Blutbasierte Biomarker zur Optimierung der Früh- und Differentialdiagnostik der Alzheimer-Demenz

Zusammenfassung

Ziele der Studie Die Demenz bei Alzheimer-Krankheit ist eine globale Herausforderung. Studien weisen auf Blutbiomarker zur Diagnose der Alzheimer-Krankheit als eine minimal invasive, schnellere, kostengünstigere und daher zukunftsträchtige Methode hin. Ziel dieser Übersicht ist es, Studien zu vielversprechenden Biomarkern der Alzheimer-Krankheit darzustellen.

Methodik Für diese Übersichtsarbeit wurden aktuelle Studien zusammengestellt.

Ergebnisse Immunassays mit anschließender Massenspektrometrie und solche mit immunmagnetischer Reduktion sind aussichtsreiche Methoden für die Bestimmung von Amyloid-ß 42 (Aß42) und Amyloid-ß 40 (Aß40) für die Bildung der Ratio von Aß42/Aß40 zur blutbasierten Früh- und Differentialdiagnostik der Alzheimer-Krankheit. Die Amyloid-ß (Aß) Peptide im Blutplasma sind ein potentieller Marker der Aß-Pathologie, da sie mit der Aß-Pathologie im Gehirn korrelieren. Das mittels der Simoa Technologie bestimmte phosphorylierte Tau-Protein 181 (p-tau181), das phosphorylierte Tau Protein 231 (p-tau231) und das phosphorylierte Tau Protein 217 (p-tau217) im Blut sind vielversprechend hinsichtlich einer möglichen Optimierung der Früh- und Differentialdiagnostik der Alzheimer-Krankheit und sind Marker einer Tau-Pathologie im Gehirn. Die Neurofilamente Leichtketten (Nfl) und das saure Gliafaserprotein (GFAP) sind als Zusatzmarker hilfreich, um eine axonale und astrogliale Hirnschädigung bei Alzheimer-Krankheit zu beurteilen. GFAP im Blut könnte vor allem als Zusatzmarker zur Frühdiagnostik und Prädiktion des Verlaufs der Alzheimer-Krankheit sinnvoll sein.

Schlussfolgerungen Blutbasierte Biomarker sind ein wichtiger Schritt in Richtung einer weniger invasiven und kostengünstigeren Diagnostik der Alzheimer-Krankheit. Die Ratio Aß42/Aß40, das p-tau181, das p-tau217, das p-tau231, die Nfl und das GFAP sind vielversprechende Blutbiomarker unter Beachtung der AT(N) Klassifikation der Alzheimer-Krankheit. Hochdurchsatzfähige Methoden sollten in großen Kohorten und Metanalysen evaluiert werden. Zudem sollten Konsensus Kriterien mit einheitlichen Protokollen mit Normwerten zur Messung dieser Biomarker erstellt werden. Die Etablierung der AT(N) Klassifikation der Alzheimer-Krankheit im Blut ist unter Berücksichtigung ethischer Gesichtspunkte sowie des Alzheimer Phänotyps ein wichtiger Baustein für die Implementierung einer minimal-invasiven Präzisionsmedizin.

Abstract

Aim Dementia in Alzheimer´s disease is a global challenge. There is growing evidence that investigating blood biomarkers to diagnose Alzheimer´s disease is a promising fast, minimally invasive, and less costly method. The aim of this study was to review available studies on promising biomarkers for Alzheimer´s disease.

Method The latest studies were collated for this review.

Results Immunoassays followed by mass spectrometry and immunomagnetic reduction were reported to be highly relevant methods for detecting amyloid-ß 42 (Aß42) and amyloid-ß 40 (Aß40) to calculate the Aß42/Aß40 ratio, thereby improving the early diagnosis of Alzheimer´s disease. Amyloid-ß (Aß) peptides in blood plasma were considered as potential markers, as they correlated with the brain’s Aß pathology. Phosphorylated tau protein 181 (p-tau181), phosphorylated tau protein 217 (p-tau217) and phosphorylated tau protein 231 (p-tau231) in blood samples assessed via Simoa technology served as parameters for the early and differential diagnosis of AD, and were markers of tau pathology in the brain. Neurofilament light chain (Nfl) and glial fibrillary acid protein (GFAP) were additional markers possibly facilitating the assessment of axonal and astroglial brain damage in Alzheimer´s disease. GFAP in blood was useful as an additional marker to detect early and to predict the time course of Alzheimer´s disease.

