Blood and CSF Homocysteine Levels in Alzheimer’s Disease: A Meta-Analysis and Meta-Regression of Case–Control Studies

References

• Crous-Bou M, Minguillon C, Gramunt N, Molinuevo JL. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017;9(1):71. doi:10.1186/s13195-017-0297-z
   PubMed Web of Science ®Google Scholar
• Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, et al. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem. 2012;287(38):32040–32053. doi:10.1074/jbc.M112.401240
   PubMed Web of Science ®Google Scholar
• Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329–344. doi:10.1056/NEJMra0909142
   PubMed Web of Science ®Google Scholar
• Ying H, Jianping C, Jianqing Y, Shanquan Z. Cognitive variations among vascular dementia subtypes caused by small-, large-, or mixed-vessel disease. Arch Med Sci. 2016;12(4):747–753. doi:10.5114/aoms.2016.60962
   Web of Science ®Google Scholar
• Kuo TC, Zhao Y, Weir S, Kramer MS, Ash AS. Implications of comorbidity on costs for patients with Alzheimer disease. Med Care. 2008;46(8):839–846. doi:10.1097/MLR.0b013e318178940b
   PubMed Web of Science ®Google Scholar
• Sons JW. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021;17(3):327–406. doi:10.1002/alz.12328
   Web of Science ®Google Scholar
• Mantzavinos V, Alexiou A. Biomarkers for Alzheimer’s disease diagnosis. Curr Alzheimer Res. 2017;14(11):1149–1154. doi:10.2174/1567205014666170203125942
   PubMed Web of Science ®Google Scholar
• Cascalheira JF, Joao SS, Pinhancos SS, et al. Serum homocysteine: interplay with other circulating and genetic factors in association to Alzheimer’s type dementia. Clin Biochem. 2009;42(9):783–790. doi:10.1016/j.clinbiochem.2009.02.006
   Web of Science ®Google Scholar
• Hooshmand B, Solomon A, Kareholt I, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology. 2010;75(16):1408–1414. doi:10.1212/WNL.0b013e3181f88162
   PubMed Web of Science ®Google Scholar
• D’Cunha NM, Georgousopoulou EN, Boyd L, et al. Relationship between B-vitamin biomarkers and dietary intake with apolipoprotein E ε4 in Alzheimer’s disease. J Nutr Gerontol Geriatr. 2019;38(2):173–195. doi:10.1080/21551197.2019.1590287
   PubMedGoogle Scholar
• Janel N, Alexopoulos P, Badel A, et al. Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer’s disease. Transl Psychiatry. 2017;7(6):e1154. doi:10.1038/tp.2017.123
   Web of Science ®Google Scholar
• Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology. 2002;58(10):1471–1475. doi:10.1212/wnl.58.10.1471
   PubMed Web of Science ®Google Scholar
• Ravaglia G, Forti P, Maioli F, et al. Elevated plasma homocysteine levels in centenarians are not associated with cognitive impairment. Mech Ageing Dev. 2000;121(1–3):251–261. doi:10.1016/s0047-6374(00)00221-9
   Web of Science ®Google Scholar
• Zhou F, Chen S. Hyperhomocysteinemia and risk of incident cognitive outcomes: an updated dose-response meta-analysis of prospective cohort studies. Ageing Res Rev. 2019;51:55–66. doi:10.1016/j.arr.2019.02.006
   PubMed Web of Science ®Google Scholar
• Droller H, Dossett JA. Vitamin B12 levels in senile dementia and confusional states. Geriatrics. 1959;14(6):367–373.
