Abstract
Alzheimer’s disease (AD) is the most common dementia with currently no known cures or disease modifying treatments (DMTs), despite much time and effort from the field. Diagnosis and intervention of AD during the early pre-symptomatic phase of the disease is thought to be a more effective strategy. Therefore, the detection of biomarkers has emerged as a critical tool for monitoring the effect of new AD therapies, as well as identifying patients most likely to respond to treatment. The establishment of the amyloid/tau/neurodegeneration (A/T/N) framework in 2018 has codified the contexts of use of AD biomarkers in neuroimaging and bodily fluids for research and diagnostic purposes. Furthermore, a renewed drive for novel AD biomarkers and innovative methods of detection has emerged with the goals of adding additional insight to disease progression and discovery of new therapeutic targets. The use of biomarkers has accelerated the development of AD drugs and will bring new therapies to patients in need. This review highlights recent methods utilized to diagnose antemortem AD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data avavilibility
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
References
Abásolo D, Hornero R, Espino P, Alvarez D, Poza J (2006) Entropy analysis of the EEG background activity in Alzheimer's disease patients. Physiological Measurement 27(3):241–253
Agliardi C, Guerini FR, Zanzottera M, Bianchi A, Nemni R, Clerici M (2019) SNAP-25 in Serum Is Carried by Exosomes of Neuronal Origin and Is a Potential Biomarker of Alzheimer’s Disease. Molecular Neurobiology 56(8):5792–5798
Alvarez XA, Franco A, Fernández-Novoa L, Cacabelos R (1996) Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease. Mol Chem Neuropathol 29(2–3):237–252
Andreasen N, Hesse C, Davidsson P, Minthon L, Wallin A, Winblad B, Vanderstichele H, Vanmechelen E, Blennow K (1999) Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 56(6):673–680
Antonell A, Mansilla A, Rami L, Lladó A, Iranzo A, Olives J, Balasa M, Sánchez-Valle R, Molinuevo JL (2014) Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer's disease. J Alzheimers Dis 42(3):901–908
Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, Machida N, Seiki H, Takase S, Clark CM, Lee VM et al (1995) Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer's disease. Ann Neurol 38(4):649–652
Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA, Leyton-Cifuentes D, Chen K, Baena A, Aguillon D, Rios-Romenets S, Giraldo M, Guzmán-Vélez E, Norton DJ, Pardilla-Delgado E, Artola A, Sanchez JS, Acosta-Uribe J, Lalli M, Kosik KS, Huentelman MJ, Zetterberg H, Blennow K, Reiman RA, Luo J, Chen Y, Thiyyagura P, Su Y, Jun GR, Naymik M, Gai X, Bootwalla M, Ji J, Shen L, Miller JB, Kim LA, Tariot PN, Johnson KA, Reiman EM, Quiroz YT (2019) Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med 25(11):1680–1683
Baik SH, Kang S, Lee W, Choi H, Chung S, Kim JI, Mook-Jung I (2019) A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease. Cell Metab 30(3):493–507.e496
Balmuș I-M, Strungaru S-A, Ciobica A, Nicoara M-N, Dobrin R, Plavan G, Ștefănescu C (2017) Preliminary Data on the Interaction between Some Biometals and Oxidative Stress Status in Mild Cognitive Impairment and Alzheimer’s Disease Patients. Oxidative Medicine and Cellular Longevity 2017:7156928
Barthel H, Luthardt J, Becker G, Patt M, Hammerstein E, Hartwig K, Eggers B, Sattler B, Schildan A, Hesse S, Meyer PM, Wolf H, Zimmermann T, Reischl J, Rohde B, Gertz H-J, Reininger C, Sabri O (2011) Individualized quantification of brain β-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls. Eur J Nucl Med Mole Imaging 38(9):1702–1714
Barthélemy NR et al (2020) Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification Alzheimers. Res Ther 12:26. https://doi.org/10.1186/s13195-020-00596-4
Basavaraju M, de Lencastre A (2016) Alzheimer's disease: presence and role of microRNAs. Biomol Concepts 7(4):241–252
Bäuerl C, Collado MC, Diaz Cuevas A, Viña J, Pérez Martínez G (2018) Shifts in gut microbiota composition in an APP/PSS1 transgenic mouse model of Alzheimer's disease during lifespan. Lett Appl Microbiol 66(6):464–471
Bekris LM, Khrestian M, Dyne E, Shao Y, Pillai JA, Rao SM, Bemiller SM, Lamb B, Fernandez HH, Leverenz JB (2018) Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease. J Neuroimmunol 319:19–27
Björkqvist M, Ohlsson M, Minthon L, Hansson O (2012) Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer's disease. PLoS One 7(1):e29868
Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6(3):131–144
Blennow K, Zetterberg H, Minthon L, Lannfelt L, Strid S, Annas P, Basun H, Andreasen N (2007) Longitudinal stability of CSF biomarkers in Alzheimer's disease. Neurosci Lett 419(1):18–22
Bogoslovsky T, Wilson D, Chen Y, Hanlon D, Gill J, Jeromin A, Song L, Moore C, Gong Y, Kenney K, Diaz-Arrastia R (2017) Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury. J Neurotrauma 34(1):66–73
Bonneh-Barkay D, Wang G, Starkey A, Hamilton RL, Wiley CA (2010) In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases. J Neuroinflammation 7:34
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica 82(4):239–259
Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ (2015) Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci 16(2):109–120
Brinkmalm A, Brinkmalm G, Honer WG, Frölich L, Hausner L, Minthon L, Hansson O, Wallin A, Zetterberg H, Blennow K, Öhrfelt A (2014) SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease. Mol Neurodegener 9:53
Bu G, Cam J, Zerbinatti C (2006) LRP in amyloid-beta production and metabolism. Ann N Y Acad Sci 1086:35–53
Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20(3):148–160
Camporesi E, Nilsson J, Brinkmalm A, Becker B, Ashton NJ, Blennow K, Zetterberg H (2020) Fluid Biomarkers for Synaptic Dysfunction and Loss. Biomark Insights 15:1177271920950319
Chakraborty A, de Wit NM, van der Flier WM, de Vries HE (2017) The blood brain barrier in Alzheimer's disease. Vascul Pharmacol 89:12–18
Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38(9):1205–1235
Chen M-K, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin S-F, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH (2018) Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol 75(10):1215–1224
Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, Jagadapillai R, Liu R, Choe K, Shivakumar B, Son F, Jin S, Kerber R, Adame A, Masliah E, Friedland RP (2016) Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep 6:34477
Cheng Y, Tian D-Y, Wang Y-J (2020) Peripheral clearance of brain-derived Aβ in Alzheimer's disease: pathophysiology and therapeutic perspectives. Trans Neurodegenerat 9(1):16
Chételat G, Arbizu J, Barthel H, Garibotto V, Law I, Morbelli S, van de Giessen E, Agosta F, Barkhof F, Brooks DJ, Carrillo MC, Dubois B, Fjell AM, Frisoni GB, Hansson O, Herholz K, Hutton BF, Jack CR, Lammertsma AA, Landau SM, Minoshima S, Nobili F, Nordberg A, Ossenkoppele R, Oyen WJG, Perani D, Rabinovici GD, Scheltens P, Villemagne VL, Zetterberg H, Drzezga A (2020) Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias. Lancet Neurol 19(11):951–962
Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su M-Y, Shankle WR, Elizarov A, Kolb HC (2013) Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimer's Disease: JAD 34(2):457–468
Cho SH, Choe YS, Kim YJ, Lee B, Kim HJ, Jang H, Kim JP, Jung YH, Kim S-J, Kim BC, Farrar G, Na DL, Moon SH, Seo SW (2020) Concordance in detecting amyloid positivity between 18F-florbetaben and 18F-flutemetamol amyloid PET using quantitative and qualitative assessments. Sci Reports 10(1):19576
Ciccocioppo F, Lanuti P, Pierdomenico L, Simeone P, Bologna G, Ercolino E, Buttari F, Fantozzi R, Thomas A, Onofrj M, Centonze D, Miscia S, Marchisio M (2019) The Characterization of Regulatory T-Cell Profiles in Alzheimer's Disease and Multiple Sclerosis. Sci Rep 9(1):8788
Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA (2018) Normal aging induces A1-like astrocyte reactivity Proc Natl Acad Sci USA 115(8):E1896-e1905 doi:https://doi.org/10.1073/pnas.1800165115
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913
Cline EN, Bicca MA, Viola KL, Klein WL (2018) The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis 64(s1):S567–s610
Cooper EH (1994) Neuron-specific enolase. Int J Biol Markers 9(4):205–210
Craft S, Raman R, Chow TW, Rafii MS, Sun C-K, Rissman RA, Donohue MC, Brewer JB, Jenkins C, Harless K, Gessert D, Aisen PS (2020) Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol 77(9):1099–1109
Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ, Mintun MA, Peskind ER, Li G, Galasko DR, Clark CM, Quinn JF, D'Angelo G, Malone JP, Townsend RR, Morris JC, Fagan AM, Holtzman DM (2010) YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biol Psychiatry 68(10):903–912
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL 3rd, Wisniewski T, Woltjer RL, Yamada M, Nelson PT (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128(6):755–766
Crowther RA, Wischik CM (1985) Image reconstruction of the Alzheimer paired helical filament. Embo j 4(13b):3661–3665
Cselényi Z, Jönhagen ME, Forsberg A, Halldin C, Julin P, Schou M, Johnström P, Varnäs K, Svensson S, Farde L (2012) Clinical validation of 18F-AZD4694, an amyloid-β-specific PET radioligand. J Nuclear Med: Off Publ, Soc Nuclear Med 53(3):415–424
Cummings J (2019) The Role of Biomarkers in Alzheimer's Disease Drug Development. Adv Exp Med Biol 1118:29–61
Curtis C, Gamez JE, Singh U, Sadowsky CH, Villena T, Sabbagh MN, Beach TG, Duara R, Fleisher AS, Frey KA, Walker Z, Hunjan A, Holmes C, Escovar YM, Vera CX, Agronin ME, Ross J, Bozoki A, Akinola M, Shi J, Vandenberghe R, Ikonomovic MD, Sherwin PF, Grachev ID, Farrar G, Smith APL, Buckley CJ, McLain R, Salloway S (2015) Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol 72(3):287–294
Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, Cagnard N, Holzenberger M, Piaggio E, Aucouturier P, Dorothée G (2016) Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139(4):1237–1251
Davidsson P, Jahn R, Bergquist J, Ekman R, Blennow K (1996) Synaptotagmin, a synaptic vesicle protein, is present in human cerebrospinal fluid: a new biochemical marker for synaptic pathology in Alzheimer disease? Mol Chem Neuropathol 27(2):195–210
de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73(4):685–697
De Meyer S, Schaeverbeke JM, Verberk IMW, Gille B, De Schaepdryver M, Luckett ES, Gabel S, Bruffaerts R, Mauroo K, Thijssen EH, Stoops E, Vanderstichele HM, Teunissen CE, Vandenberghe R, Poesen K (2020) Comparison of ELISA- and SIMOA-based quantification of plasma Aβ ratios for early detection of cerebral amyloidosis. Alzheimers Res Ther 12(1):162
de Wolf F, Ghanbari M, Licher S, McRae-McKee K, Gras L, Weverling GJ, Wermeling P, Sedaghat S, Ikram MK, Waziry R, Koudstaal W, Klap J, Kostense S, Hofman A, Anderson R, Goudsmit J, Ikram MA (2020) Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study. Brain 143(4):1220–1232
Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9(7):907–913
DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 27(5):457–464
Delacourte A, David JP, Sergeant N, Buée L, Wattez A, Vermersch P, Ghozali F, Fallet-Bianco C, Pasquier F, Lebert F, Petit H, Di Menza C (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology 52(6):1158–1165
Delay C, Mandemakers W, Hébert SS (2012) MicroRNAs in Alzheimer's disease. Neurobiol Dis 46(2):285–290
Devous MD, Joshi AD, Navitsky M, Southekal S, Pontecorvo MJ, Shen H, Lu M, Shankle WR, Seibyl JP, Marek K, Mintun MA (2018) Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F 18. J Nuclear Med: Off Publ, Soc Nucl Med 59(6):937–943
Dhiman, K., V. B. Gupta, V. L. Villemagne, D. Eratne, P. L. Graham, C. Fowler, P. Bourgeat, Q.-X. Li, S. Collins, A. I. Bush, C. C. Rowe, C. L. Masters, D. Ames, E. Hone, K. Blennow, H. Zetterberg and R. N. Martins (2020). "Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease." 12(1): e12005
Dickson TC, King CE, McCormack GH, Vickers JC (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease. Exp Neurol 156(1):100–110
Dunn BRS (2018) Early Alzheimer's Disease: Developing Drugs for Treatment; Draft Guidance for Industry; Availability. F. a. D. A. Center for Drug Evaluation and Research. Silver Spring, MD, Federal Register: 7060–7061
Durazzo TC, Korecka M, Trojanowski JQ, Weiner MW, O’Hara R, Ashford JW, Shaw LM (2016) Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. J Alzheimers Dis 54(1):99–107
Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, Sur C, Mukai Y, Voss T, Furtek C, Mahoney E, Harper Mozley L, Vandenberghe R, Mo Y, Michelson D (2018) Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med 378(18):1691–1703
Egan MF, Mukai Y, Voss T, Kost J, Stone J, Furtek C, Mahoney E, Cummings JL, Tariot PN, Aisen PS, Vellas B, Lines C, Michelson D (2019) Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease. Alzheimers Res Ther 11(1):68
Emeršič A et al (2020) CSF phosphorylated tau-217 is increased in Alzheimer’s and Creutzfeldt-Jakob diseases and correlates with amyloid pathology. Alzheimer's & Dementia 16:e045296. https://doi.org/10.1002/alz.045296
Ewers M, Biechele G, Suárez-Calvet M, Sacher C, Blume T, Morenas-Rodriguez E, Deming Y, Piccio L, Cruchaga C, Kleinberger G, Shaw L, Trojanowski JQ, Herms J, Dichgans M, t. A. s. D. N. Initiative, Brendel M, Haass C, Franzmeier N (2020) Higher CSF sTREM2 and microglia activation are associated with slower rates of beta-amyloid accumulation. 12(9):e12308
Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C (2019) Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med 11(507)
Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, Holtzman DM (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65(2):176–183
Farrell ME, Jiang S, Schultz AP, Properzi MJ, Price JC, Becker JA, Jacobs HIL, Hanseeuw BJ, Rentz DM, Villemagne VL, Papp KV, Mormino EC, Betensky RA, Johnson KA, Sperling RA, Buckley RF, S. Alzheimer's disease Neuroimaging Initiative Harvard Aging Brain (2020) Defining the lowest threshold for amyloid-PET to predict future cognitive decline and amyloid accumulation. Neurology
Finder VH, Glockshuber R (2007) Amyloid-beta aggregation. Neurodegener Dis 4(1):13–27
Forman MS, Zhukareva V, Bergeron C, Chin SSM, Grossman M, Clark C, Lee VMY, Trojanowski JQ (2002) Signature tau neuropathology in gray and white matter of corticobasal degeneration. The American Journal of Pathology 160(6):2045–2053
Foundation, A. s. D. D (2021) from https://www.alzdiscovery.org/research-and-grants/diagnostics-accelerator/recipients
Freund-Levi Y, Vedin I, Hjorth E, Basun H, Faxén Irving G, Schultzberg M, Eriksdotter M, Palmblad J, Vessby B, Wahlund L-O, Cederholm T, Basu S (2014) Effects of Supplementation with Omega-3 Fatty Acids on Oxidative Stress and Inflammation in Patients with Alzheimer's Disease: The OmegAD Study. J Alzheimer's Dis 42:823–831
Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PCG, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV (2018) Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. Cell Rep 22(3):832–847
Fu W, Jhamandas JH (2014) Role of astrocytic glycolytic metabolism in Alzheimer's disease pathogenesis. Biogerontology 15(6):579–586
Furuya TK, Silva PN, Payão SL, Bertolucci PH, Rasmussen LT, De Labio RW, Braga IL, Chen ES, Turecki G, Mechawar N, Mill J, Smith MA (2012) Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer's Disease patients. Neuroscience 220:41–46
Gallo A, Tandon M, Alevizos I, Illei GG (2012) The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PloS one 7:e30679. https://doi.org/10.1371/journal.pone.0030679
Gambi F, Reale M, Iarlori C, Salone A, Toma L, Paladini C, De Luca G, Feliciani C, Salvatore M, Salerno RM, Theoharides TC, Conti P, Exton M, Gambi D (2004) Alzheimer patients treated with an AchE inhibitor show higher IL-4 and lower IL-1 beta levels and expression in peripheral blood mononuclear cells. J Clin Psychopharmacol 24(3):314–321
Geerts H, Spiros A, Roberts P (2018) Impact of amyloid-beta changes on cognitive outcomes in Alzheimer’s disease: analysis of clinical trials using a quantitative systems pharmacology model. Alzheimer's Res Therapy 10(1):14
Gendron TF, Petrucelli L (2009) The role of tau in neurodegeneration. Mol Neurodegener 4:13
Giedraitis V, Sundelöf J, Irizarry MC, Gårevik N, Hyman BT, Wahlund LO, Ingelsson M, Lannfelt L (2007) The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease. Neurosci Lett 427(3):127–131
Gleerup HS, Hasselbalch SG, Simonsen AH (2019) Biomarkers for Alzheimer's Disease in Saliva: A Systematic Review. Dis Markers 2019:4761054
Gobbi LC, Knust H, Körner M, Honer M, Czech C, Belli S, Muri D, Edelmann MR, Hartung T, Erbsmehl I, Grall-Ulsemer S, Koblet A, Rueher M, Steiner S, Ravert HT, Mathews WB, Holt DP, Kuwabara H, Valentine H, Dannals RF, Wong DF, Borroni E (2017) Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography. J Med Chem 60(17):7350–7370
Goedert M, Crowther RA, Garner CC (1991) Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci 14(5):193–199
Goetzl EJ, Kapogiannis D, Schwartz JB, Lobach IV, Goetzl L, Abner EL, Jicha GA, Karydas AM, Boxer A, Miller BL (2016) Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. Faseb J 30(12):4141–4148
Gomez C, Poza J, Gomez-Pilar J, Bachiller A, Juan-Cruz C, Tola-Arribas MA, Carreres A, Cano M, Hornero R (2016) "Analysis of spontaneous EEG activity in Alzheimer's disease using cross-sample entropy and graph theory." Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Ann Int Conf 2016:2830–2833
Gordon BA, Friedrichsen K, Brier M, Blazey T, Su Y, Christensen J, Aldea P, McConathy J, Holtzman DM, Cairns NJ, Morris JC, Fagan AM, Ances BM, Benzinger TLS (2016) The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain: A J Neurol 139(Pt 8):2249–2260
Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM (2015) Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques. Proc Natl Acad Sci USA 112(28):E3699–E3708
Group, F.-N. B. W. (2016). BEST (Biomarkers, EndpointS, and other Tools) Resource. Silver Spring (Jansen, Ossenkoppele et al. 2015)
Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133(5):665–704
Haass C (2004) Take five--BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation. EMBO J 23(3):483–488
Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2(5):a006270
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112
Hampel, H., N. Toschi, F. Baldacci, H. Zetterberg, K. Blennow, I. Kilimann, S. J. Teipel, E. Cavedo, A. Melo dos Santos, S. Epelbaum, F. Lamari, R. Genthon, B. Dubois, R. Floris, F. Garaci, S. Lista and A. P. M. Initiative (2018). "Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ1–42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40." 14(4): 492–501