Conclusions Determining blood biomarkers represents less invasive and less costly diagnostics for Alzheimer´s disease. The investigation of blood biomarkers such as the Aß42/Aß40 ratio, p-tau217, p-tau231, Nfl and GFAP have been promising in establishing the AT(N) classification for Alzheimer´s disease. High-throughput methods should be evaluated in large patient cohort studies and via meta-analyses of studies. Consensus criteria with standard protocols for measuring these biomarkers while considering ethical issues and Alzheimer´s phenotype should unify normative values from different laboratories. The AT(N) classification of Alzheimer´s disease in blood would be a key element towards the implementation of minimally-invasive precision medicine.

Schlüsselwörter

Alzheimer Demenz - Blut - Biomarker - Diagnose

Key words

Alzheimer´s dementia - blood - biomarker - diagnosis

Publication History

Received: 01 December 2021

Accepted: 26 April 2022

Article published online:
20 July 2022

• Literatur

• 1 Alagaratnam J, von Widekind S, De Francesco D. et al. Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis. BMJ Neurol Open 2021; 3: e000143
• 2 Alcolea D, Delaby C, Muñoz L. et al. Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias. J Neurol Neurosurg Psychiatry 2021; 92: 1206-1214
• 3 Ashton NJ, Pascoal TA, Karikari TK. et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol 2021; 141: 709-724
• 4 Benedet AL, Milà-Alomà M, Vrillon A. et al. Translational Biomarkers in Aging and Dementia (TRIAD) study, Alzheimer’s and Families (ALFA) study, and BioCogBank Paris Lariboisière cohort. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum.JAMA Neurol 2021; e213671
• 5 Casanova R, Varma S, Simpson B, Kim M, An Y. Blood metabolite markers of preclinical Alzheimer’s disease in two longitudinally followed cohorts of older individuals. Alzheimer’s & Dementia 2016; 12: 815-822
• 6 Chatterjee P, Pedrini S, Ashton NJ. et al. Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease. Alzheimers Dement 2021; Online ahead of print.PMID: 34494715
• 7 Cheng Y, Tian DY, Wang YJ. Peripheral clearance of brain-derived Aβ in Alzheimer’s disease: pathophysiology and therapeutic perspectives. Transl Neurodegener 2020; 9: 16
• 8 Cicognola C, Janelidze S, Hertze J. et al. Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment. Alzheimers Res Ther 2021; 13: 68
• 9 Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S. et al. Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Lancet Neurol 2021; 20: 484-496
• 10 Dumurgier J, Sabia S. [Epidemiology of Alzheimer’s disease: latest trends]. Rev Prat 2020; 70: 149-151
• 11 Haberstroh J, Tesky VA, Pantel J. Einwilligungsfähigkeit von Menschen mit Demenz. Einblicke in die S2k-AWMF Leitlinie 108-001. Insights into the S2k AWMF guidlines 108-001. Zeitschrift für Gerontologie und Geriatrie 54: 167-175
• 12 Hampel H, Hardy J, Blennow K. et al. The Amyloid-beta Pathway in Alzheimer’s Disease. Mol Psychiatry 2021;
• 13 Hansson O, Cullen N, Zetterberg H. Alzheimer’s Disease Neuroimaging Initiative, et al. Plasma phosphorylated tau181 and neurodegeneration in Alzheimer’s disease. Ann Clin Transl Neurol 2021; 8: 259-265
• 14 Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992; 256(5054):184-5
• 15 Huynh K, Lim WLF, Giles C. et al. Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease. Nat Commun 2020; 11: 5698
• 16 Fagan AM, Henson RL, Li Y, Boerwinkle AH. et al. Alzheimer’s Biomarker Consortium–Down Syndrome; Dominantly Inherited Alzheimer Network. Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer’s disease: a cross-sectional study. Lancet Neurol 2021; Aug 20 (08) 615-626
