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Association of the MAOB rs1799836 Single Nucleotide Polymorphism and APOE ε4 Allele in Alzheimer’s Disease

Author(s): Mirjana B. Leko, Matea N. Perković, Gordana N. Erjavec, Nataša Klepac, Dubravka Š. Štrac, Fran Borovečki, Nela Pivac, Patrick R. Hof and Goran Šimić*

Volume 18, Issue 7, 2021

Published on: 17 September, 2021

Page: [585 - 594] Pages: 10

DOI: 10.2174/1567205018666210917162843

Price: $65


Background: The dopaminergic system is functionally compromised in Alzheimer’s Disease (AD). The activity of Monoamine Oxidase B (MAOB), the enzyme involved in the degradation of dopamine, is increased during AD. Also, increased expression of MAOB occurs in the postmortem hippocampus and neocortex of patients with AD. The MAOB rs1799836 polymorphism modulates MAOB transcription, consequently influencing protein translation and MAOB activity. We recently showed that cerebrospinal fluid levels of amyloid β1-42 are decreased in patients carrying the A allele in MAOB rs1799836 polymorphism.

Objective: The present study compares MAOB rs1799836 polymorphism and APOE, the only confirmed genetic risk factor for sporadic AD.

Methods: We included 253 participants, 127 of whom had AD, 57 had mild cognitive impairment, 11 were healthy controls, and 58 suffered from other primary causes of dementia. MAOB and APOE polymorphisms were determined using TaqMan SNP Genotyping Assays.

Results: We observed that the frequency of APOE ε4/ε4 homozygotes and APOE ε4 carriers is significantly increased among patients carrying the AA MAOB rs1799836 genotype.

Conclusion: These results indicate that the MAOB rs1799836 polymorphism is a potential genetic biomarker of AD and a potential target for the treatment of decreased dopaminergic transmission and cognitive deterioration in AD.

Keywords: Alzheimer's disease, MAOB, APOE, polymorphisms, genetic biomarkers, mild cognitive impairment.

Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90(5): 1977-81.
[] [PMID: 8446617]
Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993; 43(8): 1467-72.
[] [PMID: 8350998]
Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009; 10(5): 333-44.
[] [PMID: 19339974]
Belbin O, Dunn JL, Ling Y, et al. Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer’s disease. Hum Mol Genet 2007; 16(18): 2199-208.
[] [PMID: 17613540]
Conejero-Goldberg C, Gomar JJ, Bobes-Bascaran T, et al. APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms. Mol Psychiatry 2014; 19(11): 1243-50.
[] [PMID: 24492349]
Strittmatter WJ. Medicine. Old drug, new hope for Alzheimer’s disease. Science 2012; 335(6075): 1447-8.
[] [PMID: 22442467]
Kunkle BW, Grenier-Boley B, Sims R, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 2019; 51(3): 414-30.
[] [PMID: 30820047]
Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 2011; 43(5): 436-41.
[] [PMID: 21460841]
Hollingworth P, Harold D, Sims R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 2011; 43(5): 429-35.
[] [PMID: 21460840]
Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2009; 41(10): 1088-93.
[] [PMID: 19734902]
Lambert J-C, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 2009; 41(10): 1094-9.
[] [PMID: 19734903]
Deming Y, Li Z, Kapoor M, et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol 2017; 133(5): 839-56.
[] [PMID: 28247064]
Cruchaga C, Karch CM, Jin SC, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature 2014; 505(7484): 550-4.
[] [PMID: 24336208]
Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013; 368(2): 107-16.
[] [PMID: 23150908]
Adolfsson R, Gottfries C-G, Oreland L, Wiberg A, Winblad B. Increased activity of brain and platelet monoamine oxidase in dementia of Alzheimer type. Life Sci 1980; 27(12): 1029-34.
[] [PMID: 7421397]
Kennedy BP, Ziegler MG, Alford M, Hansen LA, Thal LJ, Masliah E. Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer’s disease. J Neural Transm (Vienna) 2003; 110(7): 789-801.
[] [PMID: 12811639]
Zellner M, Baureder M, Rappold E, et al. Comparative platelet proteome analysis reveals an increase of monoamine oxidase-B protein expression in Alzheimer’s disease but not in non-demented Parkinson’s disease patients. J Proteomics 2012; 75(7): 2080-92.
[] [PMID: 22270014]
Schedin-Weiss S, Inoue M, Hromadkova L, et al. Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels. Alzheimers Res Ther 2017; 9(1): 57.
[] [PMID: 28764767]
Tohgi H, Ueno M, Abe T, Takahashi S, Nozaki Y. Concentrations of monoamines and their metabolites in the cerebrospinal fluid from patients with senile dementia of the Alzheimer type and vascular dementia of the Binswanger type. J Neural Transm Park Dis Dement Sect 1992; 4(1): 69-77.
[] [PMID: 1540305]
Pinessi L, Rainero I, De Gennaro T, Gentile S, Portaleone P, Bergamasco B. Biogenic amines in cerebrospinal fluid and plasma of patients with dementia of Alzheimer type. Funct Neurol 1987; 2(1): 51-8.
[PMID: 3678940]
Sjögren M, Minthon L, Passant U, Blennow K, Wallin A. Decreased monoamine metabolites in frontotemporal dementia and Alzheimer’s disease. Neurobiol Aging 1998; 19(5): 379-84.
[] [PMID: 9880039]
Finberg JPM, Rabey JM. Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Front Pharmacol 2016; 7: 340.
[] [PMID: 27803666]
Jakubauskiene E, Janaviciute V, Peciuliene I, Söderkvist P, Kanopka A. G/A polymorphism in intronic sequence affects the processing of MAO-B gene in patients with Parkinson disease. FEBS Lett 2012; 586(20): 3698-704.
[] [PMID: 22974659]
Babić Leko M, Nikolac Perković M, Klepac N, et al. Relationships of cerebrospinal fluid Alzheimer’s disease biomarkers and COMT, DBH, and MAOB single nucleotide polymorphisms. J Alzheimers Dis 2020; 73(1): 135-45.
[] [PMID: 31771069]
McKhann GM, Knopman DS, Chertkow H, et al. 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 Dement 2011; 7(3): 263-9.
[] [PMID: 21514250]
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56(3): 303-8.
[] [PMID: 10190820]
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 270-9.
[] [PMID: 21514249]
Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51(6): 1546-54.
[] [PMID: 9855500]
Román GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993; 43(2): 250-60.
[] [PMID: 8094895]
Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975; 32(9): 632-7.
[] [PMID: 1164215]
World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310(20): 2191-4.
[] [PMID: 24141714]
