Novel Blood Biomarkers for an Earlier Diagnosis of Alzheimer’s Disease: A Literature Review

  • Shiavax J. Rao Saba University School of Medicine, Caribbean Netherlands
  • Andrew J. Boileau Saba University School of Medicine, Caribbean Netherlands
Keywords: Alzheimer's disease, Diagnosis, Biomarkers, Early diagnosis

Abstract

Alzheimer’s disease is a neurodegenerative condition associated with neurofibrillary tangles and cortical deposition of amyloid plaques. Clinical presentation of the disease involves manifestations such as memory loss, cognitive decline and dementia with some of the earliest reported deficits being episodic memory impairment and olfactory dysfunction. Current diagnostic approaches rely on autopsy characterization of gross brain pathology, or brain imaging of biomarkers late in the disease course. The aim of this literature review is to identify and compare novel blood-based biomarkers with the potential of making an earlier clinical diagnosis of Alzheimer’s disease. Utilizing such techniques may allow for earlier therapeutic intervention, reduction of disability and enhancement of patients’ quality of life. Literature review and analysis was performed by screening the PubMed database for relevant studies between July 1, 2014 and December 31, 2019. Sixteen studies were reviewed with biomarker candidates categorized under microRNAs (miRNAs), auto-antibodies, other blood-based proteins or circulating nucleic acids. Three biomarker candidates – serum neurofilament light chain, plasma β-secretase 1 activity and a panel of three miRNAs (miR-135a/193b/384) – reported statistically significant differences in testing between patients and controls, with high discriminative potential and high statistical power. In conclusion, certain blood biomarkers have shown promising results with high sensitivity and specificity, high discriminative potential for Alzheimer’s disease early in its progression, and statistically significant results in larger study samples. Utilization of such diagnostic biomarkers could increase the efficacy of making an earlier clinical diagnosis of Alzheimer’s disease.

Author Biographies

Shiavax J. Rao, Saba University School of Medicine, Caribbean Netherlands

MD, Medical Graduate.

Andrew J. Boileau, Saba University School of Medicine, Caribbean Netherlands

PhD, Professor and Course Director, Neuroscience & Neurology.

References

Berchtold NC, Cotman CW. Evolution in the conceptualization of dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol Aging. 1998 May-Jun;19(3):173-89.

Alzheimer’s Association.2019 Alzheimer’s Disease Facts and Figures. AlzheimersDement. 2019;15(3):321-87.

Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. World Alzheimer Report 2015 The Global Impact of Dementia. London: Alzheimer’s Disease International; 2015.

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, et al. "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70.

Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009 Oct;461(7266):916-22.

Leinonen V, Koivisto AM, Savolainen S, Rummukainen J, Tamminen JN, Tillgren T, et al. Amyloid and tau proteins in cortical brain biopsy and Alzheimer’s disease. Ann Neurol. 2010 Oct;68(4):446-53.

Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol. 1985 Nov;42(11):1097-105.

Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased Clearance of CNS Amyloid-B in Alzheimer’s Disease. Science. 2010 Dec;330(6012):1774.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene Dose of Apolipoprotein E Type 4 Allele and Risk of Alzheimer’s Disease in Late Onset Families. Science. 1993 Aug;261(5123):921-3.

Van Hoesen GW, Hyman BT, Damasio AR. Entorhinal cortex pathology in Alzheimer’s disease. Hippocampus. 1991 Jan;1(1):1-8.

Francis PT, Palmer AM, Sims NR, Bowen DM, Davison AN, Esiri MM, et al. Neurochemical studies of early-onset Alzheimer's disease. Possible influence on treatment. N Engl J Med. 1985 Jul;313(1):7-11.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012 Jan;8(1):1-13.

Olsson B, Lautner R, Andreasson U, Öhrfelt 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 Jun;15(7):673–84.

Song F, Poljak A, Valenzuela M, Mayeux R, Smythe GA, Sachdev PS. Meta-Analysis of Plasma Amyloid-β levels in Alzheimer’s Disease. J Alzheimers Dis. 2011;26(2):365-75.

Zetterberg H, Wilson D, Andreasson U, Minthon L, Blennow K, Randall J, et al. Plasma tau levels in Alzheimer’s disease. Alzheimers Res Ther. 2013 Mar;5(2):9.

Ashton NJ, Schöll M, Heurling K, Gkanatsiou E, Portelius E, Höglund K, et al. Update on biomarkers for amyloid pathology in Alzheimer's disease. Biomark Med. 2018 Jul;12(7):799-812.

Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Li Y, Gordon B, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019 Oct;93(17):e1647-59.