   Google Scholar
• Chen H, Liu S, Ji L, et al. Associations between Alzheimer’s disease and blood homocysteine, vitamin B12, and folate: a case-control study. Curr Alzheimer Res. 2015;12(1):88–94. doi:10.2174/1567205012666141218144035
   Web of Science ®Google Scholar
• Postiglione A, Milan G, Ruocco A, Gallotta G, Guiotto G, Di Minno G. Plasma folate, vitamin B(12), and total homocysteine and homozygosity for the C677T mutation of the 5,10-methylene tetrahydrofolate reductase gene in patients with Alzheimer’s dementia. A case-control study. Gerontology. 2001;47(6):324–329. doi:10.1159/000052822
   Web of Science ®Google Scholar
• Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785–1805. doi:10.1177/0962280216669183
   PubMed Web of Science ®Google Scholar
• Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14(1):135. doi:10.1186/1471-2288-14-135
   PubMed Web of Science ®Google Scholar
• Friedrich JO, Adhikari NK, Beyene J. Ratio of means for analyzing continuous outcomes in meta-analysis performed as well as mean difference methods. J Clin Epidemiol. 2011;64(5):556–564. doi:10.1016/j.jclinepi.2010.09.016
   PubMed Web of Science ®Google Scholar
• Popp J, Lewczuk P, Linnebank M, et al. Homocysteine metabolism and cerebrospinal fluid markers for Alzheimer’s disease. J Alzheimers Dis. 2009;18(4):819–828. doi:10.3233/JAD-2009-1187
   Web of Science ®Google Scholar
• Smach MA, Jacob N, Golmard JL, et al. Folate and homocysteine in the cerebrospinal fluid of patients with Alzheimer’s disease or dementia: a case control study. Eur Neurol. 2011;65(5):270–278. doi:10.1159/000326301
   PubMed Web of Science ®Google Scholar
• Isobe C, Abe T, Terayama Y. Homocysteine may contribute to pathogenesis of RNA damage in brains with Alzheimer’s disease. Neurodegener Dis. 2009;6(5–6):252–257. doi:10.1159/000262443
   PubMed Web of Science ®Google Scholar
• Selley ML, Close DR, Stern SE. The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer’s disease. Neurobiol Aging. 2002;23(3):383–388. doi:10.1016/s0197-4580(01
   PubMed Web of Science ®Google Scholar
• Anello G, Gueant-Rodriguez RM, Bosco P, et al. Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer’s disease. Neuroreport. 2004;15(5):859–861. doi:10.1097/00001756-200404090-00025
   Web of Science ®Google Scholar
• Arslan A, Tuzun FA, Arslan H, et al. The relationship between serum paraoxonase levels and carotid atherosclerotic plaque formation in Alzheimer’s patients. Neurol Neurochir Pol. 2016;50(6):403–409. doi:10.1016/j.pjnns.2016.07.002
   Web of Science ®Google Scholar
• Cascalheira JF, Goncalves M, Barroso M, et al. Association of the transcobalamin II gene 776C --> G polymorphism with Alzheimer’s type dementia: dependence on the 5, 10-methylenetetrahydrofolate reductase 1298A --> C polymorphism genotype. Ann Clin Biochem. 2015;52(Pt4):448–455. doi:10.1177/0004563214561770
   Web of Science ®Google Scholar
• Coppede F, Tannorella P, Pezzini I, et al. Folate, homocysteine, vitamin B12, and polymorphisms of genes participating in one-carbon metabolism in late-onset Alzheimer’s disease patients and healthy controls. Antioxid Redox Signal. 2012;17(2):195–204. doi:10.1089/ars.2011.4368
   Web of Science ®Google Scholar
• da Silva VC, Ramos FJ, Freitas EM, et al. Alzheimer’s disease in Brazilian elderly has a relation with homocysteine but not with MTHFR polymorphisms. Arq Neuropsiquiatr. 2006;64(4):941–945. doi:10.1590/s0004-282x2006000600010
   PubMed Web of Science ®Google Scholar
• de Silva HA, Gunatilake SB, Johnston C, Warden D, Smith AD. Medial temporal lobe atrophy, apolipoprotein genotype, and plasma homocysteine in Sri Lankan patients with Alzheimer’s disease. Exp Aging Res. 2005;31(3):345–354. doi:10.1080/03610730590948221
   PubMed Web of Science ®Google Scholar
• Elhawary NA, Hewedi D, Arab A, et al. The MTHFR 677T allele may influence the severity and biochemical risk factors of Alzheimer’s disease in an Egyptian population. Dis Markers. 2013;35(5):439–446. doi:10.1155/2013/524106
   PubMed Web of Science ®Google Scholar
• Fekkes D, van der Cammen TJ, van Loon CP, et al. Abnormal amino acid metabolism in patients with early stage Alzheimer dementia. J Neural Transm. 1998;105(2–3):287–294. doi:10.1007/s007020050058
   Web of Science ®Google Scholar
• Folin M, Baiguera S, Gallucci M, et al. A cross-sectional study of homocysteine-, NO-levels, and CT-findings in Alzheimer dementia, vascular dementia and controls. Biogerontology. 2005;6(4):255–260. doi:10.1007/s10522-005-2622-3
