Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and Disease    2018, Vol. 9 Issue (3) : 334-345     DOI: 10.14336/AD.2017.0809
Orginal Article |
Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4
Qiong Ding1,Kitora Tanigawa1,Jun Kaneko1,Mamoru Totsuka2,Yoshinori Katakura3,Etsuko Imabayashi4,Hiroshi Matsuda4,Tatsuhiro Hisatsune1,*
1Department of Integrated Biosciences, Graduate School of Frontier Sciences, and
2Department of Applied Biochemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
3Graduate School of Systems Life Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
4Integrative Brain Imaging Center (IBIC), National Center of Neurology and Psychiatry, Tokyo, Japan
Download: PDF(789 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

In a previously reported double-blind, randomized controlled trial (RCT), we demonstrated that daily supplementation with anserine (750 mg) and carnosine (250 mg) improves brain blood flow and memory function in elderly people. Here, we conducted a sub-analysis of MRI data and test scores from the same RCT to determine whether anserine/carnosine supplementation specifically benefits elderly people carrying the APOE e4 allele, which is a risk gene for accelerated brain aging and for the onset of Alzheimer’s Disease. We collected data from 68 participants aged 65 years or older who received anserine/carnosine supplementation (ACS) or placebo for 12 months. Subjects were assessed at the start and end of the trial using several neuropsychological tests, including the Wechsler Memory Scale-Logical Memory (WMS-LM). We also collected two types of MRI data, arterial spin labeling (ASL) and diffusion tensor imaging (DTI) at the start and end of the trial. We found that ACS significantly preserved verbal memory (WMS-LM, F[1,65] = 4.2003, p = 0.0445) and blood flow at frontal areas of the brain (FWEcluster level, p < 0.001). Sub-analysis based on the APOE4 genotype showed a significant preservation of blood flow (p = 0.002, by ASL analysis) and white-matter microstructure (p = 0.003, by DTI analysis) at prefrontal areas in APOE4+ subjects in the active group, while there was no significant difference between APOE4- subjects in the active and placebo groups. The effect of ACS in preserving brain structure and function in elderly people carrying APOE4 should be verified by further studies.

Keywords Alzheimer’s Disease      ASL      DTI      verbal memory      RCT      APOE e4     
Corresponding Authors: Tatsuhiro Hisatsune   
Issue Date: 05 June 2018
E-mail this article
E-mail Alert
Articles by authors
Qiong Ding
Kitora Tanigawa
Jun Kaneko
Mamoru Totsuka
Yoshinori Katakura
Etsuko Imabayashi
Hiroshi Matsuda
Tatsuhiro Hisatsune
Cite this article:   
Qiong Ding,Kitora Tanigawa,Jun Kaneko, et al. Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4[J]. A&D, 2018, 9(3): 334-345.
URL:     OR
[1] Ritchie K, Lovestone S (2002). The dementias. The Lancet, 360:1759-66.
[2] Lindenberger U (2014). Human cognitive aging: corriger la fortune?. Science, 346:572-8.
[3] Cooper JK (2014). Nutrition and the brain: what advice should we give?. Neurobiol Aging, (Suppl 2) 35: S79-83.
[4] Rokicki J, Li L, Imabayashi E, Kaneko J, Hisatsune T, Matsuda H (2015). Daily Carnosine and Anserine Supplementation Alters Verbal Episodic Memory and Resting State Network Connectivity in Healthy Elderly Adults. Front Aging Neurosci, 7:219.
[5] Hisatsune T, Kaneko J, Kurashige H, Cao Y, Satsu H, Totsuka M, Katakura Y, Imabayashi E, Matsuda H (2016). Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People. J Alzheimers Dis, 50:149-59.
[6] Boldyrev AA, Aldini G, Derave W (2013). Physiology and pathology of carnosine. Physiol Rev, 93:1803-1845.
[7] Hipkiss AR (2014). Aging risk factors and Parkinson’s disease: contrasting roles of common dietary constituents. Neurobiol Aging, 35:1469-72.
[8] Yeum K-J, Orioli M, Regazzoni L, Carini M, Rasmussen H, Russell RM, Aldini G (2010). Profiling histidine dipeptides in plasma and urine after ingesting beef, chicken or chicken broth in humans. Amino Acids, 38:847-858.
[9] Kubomura D, Matahira Y, Masui A, Matsuda H (2009). Intestinal Absorption and Blood Clearance of L-Histidine-Related Compounds after Ingestion of Anserine in Humans and Comparison to Anserine-Containing Diets. J Agric Food Chem, 57:1781-1785.