Zou Y, Lu D, Liu L, Zhang H, Zhou Y. Olfactory dysfunction in Alzheimer’s disease. Neuropsychiatr Dis Treat. 2016 Apr;12:869-75.

Thomann PA, Dos Santos V, Toro P, Schönknecht P, Essig M, Schröder J. Reduced olfactory bulb and tract volume in early Alzheimer’s disease-A MRI study. Neurobiol Aging. 2009 May;30(5):838-41.

Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer’s disease. J Neurol Sci. 2013 Oct;333(1-2):19-24.

Yang TT, Liu CG, Gao SC, Zhang Y, Wang PC. The Serum Exosome Derived MicroRNA-135a, -193b, and -384 Were Potential Alzheimer’s Disease Biomarkers. Biomed Environ Sci. 2018 Feb;31(2):87-96

Kumar S, Vijayan M, Reddy PH. MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer’s disease. Hum Mol Genet. 2017 Oct;26(19):3808-22.

Zeng Q, Zou L, Qian L, Zhou F, Nie H, Yu S, et al. Expression of microRNA‑222 in serum of patients with Alzheimer's disease. Mol Med Rep. 2017 Oct;16(4):5575-9.

Nagaraj S, Laskowska-Kaszub K, Dębski KJ, Wojsiat J, Dąbrowski M, Gabryelewicz T, et al. Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer's disease patients from non-demented subjects. Oncotarget. 2017 Mar;8(10):16122-43.

Dong H, Li J, Huang L, Chen X, Li D, Wang T, et al. Serum MicroRNA Profiles Serve as Novel Biomarkers for the Diagnosis of Alzheimer’s Disease. Dis Markers. 2015;2015:625659. doi: 10.1155/2015/625659.

McIntyre JA, Ramsey CJ, Gitter BD, Saykin AJ, Wagenknecht DR, Hyslop PA. Antiphospholipid autoantibodies as blood biomarkers for detection of early stage Alzheimer’s disease. Autoimmunity. 2015;48(5):344-51.

Giil LM, Kristoffersen EK, Vedeler CA, Aarsland D, Nordrehaug JE, Winblad B, et al. Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer’s Disease. J Alzheimers Dis. 2015;47(2):523-9.

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 Feb;25(2):277-83.

Kumar A, Singh S, Verma A, Mishra VN. Proteomics based identification of differential plasma proteins and changes in white matter integrity as markers in early detection of mild cognitive impaired subjects at high risk of Alzheimer’s disease. Neurosci Lett. 2018 May;676:71-7.

Ma QL, Teng E, Zuo X, Jones M, Teter B, Zhao EY, et al. Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease. Neurobiol Dis. 2018 Jun;114;120-8.

Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, et al. Increased Plasma BACE1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals With Mild Cognitive Impairment. Biol Psychiatry. 2018 Mar;83(5):447-55.

Zhuang S, Wang X, Wang HF, Li J, Wang HY, Zhang HZ, et al. Angiotensin converting enzyme serum activities: Relationship with Alzheimer's disease. Brain Res. 2016 Nov;1650:196-202.

Zhu Y, Chen Z, Chen X, Hu S. Serum sEPCR Levels Are Elevated in Patients With Alzheimer’s Disease. Am J Alzheimers Dis Other Demen. 2015 Aug;30(5):517-21.

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 Dec;30(8):729-32.

Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, Masharani U, et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J. 2015 Feb;29(2):589-96.

Pai MC, Kuo YM, Wang IF, Chiang PM, Tsai KJ. The Role of Methylated Circulating Nucleic Acids as a Potential Biomarker in Alzheimer’s Disease. Mol Neurobiol. 2019 Apr;56(4):2440-9.

Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol Cancer. 2014 Feb;13:33.

Dai M-H, Zheng H, Zeng L-D, Zhang Y. The genes associated with early-onset Alzheimer’s disease. Oncotarget. 2018 Mar;9(19):15132-43.

Lanoiselée H-M, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270.https://doi.org/10.1371/journal.pmed.1002270

Bacioglu M, Maia LF, Preische O, Schelle J, Apel A, Kaeser SA, et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron. 2016 Jul;91(2):494-6.

Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 2018 Mar;17(3):241-50.

Benzinger TL, Blazey T, Jack CR Jr, Koeppe RA, Su Y, Xiong C, et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc Natl Acad Sci U S A. 2013 Nov;110(47):E4502-9.

Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010 Feb; 31(2):224-43.

Published
2020-06-15
How to Cite
Rao, S. J., & Boileau, A. J. (2020). Novel Blood Biomarkers for an Earlier Diagnosis of Alzheimer’s Disease: A Literature Review. International Journal of Medical Students. https://doi.org/10.5195/ijms.2020.452
Section
Review