Han SH, Park JC, Byun MS, Yi D, Lee JH, Lee DY, Mook-Jung I (2019) Blood acetylcholinesterase level is a potential biomarker for the early detection of cerebral amyloid deposition in cognitively normal individuals. Neurobiol Aging 73:21–29
Handels RL, Joore MA, Tran-Duy A, Wimo A, Wolfs CA, Verhey FR, Severens JL (2015) Early cost-utility analysis of general and cerebrospinal fluid-specific Alzheimer's disease biomarkers for hypothetical disease-modifying treatment decision in mild cognitive impairment. Alzheimers Dement 11(8):896–905
Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, Cosio DMO, Farrell M, Quiroz YT, Mormino EC, Buckley RF, Papp KV, Amariglio RA, Dewachter I, Ivanoiu A, Huijbers W, Hedden T, Marshall GA, Chhatwal JP, Rentz DM, Sperling RA, Johnson K (2019) Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA Neurol 76(8):915–924
Hansen DV, Hanson JE, Sheng M (2018) Microglia in Alzheimer's disease. J Cell Biol 217(2):459–472
Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fåk F, Jucker M, Lasser T, Bolmont T (2017) Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 7:41802
Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, Tago T, Hiraoka K, Watanuki S, Shidahara M, Miyake M, Ishikawa Y, Matsuda R, Inami A, Yoshikawa T, Funaki Y, Iwata R, Tashiro M, Yanai K, Arai H, Kudo Y (2016) 18F-THK5351: A Novel PET Radiotracer for Imaging Neurofibrillary Pathology in Alzheimer Disease. J Nucl Med: Off Publ, Soc Nucl Med 57(2):208–214
Hardy JA, Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256(5054):184–185
Hartmann S, Kist TBL (2018) A review of biomarkers of Alzheimer's disease in noninvasive samples. 12(6):677–690
Hatanaka H, Hanyu H, Fukasawa R, Sato T, Shimizu S, Sakurai H (2016) Peripheral oxidative stress markers in diabetes-related dementia. 16(12):1312–1318
Honer M, Gobbi L, Knust H, Kuwabara H, Muri D, Koerner M, Valentine H, Dannals RF, Wong DF, Borroni E (2018) Preclinical Evaluation of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 as Novel PET Radiotracers for Imaging Tau Aggregates in Alzheimer Disease. J Nucl Med: Off Publ, Soc Nucl Med 59(4):675–681
Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E (2018) Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. New England J Med 378(4):321–330
Hornero R, Abásolo D, Escudero J, Gómez C (2009) "Nonlinear analysis of electroencephalogram and magnetoencephalogram recordings in patients with Alzheimer's disease." Philosophical Transactions. Series A, Math, Phys, Eng Sci 367(1887):317–336
Hortschansky P, Schroeckh V, Christopeit T, Zandomeneghi G, Fändrich M (2005) The aggregation kinetics of Alzheimer's beta-amyloid peptide is controlled by stochastic nucleation. Protein Sci 14(7):1753–1759
Hostetler ED, Walji AM, Zeng Z, Miller P, Bennacef I, Salinas C, Connolly B, Gantert L, Haley H, Holahan M, Purcell M, Riffel K, Lohith TG, Coleman P, Soriano A, Ogawa A, Xu S, Zhang X, Joshi E, Della Rocca J, Hesk D, Schenk DJ, Evelhoch JL (2016) Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles. J Nucl Med: Off Publ, Soc Nucl Med 57(10):1599–1606
Hu N, Tan MS, Yu JT, Sun L, Tan L, Wang YL, Jiang T, Tan L (2014) Increased expression of TREM2 in peripheral blood of Alzheimer's disease patients. J Alzheimers Dis 38(3):497–501
Iaccarino L, Sala A, Perani D, I. Alzheimer's Disease Neuroimaging (2019) Predicting long-term clinical stability in amyloid-positive subjects by FDG-PET. Ann Clin Trans Neurol 6(6):1113–1120
Idland A-V, Sala-Llonch R, Borza T, Watne LO, Wyller TB, Brækhus A, Zetterberg H, Blennow K, Walhovd KB, Fjell AM (2017) CSF neurofilament light levels predict hippocampal atrophy in cognitively healthy older adults. Neurobiol Aging 49:138–144
Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, DeKosky ST (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain: A J Neurol 131(Pt 6):1630–1645
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R (2018) NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement 14(4):535–562
Jahn R, Südhof TC (1999) Membrane fusion and exocytosis. Annu Rev Biochem 68:863–911
Janelidze S, Hertze J, Zetterberg H, Landqvist Waldö M, Santillo A, Blennow K, Hansson O (2016) Cerebrospinal fluid neurogranin and YKL-40 as biomarkers of Alzheimer's disease. Ann Clin Transl Neurol 3(1):12–20
Janelidze S et al (2020) Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease. Nat Comm 11:1683. https://doi.org/10.1038/s41467-020-15436-0
Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FRJ, Visser PJ, G. Amyloid Biomarker Study, Aalten P, Aarsland D, Alcolea D, Alexander M, Alisohl IS, Arnold SE, Baldeiras I, Barthel H, van Berckel BNM, Bibeau K, Blennow K, Brooks DJ, van Buchem MA, Camus V, Cavedo E, Chen K, Chetelat G, Cohen AD, Drzezga A, Engelborghs S, Fagan AM, Fladby T, Fleisher AS, van der Flier WM, Ford L, Förster S, Fortea J, Foskett N, Frederiksen KS, Freund-Levi Y, Frisoni GB, Froelich L, Gabryelewicz T, Gill KD, Gkatzima O, Gómez-Tortosa E, Gordon MF, Grimmer T, Hampel H, Hausner L, Hellwig S, Herukka S-K, Hildebrandt H, Ishihara L, Ivanoiu A, Jagust WJ, Johannsen P, Kandimalla R, Kapaki E, Klimkowicz-Mrowiec A, Klunk WE, Köhler S, Koglin N, Kornhuber J, Kramberger MG, Van Laere K, Landau SM, Lee DY, de Leon M, Lisetti V, Lleó A, Madsen K, Maier W, Marcusson J, Mattsson N, de Mendonça A, Meulenbroek O, Meyer PT, Mintun MA, Mok V, Molinuevo JL, Møllergård HM, Morris JC, Mroczko B, Van der Mussele S, Na DL, Newberg A, Nordberg A, Nordlund A, Novak GP, Paraskevas GP, Parnetti L, Perera G, Peters O, Popp J, Prabhakar S, Rabinovici GD, Ramakers IHGB, Rami L, Resende de Oliveira C, Rinne JO, Rodrigue KM, Rodríguez-Rodríguez E, Roe CM, Rot U, Rowe CC, Rüther E, Sabri O, Sanchez-Juan P, Santana I, Sarazin M, Schröder J, Schütte C, Seo SW, Soetewey F, Soininen H, Spiru L, Struyfs H, Teunissen CE, Tsolaki M, Vandenberghe R, Verbeek MM, Villemagne VL, Vos SJB, van Waalwijk van Doorn LJC, Waldemar G, Wallin A, Wallin ÅK, Wiltfang J, Wolk DA, Zboch M, Zetterberg H (2015a) Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313(19):1924–1938
Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32(18):4693–4697
Jeong J (2004) EEG dynamics in patients with Alzheimer's disease. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 115(7):1490–1505
Jiang L, Dong H, Cao H, Ji X, Luan S, Liu J (2019) Exosomes in Pathogenesis, Diagnosis, and Treatment of Alzheimer's Disease. Med Sci Monit 25:3329–3335
Jin Y, Tu Q, Liu M (2018) MicroRNA-125b regulates Alzheimer's disease through SphK1 regulation. Mol Med Rep 18(2):2373–2380
Joachim CL, Morris JH, Selkoe DJ (1989) Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease. Am J Pathol 135(2):309–319
Johnson GV, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117(Pt 24):5721–5729
Kaiser E, Kuzmits R, Pregant P, Burghuber O, Worofka W (1989) Clinical biochemistry of neuron specific enolase. Clinica Chimica Acta 183(1):13–31
Kang S, Lee YH, Lee JE (2017) Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease. Yonsei Med J 58(3):479–488
Karikari TK et al (2020) Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol 19:422–433. https://doi.org/10.1016/s1474-4422(20)30071-5
Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA, Jhee S, Kleijn HJ, Kuvelkar R, Li W, Mattson BA, Mei H, Palcza J, Scott JD, Tanen M, Troyer MD, Tseng JL, Stone JA, Parker EM, Forman MS (2016) The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med 8(363):363ra150
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I (2017) A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell 169(7):1276–1290 e1217
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang G-f, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B (2004) Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 55(3):306–319
Klunk WE, Koeppe RA, Price JC, Benzinger TL, Devous MD, Jagust WJ, Johnson KA, Mathis CA, Minhas D, Pontecorvo MJ, Rowe CC, Skovronsky DM, Mintun MA (2015) The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer's & Dementia: J Alzheimer's Ass 11(1):1–15.e11–1–15.e14
Köpke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268(32):24374–24384
Korecka MBM, Alexander J, Cabrera Y, Salazar J (2016) ADNI3 Biomarker Biofluid Collection. Processing and Shipment, Alzheimer's Disease Neuroimaging Initiative
Kountouras J, Boziki M, Gavalas E, Zavos C, Deretzi G, Grigoriadis N, Tsolaki M, Chatzopoulos D, Katsinelos P, Tzilves D, Zabouri A, Michailidou I (2009) Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer's disease. Int J Neurosci 119(6):765–777
Kountouras J, Tsolaki M, Gavalas E, Boziki M, Zavos C, Karatzoglou P, Chatzopoulos D, Venizelos I (2006) Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology 66(6):938–940
Kowalski K, Mulak A (2019) Brain-Gut-Microbiota Axis in Alzheimer's Disease. J Neurogastroenterol Motil 25(1):48–60
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47(3):566–581.e569
Krishnan S, Rani P (2014) Evaluation of Selenium, Redox Status and Their Association with Plasma Amyloid/Tau in Alzheimer’s Disease. Biol Trace Element Res 158(2):158–165
Kumar S, Reddy PH (2016) Are circulating microRNAs peripheral biomarkers for Alzheimer's disease? Biochimica et Biophysica Acta (BBA) - Mole Basis Dis 1862(9):1617–1627
Lanzrein AS, Johnston CM, Perry VH, Jobst KA, King EM, Smith AD (1998) Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. Alzheimer Dis Assoc Disord 12(3):215–227
Lee SAW, Sposato LA, Hachinski V, Cipriano LE (2017) Cost-effectiveness of cerebrospinal biomarkers for the diagnosis of Alzheimer's disease. Alzheimer's Res Therapy 9(1):18–18
Lehmann S, Delaby C, Boursier G, Catteau C, Ginestet N, Tiers L, Maceski A, Navucet S, Paquet C, Dumurgier J, Vanmechelen E, Vanderstichele H, Gabelle A (2018) Relevance of Aβ42/40 Ratio for Detection of Alzheimer Disease Pathology in Clinical Routine: The PLM(R) Scale. Front Aging Neurosci 10:138
Lehmann S, Dumurgier J, Schraen S, Wallon D, Blanc F, Magnin E, Bombois S, Bousiges O, Campion D, Cretin B, Delaby C, Hannequin D, Jung B, Hugon J, Laplanche JL, Miguet-Alfonsi C, Peoc'h K, Philippi N, Quillard-Muraine M, Sablonnière B, Touchon J, Vercruysse O, Paquet C, Pasquier F, Gabelle A (2014) A diagnostic scale for Alzheimer's disease based on cerebrospinal fluid biomarker profiles. Alzheimers Res Ther 6(3):38
Lenders MB, Peers MC, Tramu G, Delacourte A, Defossez A, Petit H, Mazzuca M (1989) Dystrophic neuropeptidergic neurites in senile plaques of Alzheimer's disease precede formation of paired helical filaments. Acta Neurol Belg 89(3–4):279–285
Lesman-Segev, O. H., R. La Joie, L. Iaccarino, I. Lobach, H. J. Rosen, S. W. Seo, M. Janabi, S. L. Baker, L. Edwards, J. Pham, J. Olichney, A. Boxer, E. Huang, M. Gorno-Tempini, C. DeCarli, M. Hepker, J.-H. L. Hwang, B. L. Miller, S. Spina, L. T. Grinberg, W. W. Seeley, W. J. Jagust and G. D. Rabinovici (2020). "Diagnostic Accuracy of Amyloid versus 18 F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia." Annals of Neurology
Leung R, Proitsi P, Simmons A, Lunnon K, Güntert A, Kronenberg D, Pritchard M, Tsolaki M, Mecocci P, Kloszewska I, Vellas B, Soininen H, Wahlund LO, Lovestone S (2013) Inflammatory proteins in plasma are associated with severity of Alzheimer's disease. PLoS One 8(6):e64971
Leuzy A, Chiotis K, Lemoine L, Gillberg P-G, Almkvist O, Rodriguez-Vieitez E, Nordberg A (2019) Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mole Psych 24(8):1112–1134
Leuzy A et al (2020) Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders, JAMA Neurol. 77:955–965. https://doi.org/10.1001/jamaneurol.2020.0989
Li Y, Tsui W, Rusinek H, Butler T, Mosconi L, Pirraglia E, Mozley D, Vallabhajosula S, Harada R, Furumoto S, Furukawa K, Arai H, Kudo Y, Okamura N, de Leon MJ (2015) Cortical laminar binding of PET amyloid and tau tracers in Alzheimer disease. J Nucl Med: Off Publ, Soc Nucl Med 56(2):270–273
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029
Llorens F, Thüne K, Tahir W, Kanata E, Diaz-Lucena D, Xanthopoulos K, Kovatsi E, Pleschka C, Garcia-Esparcia P, Schmitz M, Ozbay D, Correia S, Correia Â, Milosevic I, Andréoletti O, Fernández-Borges N, Vorberg IM, Glatzel M, Sklaviadis T, Torres JM, Krasemann S, Sánchez-Valle R, Ferrer I, Zerr I (2017) YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias. Molecular Neurodegeneration 12(1):83
Long JM, Holtzman DM (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell 179(2):312–339
Lowe VJ, Lundt ES, Albertson SM, Przybelski SA, Senjem ML, Parisi JE, Kantarci K, Boeve B, Jones DT, Knopman D, Jack CR Jr, Dickson DW, Petersen RC, Murray ME (2019) Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease. Alzheimers Dement 15(7):927–939
Lugaresi A, Di Iorio A, Iarlori C, Reale M, De Luca G, Sparvieri E, Michetti A, Conti P, Gambi D, Abate G, Paganelli R (2004) IL-4 in vitro production is upregulated in Alzheimer's disease patients treated with acetylcholinesterase inhibitors. Exp Gerontol 39(4):653–657
Lusardi TA, Phillips JI, Wiedrick JT, Harrington CA, Lind B, Lapidus JA, Quinn JF, Saugstad JA (2017) MicroRNAs in Human Cerebrospinal Fluid as Biomarkers for Alzheimer's Disease. J Alzheimers Dis 55(3):1223–1233
Maarouf CL, Walker JE, Sue LI, Dugger BN, Beach TG, Serrano GE (2018) Impaired hepatic amyloid-beta degradation in Alzheimer's disease. PLoS One 13(9):e0203659
Makin S (2018) The amyloid hypothesis on trial. Nature 559(7715):S4–S7
Malm T, Loppi S, Kanninen KM (2016) Exosomes in Alzheimer's disease. Neurochem Int 97:193–199
Mandelkow E, von Bergen M, Biernat J, Mandelkow EM (2007) Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 17(1):83–90
Manzano-Crespo M, Atienza M, Cantero JL (2019) Lower serum expression of miR-181c-5p is associated with increased plasma levels of amyloid-beta 1–40 and cerebral vulnerability in normal aging. Transl Neurodegener 8:34
Martinez B, Peplow P (2019) MicroRNAs as diagnostic and therapeutic tools for Alzheimer’s disease: advances and limitations. Neural Regen Res 14(2):242–255
Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, Zhang M-R, Trojanowski JQ, Lee VMY, Ono M, Masamoto K, Takano H, Sahara N, Iwata N, Okamura N, Furumoto S, Kudo Y, Chang Q, Saido TC, Takashima A, Lewis J, Jang M-K, Aoki I, Ito H, Higuchi M (2013) Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79(6):1094–1108
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82(12):4245–4249
Mattsson-Carlgren N et al (2020) Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv 6:eaaz2387. https://doi.org/10.1126/sciadv.aaz2387
Maturana-Candelas A, Gómez C, Poza J, Pinto N, Hornero R (2019) EEG Characterization of the Alzheimer's Disease Continuum by Means of Multiscale Entropies. Entropy (Basel, Switzerland) 21(6)
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330(6012):1774
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) 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 7(3):263–269
Meda L, Baron P, Scarlato G (2001) Glial activation in Alzheimer's disease: the role of Abeta and its associated proteins. Neurobiol Aging 22(6):885–893
Mega MS, Cummings JL, O'Connor SM, Dinov ID, Reback E, Felix J, Masterman DL, Phelps ME, Small GW, Toga AW (2001) Cognitive and metabolic responses to metrifonate therapy in Alzheimer disease. Neuropsychiatry, Neuropsychol, Behav Neurol 14(1):63–68
Mehta PD, Pirttilä T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM (2000) Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch Neurol 57(1):100–105
Mielke MM, Hagen CE, Wennberg AMV, Airey DC, Savica R, Knopman DS, Machulda MM, Roberts RO, Jack CR Jr, Petersen RC, Dage JL (2017) Association of Plasma Total Tau Level With Cognitive Decline and Risk of Mild Cognitive Impairment or Dementia in the Mayo Clinic Study on Aging. JAMA Neurol 74(9):1073–1080
Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, Jabri B, Chang EB, Tanzi RE, Sisodia SS (2017) Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP(SWE)/PS1(ΔE9) murine model of Alzheimer's disease. Sci Rep 7(1):10411
Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, Mintun MA (2009) Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol 66(12):1469–1475
Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, Lelios I, Heppner FL, Kipnis J, Merkler D, Greter M, Becher B (2018) High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity 48(3):599
Mufson EJ, Ikonomovic MD, Counts SE, Perez SE, Malek-Ahmadi M, Scheff SW, Ginsberg SD (2016) Molecular and cellular pathophysiology of preclinical Alzheimer's disease. Behav Brain Res 311:54–69
Mustapic M, Tran J, Craft S, Kapogiannis D (2019) Extracellular Vesicle Biomarkers Track Cognitive Changes Following Intranasal Insulin in Alzheimer's Disease. J Alzheimers Dis 69(2):489–498
Muszyński P, Groblewska M, Kulczyńska-Przybik A, Kułakowska A, Mroczko B (2017) YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer's Disease. Curr Neuropharmacol 15(6):906–917
Naiki H, Nakakuki K (1996) First-order kinetic model of Alzheimer's beta-amyloid fibril extension in vitro. Lab Invest 74(2):374–383
Nelissen N, Van Laere K, Thurfjell L, Owenius R, Vandenbulcke M, Koole M, Bormans G, Brooks DJ, Vandenberghe R (2009) Phase 1 study of the Pittsburgh compound B derivative 18F-flutemetamol in healthy volunteers and patients with probable Alzheimer disease. J Nucl Med: Off Publ, Soc Nucl Med 50(8):1251–1259
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71(5):362–381
Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68(1):1–14
Newington JT, Harris RA, Cumming RC (2013) Reevaluating Metabolism in Alzheimer's Disease from the Perspective of the Astrocyte-Neuron Lactate Shuttle Model. J Neurodegenerative Dis 2013:234572
Nguyen AT, Wang K, Hu G, Wang X, Miao Z, Azevedo JA, Suh E, Van Deerlin VM, Choi D, Roeder K, Li M, Lee EB (2020) APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease. Acta Neuropathologica 140(4):477–493
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64(2):113–122
Nordengen K, Kirsebom B-E, Henjum K, Selnes P, Gísladóttir B, Wettergreen M, Torsetnes SB, Grøntvedt GR, Waterloo KK, Aarsland D, Nilsson LNG, Fladby T (2019) Glial activation and inflammation along the Alzheimer’s disease continuum. J Neuroinflam 16(1):46
Nunez-Iglesias J, Liu CC, Morgan TE, Finch CE, Zhou XJ (2010) Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease cortex reveals altered miRNA regulation. PLoS One 5(2):e8898
O'Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 34:185–204
Oe T, Ackermann BL, Inoue K, Berna MJ, Garner CO, Gelfanova V, Dean RA, Siemers ER, Holtzman DM, Farlow MR, Blair IA (2006) Quantitative analysis of amyloid beta peptides in cerebrospinal fluid of Alzheimer's disease patients by immunoaffinity purification and stable isotope dilution liquid chromatography/negative electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 20(24):3723–3735
Öhrfelt A, Brinkmalm A, Dumurgier J, Brinkmalm G, Hansson O, Zetterberg H, Bouaziz-Amar E, Hugon J, Paquet C, Blennow K (2016) The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer’s disease. Alzheimer's Res Therapy 8(1):41
Okamura N, Furumoto S, Harada R, Tago T, Yoshikawa T, Fodero-Tavoletti M, Mulligan RS, Villemagne VL, Akatsu H, Yamamoto T, Arai H, Iwata R, Yanai K, Kudo Y (2013) Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nuclear Med: Off Publ, Soc Nucl Med 54(8):1420–1427
Okamura N, Harada R, Ishiki A, Kikuchi A, Nakamura T, Kudo Y (2018) The development and validation of tau PET tracers: current status and future directions. Clin Transl Imaging 6(4):305–316
Okamura N, Suemoto T, Furumoto S, Suzuki M, Shimadzu H, Akatsu H, Yamamoto T, Fujiwara H, Nemoto M, Maruyama M, Arai H, Yanai K, Sawada T, Kudo Y (2005) Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer's disease. J Neurosci: Off J Soc Neurosci 25(47):10857–10862
Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, Hölttä M, Rosén C, Olsson C, Strobel G, Wu E, Dakin K, Petzold M, Blennow K, Zetterberg H (2016) CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol 15(7):673–684
Olsson F, Schmidt S, Althoff V, Munter LM, Jin S, Rosqvist S, Lendahl U, Multhaup G, Lundkvist J (2014) Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions. J Biol Chem 289(3):1540–1550
Ong KT, Villemagne VL, Bahar-Fuchs A, Lamb F, Langdon N, Catafau AM, Stephens AW, Seibyl J, Dinkelborg LM, Reininger CB, Putz B, Rohde B, Masters CL, Rowe CC (2015) Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study. J Neurol, Neurosurg, Psychiatry 86(4):431–436
Onorato M, Mulvihill P, Connolly J, Galloway P, Whitehouse P, Perry G (1989) Alteration of neuritic cytoarchitecture in Alzheimer disease. Prog Clin Biol Res 317:781–789
Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O'Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD (2016) Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain: J Neurol 139(Pt 5):1551–1567
Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, Ashford E, Retout S, Hofmann C, Delmar P, Klein G, Andjelkovic M, Dubois B, Boada M, Blennow K, Santarelli L, Fontoura P, Investigators SCR (2017) A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease. Alzheimer's Res Therapy 9(1):95
Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ (2017) Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13(8):841–849
Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cerebral Blood Flow Metabol: Off J Int Soc Cerebral Blood Flow Metabol 32(1):1–5
Pagani M, De Carli F, Morbelli S, Öberg J, Chincarini A, Frisoni GB, Galluzzi S, Perneczky R, Drzezga A, van Berckel BNM, Ossenkoppele R, Didic M, Guedj E, Brugnolo A, Picco A, Arnaldi D, Ferrara M, Buschiazzo A, Sambuceti G, Nobili F (2015) Volume of interest-based [18F]fluorodeoxyglucose PET discriminates MCI converting to Alzheimer's disease from healthy controls. A European Alzheimer's Disease Consortium (EADC) study. NeuroImage. Clin 7:34–42
Palmert MR, Podlisny MB, Golde TE, Cohen ML, Kovacs DM, Tanzi RE, Gusella JF, Whitehouse PJ, Witker DS, Oltersdorf T et al (1989) The beta amyloid protein precursor: mRNAs, membrane-associated forms, and soluble derivatives. Prog Clin Biol Res 317:971–984
Palmqvist S, Mattsson N, Hansson O (2016) Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain 139(Pt 4):1226–1236
Palmqvist S, Zetterberg H, Blennow K, Vestberg S, Andreasson U, Brooks DJ, Owenius R, Hägerström D, Wollmer P, Minthon L, Hansson O (2014) Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol 71(10):1282–1289
Palmqvist S, Zetterberg H, Mattsson N, Johansson P, Minthon L, Blennow K, Olsson M, Hansson O (2015) Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology 85(14):1240–1249
Parbo P, Ismail R, Hansen KV, Amidi A, Mårup FH, Gottrup H, Brændgaard H, Eriksson BO, Eskildsen SF, Lund TE, Tietze A, Edison P, Pavese N, Stokholm MG, Borghammer P, Hinz R, Aanerud J, Brooks DJ (2017) Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease. Brain: J Neurol 140(7):2002–2011
Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C (2019) Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 22(2):191–204
Park JC, Han SH, Mook-Jung I (2020) Peripheral inflammatory biomarkers in Alzheimer's disease: a brief review. BMB Rep 53(1):10–19
Patel S, Knight A, Krause S, Teceno T, Tresse C, Li S, Cai Z, Gouasmat A, Carroll VM, Barret O, Gottmukkala V, Zhang W, Xiang X, Morley T, Huang Y, Passchier J (2020) Preclinical In Vitro and In Vivo Characterization of Synaptic Vesicle 2A-Targeting Compounds Amenable to F-18 Labeling as Potential PET Radioligands for Imaging of Synapse Integrity. Mole Imaging Biol 22(4):832–841
Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE (1979) Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol 6(5):371–388
Pontecorvo MJ, Devous MD, Navitsky M, Lu M, Salloway S, Schaerf FW, Jennings D, Arora AK, McGeehan A, Lim NC, Xiong H, Joshi AD, Siderowf A, Mintun MA, F. A.-A. investigators (2017) Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain: J Neurol 140(3):748–763
Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30(7):1026–1036
Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol 45(3):358–368
Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, Duong DM, Pennington MW, Lah JJ, Seyfried NT, Levey AI (2018) Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease. Mol Neurodegener 13(1):24
Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T (2007) Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 13(11):1359–1362
Ries M, Sastre M (2016) Mechanisms of Aβ Clearance and Degradation by Glial Cells. Front Aging Neurosci 8:160
Roberts RO, Aakre JA, Kremers WK, Vassilaki M, Knopman DS, Mielke MM, Alhurani R, Geda YE, Machulda MM, Coloma P, Schauble B, Lowe VJ, Jack CR, Petersen RC (2018) Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol 75(8):970–979
Rocher AB, Chapon F, Blaizot X, Baron J-C, Chavoix C (2003) Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons. NeuroImage 20(3):1894–1898
Rogers, M. B. (2018) "Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’."