• 17 Islam MR, Kaurani L, Berulava T. et al. A microRNA signature that correlates with cognition and is a target against cognitive decline EMBO Mol Med 2021; 13: e13659
• 18 Jack CR, Bennett DA, Blennow K. et al. Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14: 535-562
• 19 Janelidze S, Mattsson N, Palmqvist S. et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med 2020; 26: 379-386
• 20 Janelidze S, Teunissen CE, Zetterberg H. et al. Head-to-Head Comparison of 8 Plasma Amyloid-beta 42/40 Assays in Alzheimer Disease. JAMA Neurol 2021; 78: 1375-1382
• 21 Janelidze S, Stomrud E, Palmqvist S. et al. Plasma beta-amyloid in Alzheimer’s disease and vascular disease. Sci Rep 2016; 6: 26801
• 22 Kaddurah-Daouk R, Kristal BS, Weinshilboum RM. Metabolomics: A Global Biochemical Approach to Drug Response and Disease. Annual Review of Pharmacology and Toxicology 2008; 48: 653-683
• 23 Kaddurah-Daouk R, Krishnan KR. Metabolomics: A Global Biochemical Approach to the Study of Central Nervous System Diseases. Neuropsychopharmacology 2009; 34: 173-186
• 24 Kaneko N, Nakamura A, Washimi Y. et al. Novel plasma biomarker surrogating cerebral amyloid deposition. Proc Jpn Acad Ser B Phys Biol Sci 2014; 90: 353-64
• 25 Karikari TK, Benedet AL, Ashton NJ. et al. Alzheimer’s Disease Neuroimaging Initiative. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry 2021; 26: 429-442
• 26 Kim K, Kim MJ, Kim DW. et al. Clinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma. Nat Commun 2020; 11 (119) 31913282
• 27 Klafki HW, Rieper P, Matzen A. et al. Development and Technical Validation of an Immunoassay for the Detection of APP_669-711 (Aβ_-3-40) in Biological Samples. Int J Mol Sci 2020; 21: 6564
• 28 Koychev I, Jansen K, Dette A. et al. Blood-Based ATN Biomarkers of Alzheimer’s Disease: A Meta-Analysis. J Alzheimers Dis 2021; 79: 177-195
• 29 Lantero Rodriguez J, Karikari TK, Suárez-Calvet M. et al. Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol 2020; 140: 267-278
• 30 Lemercier P, Vergallo A, Lista S. et al. INSIGHT-preAD study group and the Alzheimer Precision Medicine Initiative (APMI). Association of plasma Abeta40/Abeta42 ratio and brain Abeta accumulation: testing a whole-brain PLS-VIP approach in individuals at risk of Alzheimer’s disease. Neurobiol Aging 2021; 107: 57-69
• 31 Li Y, Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Weiner MW, Shaw LM, Masters CL, Fowler CJ, Trojanowski JQ, Korecka M, Martins RN, Janelidze S, Hansson O, Bateman RJ. Validation of Plasma Amyloid-beta 42/40 for Detecting Alzheimer Disease Amyloid Plaque. Neurology. 2022 Feb 15;98(7):e688-e699
• 32 Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR. 2014; Plasma phospholipids identify antecedent memory impairment in older adults. Nature Medicine 20: 415-418
• 33 McKhann GM, Knopman DS, Chertkow H. et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263-9
• 34 Monllor P, Giraldo E, Badia MC. et al. Serum Levels of Clusterin, PKR, and RAGE Correlate with Amyloid Burden in Alzheimer’s Disease J Alzheimers Dis 2021; 80: 1067-1077
• 35 Moscoso A, Grothe MJ. et al. Alzheimer’s Disease Neuroimaging InitiativeLongitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease JAMA Neurol 2021; 78: 396-406
• 36 Nabers A, Perna L, Lange J. et al. Amyloid blood biomarker detects Alzheimer’s disease EMBO Mol Med 2018; 10: e8763
• 37 Nakamura A, Kaneko N, Villemagne VL. et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease Nature 2018; 554: 249-254
• 38 O’Connor A, Karikari TK, Poole T. et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry 2020;
• 39 Palmqvist S, Janelidze S, Stomrud E. et al. Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status. JAMA Neurol 2019; 76: 1060-1069
• 40 Palmqvist S, Janelidze S, Quiroz YT. et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.JAMA 2020; 324: 772-781
• 41 Palmqvist S, Tideman P, Cullen N. et al. Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 2021; 27 (06) 1034-1042
• 42 Pannee J, Törnqvist U, Westerlund A. et al. The amyloid-beta degradation pattern in plasma--a possible tool for clinical trials in Alzheimer’s disease. Neurosci Lett 2014; 573: 7-12
• 43 Pase MP, Beiser AS, Himali JJ. et al. Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes. JAMA Neurol 2019; 76: 598-606
• 44 Pereira JB, Janelidze S, Stomrud E. et al. Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects. Brain 2021; 144: 2826-2836
• 45 Pereira JB, Janelidze S, Smith R. et al. Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease. Brain 2021b:awab223
• 46 Raket LL, Kühnel L, Schmidt E. et al. Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer’s disease. Alzheimers Dement (Amst) 2020; 12: e12099
• 47 Shahpasand-Kroner H, Klafki HW, Bauer C. et al. A two-step immunoassay for the simultaneous assessment of Aβ38, Aβ40 and Aβ42 in human blood plasma supports the Aβ42/Aβ40 ratio as a promising biomarker candidate of Alzheimer’s disease. Alzheimers Res Ther 2018; 10: 121
• 48 Simrén J, Ashton NJ, Blennow K. et al. Blood neurofilament light in remote settings: Alternative protocols to support sample collection in challenging pre-analytical conditions. Alzheimers Dement (Amst) 2021b 13: e12145
• 49 Simrén J, Leuzy A, Karikari TK, Hye A, Lessa Benedet A, Lantero-Rodriguez J. et al. The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer´s disease. Alzheimers Dementia 2021; 17: 1145-1156
• 50 Soares Martins T, Marçalo R, Ferreira M. et al. Exosomal Aβ-Binding Proteins Identified by “In Silico” Analysis Represent Putative Blood-Derived Biomarker Candidates for Alzheimer´s Disease. Int J Mol Sci 2021; 22: 3933
• 51 Swarbrick S, Wragg N, Ghosh S, Stolzing A. Systematic Review of miRNA as Biomarkers in Alzheimer’s Disease 2019; 56: 6156-6167
• 52 Thijssen EH, La Joie R, Wolf A. et al. Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 2020; 26: 387-397
• 53 Thijssen EH, La Joie R, Strom A. et al. Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol 2021; 20: 739-752
• 54 Toombs J, Zetterberg H. In the blood: biomarkers for amyloid pathology and neurodegeneration in Alzheimer’s disease. Brain Commun 2020; 2: fcaa054
• 55 Tromp D, Dufour A, Lithfous S. et al. Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studiesAgeing Res Rev 2015; 24: 232-62
• 56 Trushina E, Mielke MM. Recent advances in the application of metabolomics to Alzheimer’s Disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2014; 1842 (08) 1232-1239
• 57 Villain N, Dubois B. Alzheimer’s Disease Including Focal Presentations. Semin Neurol 2019; 39: 213-226
• 58 Walter M, Wiltfang J, Vogelgsang J. Pre-Analytical sampling and storage conditions of amyloid-ß peptides in venous and capillary blood. J Alzheimer Dis 2020; 78: 529-535
• 59 Weston PSJ, Poole T, Ryan NS. et al. Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration. Neurology. 2017; 89: 2167-2175
• 60 Yang CC, Chiu MJ, Chen TF. et al. Assay of Plasma Phosphorylated Tau Protein (Threonine 181) and Total Tau Protein in Early-Stage Alzheimer’s Disease J Alzheimers Dis 2018; 61: 1323-1332
• 61 Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegener 2021; 16: 10
• 62 Zetterberg H, Mörtberg E, Song L. et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 2011; 6: e28263