[10] Szcześniak D, Budzen S, Kopec W, Rymaszewska J (2014). Anserine and carnosine supplementation in the elderly: Effects on cognitive functioning and physical capacity. Arch. Gerontol Geriatr, 59:485-490.
[11] Kawano N, Awata S, Ijuin M, Iwamoto K, Ozaki N (2013). Necessity of normative data on the Japanese version of the Wechsler Memory Scale-Revised Logical Memory subtest for old-old people. Geriatr Gerontol Int, 13:726-30.
[12] Liu Y, Zhu X, Feinberg D, Guenther M, Gregori J, Weiner MW, Schuff N (2012). Arterial spin labeling MRI study of age and gender effects on brain perfusion hemodynamics. Magn Reson Med, 68:912-22.
[13] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA, 278:1349-56.
[14] Giri M, Zhang M, Lü Y (2016). Genes associated with Alzheimer’s disease: an overview and current status. Clin Interv Aging, 11:665-81.
[15] Tai LM, Thomas R, Marottoli FM, Koster KP, Kanekiyo T, Morris AWJ, Bu G (2016). The role of APOE in cerebrovascular dysfunction. Acta Neuropathol, 131:709-723.
[16] Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM (2010). APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol, 67:93-8.
[17] Gietl AF, Warnock G, Riese F, Kälin AM, Saake A, Gruber E, Leh SE, Unschuld PG, Kuhn FP, Burger C, Mu L, Seifert B, Nitsch RM, Schibli R, Ametamey SM, Buck A, Hock C (2015). Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner. Neurobiol Aging, 36:1619-28.
[18] Michels L, Warnock G, Buck A, Macauda G, Leh SE, Kaelin AM, Riese F, Meyer R, O’Gorman R, Hock C, Kollias S, Gietl AF (2016). Arterial spin labeling imaging reveals widespread and Aβ-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers. J Cereb Blood Flow Metab, 36:581-95.
[19] Sato Y, Chin Y, Kato T, Tanaka Y, Tozuka Y, Mase M, Ageyama N, Ono F, Terao K, Yoshikawa Y, Hisatsune T (2009). White matter activated glial cells produce BDNF in a stroke model of monkeys. Neurosci Res, 65:71-78.
[20] Cox SR, Ritchie SJ, Dickie DA, Pattie A, Royle NA, Corley J, Aribisala BS, Harris SE, Valdés Hernández M, Gow AJ, Muñoz Maniega S, Starr JM, Bastin ME, Wardlaw JM, Deary IJ (2017). Interaction of APOE e4 and poor glycemic control predicts white matter hyperintensity growth from 73 to 76. Neurobiol Aging, 54:54-58.
[21] Chin Y, Sato Y, Mase M, Kato T, Herculano B, Sekino M, Ohsaki H, Ageyama N, Ono F, Terao K, Yoshikawa Y, Hisatsune T (2010). Transient decrease in cerebral motor pathway fractional anisotropy after focal ischemic stroke in monkey. Neurosci Res, 66:406-411.
[22] Chin Y, Kishi M, Sekino M, Nakajo F, Abe Y, Terazono Y, Ohsaki H, Kato F, Koizumi S, Gachet C, Hisatsune T (2013). Involvement of glial P2Y1 receptors in the cognitive deficits after focal cerebral stroke in a rodent model. J Neuroinflammation, 10:95.
[23] Aoyagi S, Sugino T, Kajimoto Y, Nishitani M (2008a). Safety of long-term administration of CBEX-Dr-containing drink of healthy people. Jpn Pharmacol Ther, 36:213-24.
[24] Aoyagi S, Sugino T, Kajimoto Y, Nishitani M (2008b). Safety of excess administration of CBEX-Dr-containing drink of healthy people. Jpn Pharmacol Ther, 36:225-35.
[25] Kiyohara Y, Shinohara A, Kato I, Shirota T, Kubo M, Tanizaki Y, Fujishima M, Iida M (2003). Dietary factors and development of impaired glucose tolerance and diabetes in a general Japanese population: The Hisayama Study. J Epidemiology, 13:251-258.
[26] Homma A, Fukuzawa K, Tsukada Y, Ishii T, Hasegawa K, Mohs RC (1992). Development of a Japanese version of Alzheimer’s disease Assessment Scale (ADAS). Jpn J Geriatr Psychiatry, 3:647-55.
[27] Uchida K, Shan L, Suzuki H, Tabuse Y, Nishimura Y, Hirokawa Y, Mizukami K, Akatsu H, Meno K, Asada T (2015). Amyloid-β sequester proteins as blood-based biomarkers of cognitive decline. Alzheimers Dement: Diagnosis Assessment Disease Monitoring, 1:270-80.
[28] Beck AT, Steer RA, Brown GK (1996). Manual for the Beck Depression Inventory, 2nd Ed., Pearson, Texas.
[29] Kojima M, Furukawa TA (2003). Japanese manual of the Beck Depression Inventory, 2nd ed., Nihon Bunka Kagakusha, Tokyo.
[30] Ware JE, Sherbourne CD (1992). The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care, 30:474-83.
[31] Lu Y, Nyunt MS, Gwee X, Feng L, Feng L, Kua EH, Kumar R, Ng TP (2012). Life event stress and chronic obstructive pulmonary disease (COPD): associations with mental well-being and quality of life in a population-based study. BMJ Open, 2: e001674.
[32] Yang YG, Kim JY, Park SJ, Kim SW, Jeon OH, Kim DS (2007). Apolipoprotein E genotyping by multiplex tetra-primer amplification refractory mutation system PCR in single reaction tube. J Biotechnol, 131:106-10.
[33] Matsuda H (2013). Voxel-based morphometry of brain MRI in normal aging and Alzheimer’s Disease. Aging Dis, 4:29-37.
[34] Ashburner J (2007). A fast-diffeomorphic image registration algorithm. Neuroimage, 38: 95-113.
[35] Wang R, Benner T, Sorensen AG, Wedeen VJ (2007). Diffusion toolkit: a software package for diffusion imaging data processing and tractography. Proc Intl Soc Mag Reson Med, 15: 3720
[36] Andersson JL, Sotiropoulos SN (2016). An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. Neuroimage. 125:1063-78.
[37] Smith SM (2002). Fast robust automated brain extraction. Hum Brain Mapp, 17:143-55.
[38] Daiello LA, Gongvatana A, Dunsiger S, Cohen RA, Ott BR; Alzheimer’s Disease Neuroimaging Initiative. (2015). Association of fish oil supplement use with preservation of brain volume and cognitive function. Alzheimers Dement, 11:226-35.
[39] Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, Harrington MG, Chui HC (2017). Association of Docosahexaenoic Acid Supplementation with Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review. JAMA Neurol, 74:339-347.
[40] Herculano B, Tamura M, Ohba A., Shimatani M, Kutsuna N, Hisatsune T (2013). β-alanyl-L-histidine rescues cognitive deficits caused by feeding a high fat diet in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis, 33:983-997.
[41] Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature, 485:512-6.
[42] Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV (2016). Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab, 36:216-227.
[43] Hipkiss AR (2017). On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine. Aging Dis, 8:334-345.
[44] Hamanaka H, Katoh-Fukui Y, Suzuki K, Kobayashi M, Suzuki R, Motegi Y, Nakahara Y, Takeshita A, Kawai M, Ishiguro K, Yokoyama M, Fujita SC (2000). Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum Mol Genet, 9:353-61.
[45] Jankowsky JL, Slunt HH, Ratoviski T, Jenkins NA, Copeland NG, Borchelt DR (2001). Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomolecular Engineering, 17:157-165.
[46] Fujishima M, Kawaguchi A, Maikusa N, Kuwano R, Iwatsubo T, Matsuda H (2017). Sample Size Estimation for Alzheimer’s Disease Trials from Japanese ADNI Serial Magnetic Resonance Imaging. J Alzheimers Dis, 56:75-88.
[47] Rajah MN, Wallace LMK, Ankudowich E, Yu EH, Swierkot A, Patel R, Chakravarty MM, Naumova D, Pruessner J, Joober R, Gauthier S, Pasvanis S (2017). Family history and APOE4 risk for Alzheimer’s disease impact the neural correlates of episodic memory by early midlife. Neuroimage Clin, 14:760-774.
[48] Kljajevic V, Meyer P, Holzmann C, Dyrba M, Kasper E, Bokde AL, Fellgiebel A, Meindl T, Hampel H, Teipel S; EDSD study group (2014). The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer’s disease. Alzheimers Dement, 10:401-4.
[49] Adluru N, Destiche DJ, Lu SY, Doran ST, Birdsill AC, Melah KE, Okonkwo OC, Alexander AL, Dowling NM, Johnson SC, Sager MA, Bendlin BB (2014). White matter microstructure in late middle-age: Effects of apolipoprotein E4 and parental family history of Alzheimer’s disease. Neuroimage Clin, 4:730-42.
[50] Racine AM, Adluru N, Alexander AL, Christian BT, Okonkwo OC, Oh J, Cleary CA, Birdsill A, Hillmer AT, Murali D, Barnhart TE, Gallagher CL, Carlsson CM, Rowley HA, Dowling NM, Asthana S, Sager MA, Bendlin BB, Johnson SC (2014). Associations between white matter microstructure and amyloid burden in preclinical Alzheimer’s disease: A multimodal imaging investigation. Neuroimage Clin, 4:604-14.
[51] Reinvang I, Espeseth T, Westlye LT (2013). APOE-related biomarker profiles in non-pathological aging and early phases of Alzheimer’s disease. Neurosci Biobehav Rev, 37:1322-35.
[1] Daichi Sone,Etsuko Imabayashi,Norihide Maikusa,Masayo Ogawa,Noriko Sato,Hiroshi Matsuda,Japanese-Alzheimer’s Disease Neuroimaging Initiative. Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on 3-tesla Normal Database: Diagnostic Accuracy in Two Independent Cohorts with Early Alzheimer’s Disease[J]. A&D, 2018, 9(4): 755-760.
[2] Fabiana Morroni,Giulia Sita,Agnese Graziosi,Eleonora Turrini,Carmela Fimognari,Andrea Tarozzi,Patrizia Hrelia. Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway[J]. A&D, 2018, 9(4): 605-622.
[3] Yangqi Xu,Xiaoli Liu,Junyi Shen,Wotu Tian,Rong Fang,Binyin Li,Jianfang Ma,Li Cao,Shengdi Chen,Guanjun Li,Huidong Tang. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia[J]. A&D, 2018, 9(4): 696-705.
[4] Xin Xu,Yuanyuan Gao,Renyuan Liu,Lai Qian,Yan Chen,Xiaoying Wang,Yun Xu. Progression of White Matter Hyperintensities Contributes to Lacunar Infarction[J]. A&D, 2018, 9(3): 444-452.
[5] Ting Shen,Yuyi You,Chitra Joseph,Mehdi Mirzaei,Alexander Klistorner,Stuart L. Graham,Vivek Gupta. BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders[J]. A&D, 2018, 9(3): 523-536.
[6] Fangyu Peng,Fang Xie,Otto Muzik. Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT[J]. A&D, 2018, 9(1): 109-118.
[7] Diana L Castillo-Carranza,Ashley N Nilson,Candice E Van Skike,Jordan B Jahrling,Kishan Patel,Prajesh Garach,Julia E Gerson,Urmi Sengupta,Jose Abisambra,Peter Nelson,Juan Troncoso,Zoltan Ungvari,Veronica Galvan,Rakez Kayed. Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer’s Disease and Related Tauopathies[J]. A&D, 2017, 8(3): 257-266.
[8] Zohara Sternberg,Zihua Hu,Daniel Sternberg,Shayan Waseh,Joseph F. Quinn,Katharine Wild,Kaye Jeffrey,Lin Zhao,Michael Garrick. Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease[J]. A&D, 2017, 8(2): 215-227.
[9] Jianhui Wang,Xiaorui Cheng,Ju Zeng,Jiangbei Yuan,Zhongfu Wang,Wenxia Zhou,Yongxiang Zhang. LW-AFC Effects on N-glycan Profile in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer’s Disease[J]. A&D, 2017, 8(1): 101-114.
[10] Annamaria Zaia,Pierluigi Maponi,Giuseppina Di Stefano,Tiziana Casoli. Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Focus on Mitochondrial DNA and Alzheimer’s Disease[J]. A&D, 2017, 8(1): 44-56.
[11] Mei-Yan Liu,Yan-Ping Ren,Li-Jun Zhang,Jamie Y. Ding. Pretreatment with Ginseng Fruit Saponins Affects Serotonin Expression in an Experimental Comorbidity Model of Myocardial Infarction and Depression[J]. A&D, 2016, 7(6): 680-686.
[12] Murat Serdar Gurses,Mustafa Numan Ural,Mehmet Akif Gulec,Omer Akyol,Sumeyya Akyol. Pathophysiological Function of ADAMTS Enzymes on Molecular Mechanism of Alzheimer’s Disease[J]. A&D, 2016, 7(4): 479-490.
[13] Ryan J. Day,Katie L. McCarty,Kayla E. Ockerse,Elizabeth Head,Troy T. Rohn. Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain[J]. A&D, 2016, 7(3): 267-277.
[14] Isaac G. Onyango,Jameel Dennis,Shaharyah M. Khan. Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies[J]. A&D, 2016, 7(2): 201-214.
[15] J. De Reuck,F. Auger,N. Durieux,V. Deramecourt,C. Cordonnier,F. Pasquier,C.A. Maurage,D. Leys,R. Bordet. Topography of Cortical Microbleeds in Alzheimer’s Disease with and without Cerebral Amyloid Angiopathy: A Post-Mortem 7.0-Tesla MRI Study[J]. A&D, 2015, 6(6): 437-443.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd