The Impact of Angiotensin-Converting Enzyme Gene on Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease

Author(s): Sun-Wung Hsieh, Ming-Wei Liu, Ling-Chun Huang, Meng-Ni Wu, Yuan-Han Yang*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 14 , 2019

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Background: The Angiotensin-Converting Enzyme (ACE) gene has drawn attention for its possible role in regulating the degradation of β-amyloid (Aβ), yet its role in affecting the cognitive and psychiatric symptoms of Alzheimer`s Disease (AD) patients has yet to be elucidated.

Objective: This study aimed to investigate whether the ACE gene acts as a risk factor of Behavioral and Psychological Symptoms of Dementia (BPSD) in the AD population.

Methods: The genotyping of ACE and Apolipoprotein E gene with allele ε4(APOEε4) was determined among 360s clinically diagnosed AD patients. Symptoms and severity of BPSD were evaluated annually via Neuropsychiatric Inventory (NPI).

Results: At the base measurement of the first year of patient recruitment, there were no significant contributory risk factors to NPI score. In the two-year follow-up, ACE insertion polymorphism showed a significant risk (adjusted odds ratio=1.65, 95% CI=1.1- 2.5, p=0.019) of progression of NPI total score.

Conclusion: ACE gene is involved in aggravating BPSD among AD patients.

Keywords: Alzheimer's disease, angiotensin-converting enzyme gene, apolipoprotein E gene, behavioral and psychological symptoms of dementia, neuropsychiatric inventory, β-amyloid.

Finkel SI, Costa e Silva J, Cohen G, Miller S, Sartorius N. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr 8(3): 497-500. (1996)
[] [PMID: 9154615]
Ferreira ST, Klein WL. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 96(4): 529-43. (2011)
[] [PMID: 21914486]
Fein JA, Sokolow S, Miller CA, Vinters HV, Yang F, Cole GM, et al. Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am J Pathol 172(6): 1683-92. (2008)
[] [PMID: 18467692]
Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK. Co-occurrence of Alzheimer’s disease ß-amyloid and τ pathologies at synapses. Neurobiol Aging 31(7): 1145-52. (2010)
[] [PMID: 18771816]
Li K, Wei Q, Liu FF, Hu F, Xie AJ, Zhu LQ, et al. Synaptic dysfunction in alzheimer’s disease: Aβ, tau, and epigenetic alterations. Mol Neurobiol 55(4): 3021-32. (2018)
[] [PMID: 28456942]
DeMichele-Sweet MA, Sweet RA. Genetics of Psychosis in Alzheimer Disease. Curr Genet Med Rep 2(1): 30-8. (2014)
[] [PMID: 24883238]
Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol 162(4): 305-17. (2005)
[] [PMID: 16033878]
Jochemsen HM, Teunissen CE, Ashby EL, van der Flier WM, Jones RE, Geerlings MI, et al. The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease. Alzheimers Res Ther 6(3): 27. (2014)
[] [PMID: 24987467]
Barnes JM, Barnes NM, Costall B, Horovitz ZP, Ironside JW, Naylor RJ, et al. Angiotensin II inhibits cortical cholinergic function: implications for cognition. J Cardiovasc Pharmacol 16(2): 234-8. (1990)
[] [PMID: 1697379]
Chou PS, Wu MN, Chou MC, Chien I, Yang YH. Angiotensin-converting enzyme insertion/deletion polymorphism and the longitudinal progression of Alzheimer’s disease. Geriatr Gerontol Int 17(10): 1544-50. (2017)
[PMID: 27862810]
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34(7): 939-44. (1984)
[] [PMID: 6610841]
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3): 189-98. (1975)
[] [PMID: 1202204]
Teng EL, Hasegawa K, Homma A, Imai Y, Larson E, Graves A, et al. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 6(1): 45-58. (1994)
[] [PMID: 8054493]
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44(12): 2308-14. (1994)
[] [PMID: 7991117]
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43(11): 2412-4. (1993)
[] [PMID: 8232972]
Yang YH, Fuh JL, Mok VC. Vascular contribution to cognition in stroke and Alzheimer’s disease. Brain Sci Adv 4: 39-48. (2018)
Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 20(6): 1433. (1992)
[] [PMID: 1313972]
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86(4): 1343-6. (1990)
[] [PMID: 1976655]
Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 332(11): 706-11. (1995)
[] [PMID: 7854377]
Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J. Variation at APOE and STH loci and Alzheimer’s disease. Behav Brain Funct 2: 13. (2006)
[] [PMID: 16603077]
Rohn TT. Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer’s disease. Int J Mol Sci 14(7): 14908-22. (2013)
[] [PMID: 23867607]
Ballard C, Massey H, Lamb H, Morris C. Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer’s disease. J Neurol Neurosurg Psychiatry 63(2): 273-4. (1997)
[] [PMID: 9285479]
Harwood DG, Barker WW, Ownby RL, St George-Hyslop P, Duara R. Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer’s disease. Am J Geriatr Psychiatry 7(2): 119-23. (1999)
[] [PMID: 10322238]
Cao QY, Guo WH, Yang HL, Shen DW, Zhao P, Jiang KD, et al. Change of cerebral metabolism rate of glucose of cerebral white matter in Alzheimer’s disease: a study with statistical parametric mapping software. Zhonghua Yi Xue Za Zhi 87(39): 2777-9. (2007)
[PMID: 18167271]
Tian J, Shi J, Bailey K, Mann DM. Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer’s disease. Neuropathol Appl Neurobiol 30(1): 46-56. (2004)
[] [PMID: 14720176]
Rutten-Jacobs LC, de Leeuw FE, Geurts-van Bon L, Gordinou de Gouberville MC, Schepens-Franke AN, Dederen PJ, et al. White matter lesions are not related to β-amyloid deposition in an autopsy-based study. Curr Gerontol Geriatr Res 2011826862 (2011)
[] [PMID: 22203842]
Tian J, Shi J, Bailey K, Harris JM, Pritchard A, Lambert JC, et al. A polymorphism in the angiotensin 1-converting enzyme gene is associated with damage to cerebral cortical white matter in Alzheimer’s disease. Neurosci Lett 354(2): 103-6. (2004)
[] [PMID: 14698449]
Baranello RJ, Bharani KL, Padmaraju V, Chopra N, Lahiri DK, Greig NH, et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr Alzheimer Res 12(1): 32-46. (2015)
[] [PMID: 25523424]
Barnes NM, Cheng CH, Costall B, Naylor RJ, Williams TJ, Wischik CM. Angiotensin converting enzyme density is increased in temporal cortex from patients with Alzheimer’s disease. Eur J Pharmacol 200(2-3): 289-92. (1991)
[] [PMID: 1664329]
Shaw S, Bencherif M, Marrero MB. Angiotensin II blocks nicotine-mediated neuroprotection against beta-amyloid (1-42) via activation of the tyrosine phosphatase SHP-1. J Neurosci 23(35): 11224-8. (2003)
[] [PMID: 14657181]
Barnes JM, Barnes NM, Costall B, Horovitz ZP, Ironside JW, Naylor RJ, et al. Angiotensin II inhibits acetylcholine release from human temporal cortex: implications for cognition. Brain Res 507(2): 341-3. (1990)
[] [PMID: 2337775]
Ohrui T, Tomita N, Sato-Nakagawa T, Matsui T, Maruyama M, Niwa K, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology 63(7): 1324-5. (2004)
[] [PMID: 15477567]
Miners S, Ashby E, Baig S, Harrison R, Tayler H, Speedy E, et al. Angiotensin-converting enzyme levels and activity in Alzheimer’s disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am J Transl Res 1(2): 163-77. (2009)
[PMID: 19956428]
Wu SJ, Hsieh TJ, Kuo MC, Tsai ML, Tsai KL, Chen CH, et al. Functional regulation of Alu element of human angiotensin-converting enzyme gene in neuron cells. Neurobiol Aging 34(7): 1921.e1-7. (2013)
[] [PMID: 23391425]
Miners JS, van Helmond Z, Raiker M, Love S, Kehoe PG. ACE variants and association with brain Aβ levels in Alzheimer’s disease. Am J Transl Res 3(1): 73-80. (2010)
[PMID: 21139807]
Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 11(2): 131-45. (2003)
[] [PMID: 12611743]
Wright JW, Harding JW. Brain renin-angiotensin--a new look at an old system. Prog Neurobiol 95(1): 49-67. (2011)
[] [PMID: 21777652]
Tamano H, Ide K, Adlard PA, Bush AI, Takeda A. Involvement of hippocampal excitability in amyloid β-induced behavioral and psychological symptoms of dementia. J Toxicol Sci 41(4): 449-57. (2016)
[] [PMID: 27432231]
Tana C, Wegener S, Borys E, Pambuccian S, Tchernev G, Tana M, et al. Challenges in the diagnosis and treatment of neurosarcoidosis. Ann Med 47(7): 576-91. (2015)
[] [PMID: 26469296]
Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, Müller-Quernheim J. Sarcoidosis. Lancet 383(9923): 1155-67. (2014)
[] [PMID: 24090799]
Tana C, Giamberardino MA, Di Gioacchino M, Mezzetti A, Schiavone C. Immunopathogenesis of sarcoidosis and risk of malignancy: a lost truth? Int J Immunopathol Pharmacol 26(2): 305-13. (2013)
[] [PMID: 23755746]
Oliveira FF, Chen ES, Smith MC, Bertolucci PH. Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia. Br J Psychiatry 39(2): 95-103. (2017)
[] [PMID: 28099631]
Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg SM, Knopman D, et al. Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement 11(6): 710-7. (2015)
[] [PMID: 25510382]
de Oliveira FF, Bertolucci PH, Chen ES, Smith Mde A. Assessment of sleep satisfaction in patients with dementia due to Alzheimer’s disease. J Clin Neurosci 21(12): 2112-7. (2014)
[] [PMID: 25194823]
Lyketsos CG, Baker L, Warren A, Steele C, Brandt J, Steinberg M, et al. Depression, delusions, and hallucinations in Alzheimer’s disease: no relationship to apolipoprotein E genotype. J Neuropsychiatry Clin Neurosci 9(1): 64-7. (1997)
[] [PMID: 9017530]
van der Flier WM, Staekenborg S, Pijnenburg YA, et al. Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease. Dement Geriatr Cogn Disord 23(1): 42-6. (2007)
[] [PMID: 17077632]

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Year: 2019
Published on: 28 January, 2020
Page: [1269 - 1275]
Pages: 7
DOI: 10.2174/1567205017666200103114550
Price: $65

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