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16(3): 1215.
[] [PMID: 3344216]
Šimić G, Babić Leko M, Wray S, et al. Monoaminergic neuropathology in Alzheimer’s disease. Prog Neurobiol 2017; 151: 101-38.
[] [PMID: 27084356]
Babić Leko M, Hof PR, Šimić G. Alterations and interactions of subcortical modulatory systems in Alzheimer’s disease. Prog Brain Res 2021; 261: 379-421.
[] [PMID: 33785136]
Trillo L, Das D, Hsieh W, et al. Ascending monoaminergic systems alterations in Alzheimer’s disease. translating basic science into clinical care. Neurosci Biobehav Rev 2013; 37(8): 1363-79.
[] [PMID: 23707776]
Krashia P, Nobili A, D’Amelio M. Unifying hypothesis of dopamine neuron loss in neurodegenerative diseases: Focusing on Alzheimer’s disease. Front Mol Neurosci 2019; 12: 123.
[] [PMID: 31156387]
Martorana A, Koch G. “Is dopamine involved in Alzheimer’s disease?”. Front Aging Neurosci 2014; 6: 252.
[] [PMID: 25309431]
Nobili A, Latagliata EC, Viscomi MT, et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun 2017; 8: 14727.
[] [PMID: 28367951]
Guzmán-Ramos K, Moreno-Castilla P, Castro-Cruz M, et al. Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease. Learn Mem 2012; 19(10): 453-60.
[] [PMID: 22984283]
Serra L, D’Amelio M, Di Domenico C, et al. In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer’s disease. Neurobiol Aging 2018; 72: 72-82.
[] [PMID: 30237073]
D’Amelio M, Serra L, Bozzali M. Ventral tegmental area in prodromal Alzheimer’s disease: Bridging the gap between mice and humans. J Alzheimers Dis 2018; 63(1): 181-3.
[] [PMID: 29630556]
De Marco M, Venneri A. Volume and connectivity of the ventral tegmental area are linked to neurocognitive signatures of Alzheimer’s disease in humans. J Alzheimers Dis 2018; 63(1): 167-80.
[] [PMID: 29578486]
Guzman JN, Sánchez-Padilla J, Chan CS, Surmeier DJ. Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci 2009; 29(35): 11011-9.
[] [PMID: 19726659]
Zubenko GS, Marquis JK, Volicer L, Direnfeld LK, Langlais PJ, Nixon RA. Cerebrospinal fluid levels of angiotensin-converting enzyme, acetylcholinesterase, and dopamine metabolites in dementia associated with Alzheimer’s disease and Parkinson’s disease: a correlative study. Biol Psychiatry 1986; 21(14): 1365-81.
[] [PMID: 3024746]
Bareggi SR, Franceschi M, Bonini L, Zecca L, Smirne S. Decreased CSF concentrations of homovanillic acid and γ-aminobutyric acid in Alzheimer’s disease. Age- or disease-related modifications? Arch Neurol 1982; 39(11): 709-12.
[] [PMID: 6181768]
Blennow K, Wallin A, Gottfries CG, et al. Significance of decreased lumbar CSF levels of HVA and 5-HIAA in Alzheimer’s disease. Neurobiol Aging 1992; 13(1): 107-13.
[] [PMID: 1371850]
Kemppainen N, Laine M, Laakso MP, et al. Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer’s disease. Eur J Neurosci 2003; 18(1): 149-54.
[] [PMID: 12859348]
Kumar U, Patel SC. Immunohistochemical localization of dopamine receptor subtypes (D1R-D5R) in Alzheimer’s disease brain. Brain Res 2007; 1131(1): 187-96.
[] [PMID: 17182012]
Borroni B, Agosti C, Archetti S, et al. Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer Disease. Neurosci Lett 2004; 370(2-3): 127-9.
[] [PMID: 15488308]
Holmes C, Smith H, Ganderton R, et al. Psychosis and aggression in Alzheimer’s disease: the effect of dopamine receptor gene variation. J Neurol Neurosurg Psychiatry 2001; 71(6): 777-9.
[] [PMID: 11723200]
Kiive E, Eensoo D, Harro M, Harro J. Platelet monoamine oxidase activity in association with childhood aggressive and hyperactive behaviour: the effect of smoking? Pers Individ Dif 2002; 33: 355-63.
Muck-Seler D, Sagud M, Mustapic M, et al. The effect of lamotrigine on platelet monoamine oxidase type B activity in patients with bipolar depression. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(5): 1195-8.
[] [PMID: 18423830]
Muck-Seler D, Presecki P, Mimica N, et al. Platelet serotonin concentration and monoamine oxidase type B activity in female patients in early, middle and late phase of Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(7): 1226-31.
[] [PMID: 19602426]
Nedic Erjavec G, Nenadic Sviglin K, Nikolac Perkovic M, Muck-Seler D, Jovanovic T, Pivac N. Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes. Prog Neuropsychopharmacol Biol Psychiatry 2014; 54: 321-7.
[] [PMID: 25035107]
Oreland L. Platelet monoamine oxidase, personality and alcoholism: the rise, fall and resurrection. Neurotoxicology 2004; 25(1-2): 79-89.
[] [PMID: 14697883]
Pivac N, Mück-Seler D, Šagud M, Jakovljević M, Mustapić M, Mihaljević-Peles A. Long-term sertraline treatment and peripheral biochemical markers in female depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27(5): 759-65.
[] [PMID: 12921906]
Pivac N, Knezevic J, Mustapic M, et al. The lack of association between monoamine oxidase (MAO) intron 13 polymorphism and platelet MAO-B activity among men. Life Sci 2006; 79(1): 45-9.
[] [PMID: 16427095]
Pivac N, Knezevic J, Kozaric-Kovacic D, et al. Monoamine oxidase (MAO) intron 13 polymorphism and platelet MAO-B activity in combat-related posttraumatic stress disorder. J affect Disord 2007; 103(1-3): 131-8.
[] [PMID: 17289152]
Veitinger M, Oehler R, Umlauf E, et al. A platelet protein biochip rapidly detects an Alzheimer’s disease-specific phenotype. Acta Neuropathol 2014; 128(5): 665-77.
[] [PMID: 25248508]
Veitinger M, Varga B, Guterres SB, Zellner M. Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers? Acta Neuropathol Commun 2014; 2: 65.
[] [PMID: 24934666]
Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 2016; 139(Pt 3): 922-36.
[] [PMID: 26813969]
Reinikainen KJ, Paljärvi L, Halonen T, et al. Dopaminergic system and monoamine oxidase-B activity in Alzheimer’s disease. Neurobiol Aging 1988; 9(3): 245-52.
[] [PMID: 3398991]
Emilsson L, Saetre P, Balciuniene J, Castensson A, Cairns N, Jazin EE. Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer’s disease patients. Neurosci Lett 2002; 326(1): 56-60.
[] [PMID: 12052537]
Quartey MO, Nyarko JNK, Pennington PR, et al. Alzheimer disease and selected risk factors disrupt a co-regulation of monoamine oxidase-A/B in the hippocampus, but not in the cortex. Front Neurosci 2018; 12: 419.
[] [PMID: 29997470]
Saura J, Luque JM, Cesura AM, et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 1994; 62(1): 15-30.
[] [PMID: 7816197]
Riederer P, Danielczyk W, Grünblatt E. Monoamine oxidase-B inhibition in Alzheimer’s disease. Neurotoxicology 2004; 25(1-2): 271-7.
[] [PMID: 14697902]
Wong KY, Roy J, Fung ML, Heng BC, Zhang C, Lim LW. Relationships between mitochondrial dysfunction and neurotransmission failure in Alzheimer’s disease. Aging Dis 2020; 11(5): 1291-316.
[] [PMID: 33014538]
Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997; 336(17): 1216-22.
[] [PMID: 9110909]
Magni G, Meibach RC. Lazabemide for the long-term treatment of Alzheimer’s disease. Eur Neuropsychopharmacol 1999; 9: 142.
Nave S, Doody RS, Boada M, et al. Sembragiline in moderate Alzheimer’s disease: Results of a randomized, double-blind, placebo-controlled phase II trial (MAyflOwer RoAD). J Alzheimers Dis 2017; 58(4): 1217-28.
[] [PMID: 28550255]
Marco-Contelles J, Unzeta M, Bolea I, et al. ASS234, as a new multi-target directed propargylamine for Alzheimer’s disease therapy. Front Neurosci 2016; 10: 294.
[] [PMID: 27445665]
Bolea I, Colivicchi MA, Ballini C, et al. Neuroprotective effects of the MAO-B inhibitor, PF9601N, in an in vivo model of excitotoxicity. CNS Neurosci Ther 2014; 20(7): 641-50.
[] [PMID: 24767579]
Zheng H, Youdim MBH, Fridkin M. Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer’s therapy. ACS Chem Biol 2010; 5(6): 603-10.
[] [PMID: 20455574]
Schneider LS, Geffen Y, Rabinowitz J, et al. Ladostigil Study Group Low-dose ladostigil for mild cognitive impairment. Neurology 2019; 93: e1474-84.
[] [PMID: 31492718]
Balciuniene J, Emilsson L, Oreland L, Pettersson U, Jazin E. Investigation of the functional effect of monoamine oxidase polymorphisms in human brain. Hum Genet 2002; 110(1): 1-7.
[] [PMID: 11810289]
Garpenstrand H, Ekblom J, Forslund K, Rylander G, Oreland L. Platelet monoamine oxidase activity is related to MAOB intron 13 genotype. J Neural Transm (Vienna) 2000; 107(5): 523-30.
[] [PMID: 11072748]
Kakinuma S, Beppu M, Sawai S, et al. Monoamine oxidase B rs1799836 G allele polymorphism is a risk factor for early development of levodopa-induced dyskinesia in Parkinson’s disease. eNeurologicalSci 2020; 19: 100239.
[] [PMID: 32346620]
Löhle M, Mangone G, Wolz M, et al. Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson’s disease. Mov Disord 2018; 33(9): 1496-501.
[] [PMID: 30216543]
Tunbridge EM, Narajos M, Harrison CH, Beresford C, Cipriani A, Harrison PJ. Which dopamine polymorphisms are functional? systematic review and meta-analysis of COMT, DAT, DBH, DDC, DRD1-5, MAOA, MAOB, TH, VMAT1, and VMAT2. Biol Psychiatry 2019; 86(8): 608-20.
[] [PMID: 31303260]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy