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Blood Biomarkers for Alzheimer's Dementia Diagnosis

알츠하이머성 치매에서 혈액 진단을 위한 바이오마커

  • Chang-Eun, Park (Department of Biomedical Laboratory Science, Molecular Diagnostics Research Institute, Namseoul University)
  • 박창은 (남서울대학교 임상병리학과.분자진단연구소)
  • Received : 2022.11.26
  • Accepted : 2022.12.05
  • Published : 2022.12.31

Abstract

Alzheimer's disease (AD) represents a major public health concern and has been identified as a research priority. Clinical research evidence supports that the core cerebrospinal fluid (CSF) biomarkers for AD, including amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau), reflect key elements of AD pathophysiology. Nevertheless, advances in the clinical identification of new indicators will be critical not only for the discovery of sensitive, specific, and reliable biomarkers of preclinical AD pathology, but also for the development of tests that facilitate the early detection and differential diagnosis of dementia and disease progression monitoring. The early detection of AD in its presymptomatic stages would represent a great opportunity for earlier therapeutic intervention. The chance of successful treatment would be increased since interventions would be performed before extensive synaptic damage and neuronal loss would have occurred. In this study, the importance of developing an early diagnostic method using cognitive decline biomarkers that can discriminate between normal, mild cognitive impairment (MCI), and AD preclinical stages has been emphasized.

알츠하이머병은 주요한 공중보건 문제로 나타나며 연구분야에서도 최우선적인 과제이다. 알츠하이머병(AD)에서 뇌척수액(CSF)을 활용한 바이오마커인 아밀로이드-β(Aβ42), 총 타우(T-tau) 및 인산화 타우(P-tau)가 알츠하이머병 병태생리학의 핵심 요소를 반영한다. 임상 연구 및 새로운 측정법을 통한 임상적으로 활용되는 진단은 전임상 알츠하이머병에 대해 민감적이고 특이적이며 신뢰할 수 있는 바이오마커의 발굴, 뿐만 아니라 치매의 조기 발견 및 감별 진단과 질병 진행 모니터링에 도움이 되는 검사법의 개발에도 중요할 것이다. 증상 전 단계에서 AD의 조기 발견은 시냅스 손상 및 신경 손실이 확장되기 전에 개입이 수행되기 때문에 치료 개입을 조기에 가능하게 하고 치료 성공을 위한 가능성이 더 큰 좋은 기회로 이어진다. 따라서 새롭고 접근하기 쉽고 비용이 적게 드는 바이오마커를 임상 진단에 활용하는 것이 매우 유익할 것이다. 치매의 초기단계에 일어나는 병리학적 변화나, 질병의 진행정도를 추적할 수 있는 다양한 바이오마커들의 진단방법을 찾는 일은 치료제 개발처럼 중요한 연구 분야이다. 조기진단을 위해 임상증상을 대변하거나(surrogate marker), 증상이 나타나기 이전 상태를 측정할 수 있는 새로운 진단마커가 필요한 상황이다. 이러한 이유로 인지기능 저하정도를 측정하여 정상, 경도인지장애(mild cognition impairment, MCI) 및 전임상(preclinical) 상태의 사람을 판별할 수 있는 바이오마커(biomarker)를 활용한 조기진단법 개발의 중요성이 강조되고 있다.

Keywords

Acknowledgement

Funding for this paper was provided by Namseoul University year 2022.

References

  1. Luu L, Ciccotosto GD, Cappai R. The Alzheimer's disease amyloid precursor protein and its neuritogenic actions. Curr Alzheimer Res. 2021;18:772-786. https://doi.org/10.2174/156720501866621120814101
  2. Hansson O, Mikulskis A, Fagan AM, Teunissen C, Zetterberg H, Vanderstichele H, et al. The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: a review. Alzheimers Dement. 2018;14:1313-1333. https://doi.org/10.1016/j.jalz.2018.05.008
  3. Wegmann S, Biernat J, Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer's disease. Curr Opin Neurobiol. 2021;69:131-138. https://doi.org/10.1016/j.conb.2021.03.003
  4. Babapour Mofrad R, Scheltens P, Kim S, Kang S, Youn YC, An SSA, et al. Plasma amyloid-β oligomerization assay as a pre-screening test for amyloid status. Alzheimers Res Ther. 2021;13:133. https://doi.org/10.1186/s13195-021-00873-w
  5. Choi Y, Joh Y, Ryu JS, Kim K, Seo D, Kim S. Endogenous Aβ peptide promote Aβ oligomerization tendency of spiked synthetic Aβ in Alzheimer's disease plasma. Mol Cell Neurosci. 2021;111: 103588. https://doi.org/10.1016/j.mcn.2021.103588
  6. Pyun JM, Ryu JS, Lee R, Shim KH, Youn YC, Ryoo N, et al. Plasma amyloid-β oligomerization tendency predicts amyloid PET positivity. Clin Interv Aging. 2021 Apr 30;16:749-755. https://doi.org/10.2147/CIA.S312473
  7. Konietzko U. AICD nuclear signaling and its possible contribution to Alzheimer's disease. Curr Alzheimer Res. 2012;9:200-216. https://doi.org/10.2174/156720512799361673
  8. Irwin DJ, Lee VM, Trojanowski JQ. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci. 2013;14:626-436. https://doi.org/10.1038/nrn3549
  9. Youn YC, Lee BS, Kim GJ, Ryu JS, Lim K, Lee R, et al. Blood amyloid-β oligomerization as a biomarker of Alzheimer's disease: a blinded validation study. J Alzheimers Dis. 2020;75:493-499. https://doi.org/10.3233/JAD-200061
  10. Meng X, Li T, Wang X, Lv X, Sun Z, Zhang J, et al. Association between increased levels of amyloid-β oligomers in plasma and episodic memory loss in Alzheimer's disease. Alzheimers Res Ther. 2019;11:89. https://doi.org/10.1186/s13195-019-0535-7
  11. An SSA, Lee BS, Yu JS, Lim K, Kim GJ, Lee R, et al. Dynamic changes of oligomeric amyloid β levels in plasma induced by spiked synthetic Aβ42. Alzheimers Res Ther. 2017;9:86. https://doi.org/10.1186/s13195-017-0310-6
  12. Ivanov SM, Atanasova M, Dimitrov I, Doytchinova IA. Cellular polyamines condense hyperphosphorylated Tau, triggering Alzheimer's disease. Sci Rep. 2020;10:10098. https://doi.org/10.1038/s41598-020-67119-x
  13. Lan G, Cai Y, Li A, Liu Z, Ma S, Guo T, et al. Association of presynaptic loss with Alzheimer's disease and cognitive decline. Ann Neurol. 2022;92:1001-1015. https://doi.org/10.1002/ana.2649
  14. Williams SM, Schulz P, Sierks MR. Oligomeric alpha-synuclein and beta-amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases. Eur J Neurosci. 2016;43:3-16. https://doi.org/10.1111/ejn.13056
  15. Meneses A, Koga S, O'Leary J, Dickson DW, Bu G, Zhao N. TDP-43 Pathology in Alzheimer's disease. Mol Neurodegener. 2021;16:84. https://doi.org/10.1186/s13024-021-00503-x
  16. Zheng Y, Zhang L, Zhao J, Li L, Wang M, Gao P, et al. Advances in aptamers against Aβ and applications in Aβ detection and regulation for Alzheimer's disease. Theranostics. 2022;12:2095-2114. https://doi.org/10.7150/thno.69465
  17. Hugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med. 2014;30: 421-442. https://doi.org/10.1016/j.cger.2014.04.001
  18. Harris LD, Jasem S, Licchesi JDF. The ubiquitin system in Alzheimer's disease. Adv Exp Med Biol. 2020;1233:195-221. https://doi.org/10.1007/978-3-030-38266-7_8
  19. Ruan Z, Pathak D, Venkatesan Kalavai S, Yoshii-Kitahara A, Muraoka S, Bhatt N, et al. Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2021;144:288-309. https://doi.org/10.1093/brain/awaa376
  20. Hu S, Tan J, Qin L, Lv L, Yan W, Zhang H, et al. Molecular chaperones and Parkinson's disease. Neurobiol Dis. 2021;160:105527. https://doi.org/10.1016/j.nbd.2021.105527
  21. Varesi A, Pierella E, Romeo M, Piccini GB, Alfano C, Bjorklund G, et al. The potential role of gut microbiota in Alzheimer's disease: from diagnosis to treatment. Nutrients. 2022;14:668. https://doi.org/10.3390/nu14030668
  22. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer's disease. J Alzheimers Dis. 2017;58:1-15. https://doi.org/10.3233/JAD-161141
  23. Chong JR, Ashton NJ, Karikari TK, Tanaka T, Scholl M, Zetterberg H, et al. Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer's disease: a focused review on recent advances. J Neurol Neurosurg Psychiatry. 2021;92:1231-1241. https://doi.org/10.1136/jnnp-2021-327370
  24. Leuzy A, Cullen NC, Mattsson-Carlgren N, Hansson O. Current advances in plasma and cerebrospinal fluid biomarkers in Alzheimer's disease. Curr Opin Neurol. 2021 ;34:266-274. https://doi.org/10.1097/WCO.0000000000000904
  25. Hansson O, Lehmann S, Otto M, Zetterberg H, Lewczuk P. Advantages and disadvantages of the use of the CSF amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer's disease. Alzheimers Res Ther. 2019;11:34. https://doi.org/10.1186/s13195-019-0485-0
  26. Cervellati C, Trentini A, Rosta V, Passaro A, Bosi C, Sanz JM, et al. Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer's disease. Geroscience. 2020;42:159-167. https://doi.org/10.1007/s11357-019-00127-6
  27. Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019;25:277-283. https://doi.org/10.1038/s41591-018-0304-3
  28. Mavroudis I, Chowdhury R, Petridis F, Karantali E, Chatzikonstantinou S, Balmus IM, et al. YKL-40 as a potential biomarker for the differential diagnosis of Alzheimer's disease. Medicina (Kaunas). 2021;58:60. https://doi.org/10.3390/medicina58010060
  29. Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer's disease. J Neurogastroenterol Motil. 2019;25:48-60. https://doi.org/10.5056/jnm18087
  30. Moscoso A, Grothe MJ, Ashton NJ, Karikari TK, Lantero Rodriguez J, Snellman A, et al. Longitudinal associations of blood phosphorylated tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol. 2021;78:396-406. https://doi.org/10.1001/jamaneurol.2020.4986
  31. Rojas JC, Karydas A, Bang J, Tsai RM, Blennow K, Liman V, et al. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann Clin Transl Neurol. 2016;3: 216-225. https://doi.org/10.1002/acn3.290
  32. Katayama T, Sawada J, Takahashi K, Yahara O, Hasebe N. Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alzheimers Res Ther. 2021;13:163. https://doi.org/10.1186/s13195-021-00907-3
  33. Tarawneh R, D'Angelo G, Macy E, Xiong C, Carter D, Cairns NJ, et al. Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. Ann Neurol. 2011 Aug;70(2):274-85. https://doi.org/10.1002/ana.2244
  34. Sturchio A, Dwivedi AK, Malm T, Wood MJA, Cilia R, Sharma JS, et al. High soluble amyloid-β42 predicts normal cognition in amyloid-positive individuals with Alzheimer's disease-causing mutations. J Alzheimers Dis. 2022;90:333-348. https://doi.org/10.3233/JAD-220808
  35. Mizoi M, Yoshida M, Saiki R, Waragai M, Uemura K, Akatsu H, et al. Distinction between mild cognitive impairment and Alzheimer's disease by CSF amyloid β40 and β42, and protein-conjugated acrolein. Clin Chim Acta. 2014;430:150-155. https://doi.org/10.1016/j.cca.2014.01.007
  36. Mulugeta E, Londos E, Ballard C, Alves G, Zetterberg H, Blennow K, et al. CSF amyloid β38 as a novel diagnostic marker for dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2011;82:160-164. https://doi.org/10.1136/jnnp.2009.199398
  37. Xu Y, Shen YY, Zhang XP, Gui L, Cai M, Peng GP, et al. Diagnostic potential of urinary monocyte chemoattractant protein-1 for Alzheimer's disease and amnestic mild cognitive impairment. Eur J Neurol. 2020;27:1429-1435. https://doi.org/10.1111/ene.14254
  38. Oeckl P, Halbgebauer S, Anderl-Straub S, Steinacker P, Huss AM, Neugebauer H, et al. Glial fibrillary acidic protein in serum is increased in Alzheimer's disease and correlates with cognitive impairment. J Alzheimers Dis. 2019;67:481-488. https://doi.org/10.3233/JAD-180325
  39. Wang X, Zhang S, Lin F, Chu W, Yue S. Elevated galectin-3 levels in the serum of patients with Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2015;30:729-732. https://doi.org/10.1177/1533317513495107
  40. Wang MJ, Yi S, Han JY, Park SY, Jang JW, Chun IK, et al. Oligomeric forms of amyloid-β protein in plasma as a potential blood-based biomarker for Alzheimer's disease. Alzheimers Res Ther. 2017;9:98. https://doi.org/10.1186/s13195-017-0324-0
  41. Guo Y, Hu Z, Wang Z. Corrigendum: recent advances in the application peptide and peptoid in diagnosis biomarkers of Alzheimer's disease in blood. Front Mol Neurosci. 2022;15:865110. https://doi.org/10.3389/fnmol.2022.865110
  42. Shi Y, Bao Q, Chen W, Wang L, Peng D, Liu J, et al. Potential roles of extracellular vesicles as diagnosis biomarkers and therapeutic approaches for cognitive impairment in Alzheimer's disease. J Alzheimers Dis. 2022;87:1-15. https://doi.org/10.3233/JAD-215666
  43. Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673-684. https://doi.org/10.1016/S1474-4422(16)00070-3
  44. Jia L, Zhu M, Kong C, Pang Y, Zhang H, Qiu Q, et al. Blood neuro-exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage. Alzheimers Dement. 2021;17:49-60. https://doi.org/10.1002/alz.12166
  45. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 2021;20:68-80. https://doi.org/10.1016/S1474-4422(20)30412-9
  46. Jung AN, Lee YJ, Choi SK, Park JO, Woo MS, Yu KN. A study on the statistical evaluation of apolipoprotein E genotype and Alzheimer's disease. Korean J Clin Lab Sci. 2004;36:110-114.
  47. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer's disease. J Alzheimers Dis. 2017;58:1-15. https://doi.org/10.3233/JAD-161141
  48. Leuzy A, Mattsson-Carlgren N, Palmqvist S, Janelidze S, Dage JL, Hansson O. Blood-based biomarkers for Alzheimer's disease. EMBO Mol Med. 2022;14:e14408. https://doi.org/10.15252/emmm.202114408
  49. Zetterberg H, Burnham SC. Blood-based molecular biomarkers for Alzheimer's disease. Mol Brain. 2019;12:26. https://doi.org/10.1186/s13041-019-0448-1
  50. Sharma L, Sharma A, Kumar D, Asthana MK, Lalhlenmawia H, Kumar A, et al. Promising protein biomarkers in the early diagnosis of Alzheimer's disease. Metab Brain Dis. 2022;37:1727-1744. https://doi.org/10.1007/s11011-021-00847-9