   Web of Science ®Google Scholar
• Gallucci M, Zanardo A, De Valentin L, Vianello A. Homocysteine in Alzheimer disease and vascular dementia. Arch Gerontol Geriatr Suppl. 2004;38:195–200. doi:10.1016/j.archger.2004.04.027
   Google Scholar
• Guidi I, Galimberti D, Lonati S, et al. Oxidative imbalance in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2006;27(2):262–269. doi:10.1016/j.neurobiolaging.2005.01.001
   Web of Science ®Google Scholar
• Hagnelius NO, Wahlund LO, Nilsson TK. CSF/serum folate gradient: physiology and determinants with special reference to dementia. Dement Geriatr Cogn Disord. 2008;25(6):516–523. doi:10.1159/000129696
   Web of Science ®Google Scholar
• Hogervorst E, Ribeiro HM, Molyneux A, Budge M, Smith AD. Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol. 2002;59(5):787–793. doi:10.1001/archneur.59.5.787
   PubMedGoogle Scholar
• Leblhuber F, Walli J, Artner-Dworzak E, et al. Hyperhomocysteinemia in dementia. J Neural Transm. 2000;107(12):1469–1474. doi:10.1007/s007020070010
   Web of Science ®Google Scholar
• Lv X, Zhou D, Ge B, et al. Association of folate metabolites and mitochondrial function in peripheral blood cells in Alzheimer’s disease: a matched case-control study. J Alzheimers Dis. 2019;70(4):1133–1142. doi:10.3233/JAD-190477
   Web of Science ®Google Scholar
• Ma F, Lv X, Du Y, et al. Association of leukocyte telomere length with mild cognitive impairment and Alzheimer’s disease: role of folate and homocysteine. Dement Geriatr Cogn Disord. 2019;48(1–2):56–67. doi:10.1159/000501958
   PubMed Web of Science ®Google Scholar
• Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med. 2004;42(9):1032–1035. doi:10.1515/CCLM.2004.208
   Web of Science ®Google Scholar
• Mansoori N, Tripathi M, Luthra K, et al. MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer’s and vascular dementia and their epistatic interaction. Neurobiol Aging. 2012;33(5):1003e1–8. doi:10.1016/j.neurobiolaging.2011.09.018
   Web of Science ®Google Scholar
• McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry. 1998;13(4):235–239. doi:10.1002/(sici)1099-1166(199804)13:4<235::aid-gps761>3.0.co;2-8
   Web of Science ®Google Scholar
• Mizrahi EH, Bowirrat A, Jacobsen DW, et al. Plasma homocysteine, vitamin B12 and folate in Alzheimer’s patients and healthy Arabs in Israel. J Neurol Sci. 2004;227(1):109–113. doi:10.1016/j.jns.2004.08.011
   Web of Science ®Google Scholar
• Nagga K, Rajani R, Mardh E, Borch K, Mardh S, Marcusson J. Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement Geriatr Cogn Disord. 2003;16(4):269–275. doi:10.1159/000072812
   PubMed Web of Science ®Google Scholar
• Nazef K, Khelil M, Chelouti H, et al. Hyperhomocysteinemia is a risk factor for Alzheimer’s disease in an Algerian population. Arch Med Res. 2014;45(3):247–250. doi:10.1016/j.arcmed.2014.03.001
   PubMed Web of Science ®Google Scholar
• Pollak RD, Pollak A, Idelson M, Bejarano-Achache I, Doron D, Blumenfeld A. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia. J Am Geriatr Soc. 2000;48(6):664–668. doi:10.1111/j.1532-5415.2000.tb04725.x
   PubMed Web of Science ®Google Scholar
• Weiner MF, Hynan LS, Rossetti H, et al. The relationship of cardiovascular risk factors to Alzheimer disease in Choctaw Indians. Am J Geriatr Psychiatry. 2011;19(5):423–429. doi:10.1097/JGP.0b013e3181e89a46
   Web of Science ®Google Scholar
• Tannorella P, Stoccoro A, Tognoni G, et al. Methylation analysis of multiple genes in blood DNA of Alzheimer’s disease and healthy individuals. Neurosci Lett. 2015;600:143–147. doi:10.1016/j.neulet.2015.06.009
   PubMed Web of Science ®Google Scholar
• Ruiz A, Pesini P, Espinosa A, et al. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer’s disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates. PLoS One. 2013;8(11):e81334. doi:10.1371/journal.pone.0081334
   Web of Science ®Google Scholar
• Villa P, Bosco P, Ferri R, et al. Fasting and post-methionine homocysteine levels in Alzheimers disease and vascular dementia. Int J Vitam Nutr Res. 2009;79(3):166–172. doi:10.1024/0300-9831.79.3.166
   Web of Science ®Google Scholar
• Wang Q, Zhao J, Chang H, Liu X, Zhu R. Homocysteine and folic acid: risk factors for Alzheimer’s disease-an updated meta-analysis. Front Aging Neurosci. 2021;13:665114. doi:10.3389/fnagi.2021.665114
   Web of Science ®Google Scholar
• Shen L, Ji HF. Associations between homocysteine, folic acid, vitamin B12 and Alzheimer’s disease: insights from meta-analyses. J Alzheimers Dis. 2015;46(3):777–790. doi:10.3233/JAD-150140
   Web of Science ®Google Scholar
• Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002;346(7):476–483. doi:10.1056/NEJMoa011613
   PubMed Web of Science ®Google Scholar
• Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82(3):636–643. doi:10.1093/ajcn.82.3.636
   PubMed Web of Science ®Google Scholar
• Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49(1):31–62. doi:10.1146/annurev.med.49.1.31
   PubMed Web of Science ®Google Scholar
• Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998;316(7135):894–898. doi:10.1136/bmj.316.7135.894
   PubMed Web of Science ®Google Scholar
• Riddell LJ, Chisholm A, Williams S, Mann JI. Dietary strategies for lowering homocysteine concentrations. Am J Clin Nutr. 2000;71(6):1448–1454. doi:10.1093/ajcn/71.6.1448
   Web of Science ®Google Scholar
• Broekmans WM, Klopping-Ketelaars IA, Schuurman CR, et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr. 2000;130(6):1578–1583. doi:10.1093/jn/130.6.1578
   PubMed Web of Science ®Google Scholar
• Baroni L, Bonetto C, Rizzo G, Bertola C, Caberlotto L, Bazzerla G. Association between cognitive impairment and vitamin B12, folate, and homocysteine status in elderly adults: a retrospective study. J Alzheimers Dis. 2019;70(2):443–453. doi:10.3233/JAD-190249
   PubMed Web of Science ®Google Scholar
• Zylberstein DE, Lissner L, Bjorkelund C, et al. Midlife homocysteine and late-life dementia in women. A prospective population study. Neurobiol Aging. 2011;32(3):380–386. doi:10.1016/j.neurobiolaging.2009.02.024
   Web of Science ®Google Scholar
• Nilsson K, Gustafson L, Hultberg B. Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer’s disease. Int J Geriatr Psychiatry. 2004;19(7):666–672. doi:10.1002/gps.1140
   Web of Science ®Google Scholar
• Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55(11):1449–1455. doi:10.1001/archneur.55.11.1449
   PubMedGoogle Scholar
• Luchsinger JA, Tang MX, Miller J, Green R, Mehta PD, Mayeux R. Relation of plasma homocysteine to plasma amyloid beta levels. Neurochem Res. 2007;32(4–5):775–781. doi:10.1007/s11064-006-9207-7
   Web of Science ®Google Scholar
• Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study. Am J Clin Nutr. 2000;71(4):993–998. doi:10.1093/ajcn/71.4.993
   PubMed Web of Science ®Google Scholar
• Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S, et al. Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Neurobiol Dis. 2006;22(3):651–656. doi:10.1016/j.nbd.2006.01.005
   PubMed Web of Science ®Google Scholar
• Novakovic P, Stempak JM, Sohn KJ, Kim YI. Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006;27(5):916–924. doi:10.1093/carcin/bgi312
   Web of Science ®Google Scholar
• Tian H, Tian D, Zhang C, et al. Efficacy of folic acid therapy in patients with hyperhomocysteinemia. J Am Coll Nutr. 2017;36(7):528–532. doi:10.1080/07315724.2017.1330162
   PubMed Web of Science ®Google Scholar
• Price BR, Wilcock DM, Weekman EM. Hyperhomocysteinemia as a risk factor for vascular contributions to cognitive impairment and dementia. Front Aging Neurosci. 2018;10:350. doi:10.3389/fnagi.2018.00350
   PubMed Web of Science ®Google Scholar
• Li JG, Chu J, Barrero C, Merali S, Pratico D. Homocysteine exacerbates beta-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol. 2014;75(6):851–863. doi:10.1002/ana.24145
   Web of Science ®Google Scholar
• Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol. 2003;53(2):214–221. doi:10.1002/ana.10440
   Web of Science ®Google Scholar
• Shirafuji N, Hamano T, Yen SH, et al. Homocysteine increases tau phosphorylation, truncation and oligomerization. Int J Mol Sci. 2018;19(3):891. doi:10.3390/ijms19030891
   Web of Science ®Google Scholar
• Obeid R, Kasoha M, Knapp JP, et al. Folate and methylation status in relation to phosphorylated tau protein(181P) and beta-amyloid(1-42) in cerebrospinal fluid. Clin Chem. 2007;53(6):1129–1136. doi:10.1373/clinchem.2006.085241
   Web of Science ®Google Scholar
• Zhuo JM, Pratico D. Normalization of hyperhomocysteinemia improves cognitive deficits and ameliorates brain amyloidosis of a transgenic mouse model of Alzheimer’s disease. FASEB J. 2010;24(10):3895–3902. doi:10.1096/fj.10-161828
   Web of Science ®Google Scholar