Rosengren LE, Karlsson J-E, Sjögren M, Blennow K, Wallin A (1999) Neurofilament protein levels in CSF are increased in dementia. 52(5):1090–1090
Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O'Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL (2010) Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 31(8):1275–1283
Sabbagh MN, Shi J, Lee M, Arnold L, Al-Hasan Y, Heim J, McGeer P (2018) Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer's disease dementia from normal controls: preliminary findings. BMC Neurol 18(1):155
Saido T, Leissring MA (2012) Proteolytic degradation of amyloid β-protein. Cold Spring Harb Perspect Med 2(6):a006379
Salloway S, Gamez JE, Singh U, Sadowsky CH, Villena T, Sabbagh MN, Beach TG, Duara R, Fleisher AS, Frey KA, Walker Z, Hunjan A, Escovar YM, Agronin ME, Ross J, Bozoki A, Akinola M, Shi J, Vandenberghe R, Ikonomovic MD, Sherwin PF, Farrar G, Smith APL, Buckley CJ, Thal DR, Zanette M, Curtis C (2017) Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease. Alzheimer’s & Dementia (Amsterdam, Netherlands) 9:25–34
Salloway S, Honigberg LA, Cho W, Ward M, Friesenhahn M, Brunstein F, Quartino A, Clayton D, Mortensen D, Bittner T, Ho C, Rabe C, Schauer SP, Wildsmith KR, Fuji RN, Suliman S, Reiman EM, Chen K, Paul R (2018) Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer's disease (Gordon, Friedrichsen et al. 2016). Alzheimer's Res Ther 10(1):96
Sancesario GM, Bernardini S (2018) Diagnosis of neurodegenerative dementia: where do we stand, now? Ann Transl Med 6(17):340
Scarf AM, Kassiou M (2011) The translocator protein. J Nuclear Med: Off Publ, Soc Nuclear Med 52(5):677–680
Schmidt FM, Mergl R, Stach B, Jahn I, Gertz H-J, Schönknecht P (2014) Elevated levels of cerebrospinal fluid neuron-specific enolase (NSE) in Alzheimer's disease. Neurosci Lett 570:81–85
Schonrock N, Humphreys DT, Preiss T, Götz J (2012) Target Gene Repression Mediated by miRNAs miR-181c and miR-9 Both of Which Are Down-regulated by Amyloid-β. J Mole Neurosci 46(2):324–335
Schwarz AJ, Shcherbinin S, Slieker LJ, Risacher SL, Charil A, Irizarry MC, Fleisher AS, Southekal S, Joshi AD, Devous MD, Miller BB, Saykin AJ, I. Alzheimer's Disease Neuroimaging (2018) Topographic staging of tau positron emission tomography images. Alzheimer's & Dementia (Amsterdam, Netherlands) 10:221–22s
Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, Joshi AD, Devous MD, Mintun MS (2016) Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain: A J Neurol 139(Pt 5):1539–1550
Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8(6):595–608
Sengupta U, Nilson AN, Kayed R (2016) The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMed 6:42–49
Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C et al (1992) Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature 359(6393):325–327
Shaffer, J. L., J. R. Petrella, F. C. Sheldon, K. R. Choudhury, V. D. Calhoun, R. E. Coleman, P. M. Doraiswamy and I. Alzheimer’s Disease Neuroimaging (2013). "Predicting cognitive decline in subjects at risk for Alzheimer disease by using combined cerebrospinal fluid, MR imaging, and PET biomarkers." Radiology 266(2): 583–591
Sharoar, M. G., X. Hu, X. M. Ma, X. Zhu and R. Yan (2019). "Sequential formation of different layers of dystrophic neurites in Alzheimer's brains." Mol Psychiatry
Sharoar MG, Shi Q, Ge Y, He W, Hu X, Perry G, Zhu X, Yan R (2016) Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry 21(9):1263–1271
Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ (2009) Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol 65(4):403–413
Shaw LM, Vanderstichele H, Knapik-Czajka M, Figurski M, Coart E, Blennow K, Soares H, Simon AJ, Lewczuk P, Dean RA, Siemers E, Potter W, Lee VM, Trojanowski JQ (2011) Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol 121(5):597–609
Shimada A, Hashimoto H, Kawabe J, Higashiyama S, Kai T, Kataoka K, Tagawa R, Kawarada Y, Nakanishi A, Inoue K, Shiomi S, Kiriike N (2011) Evaluation of therapeutic response to donepezil by positron emission tomography. Osaka City Med J 57(1):11–19
Shumbayawonda E, López-Sanz D, Bruña R, Serrano N, Fernández A, Maestú F, Abasolo D (2020) Complexity changes in preclinical Alzheimer's disease: An MEG study of subjective cognitive decline and mild cognitive impairment. Clin Neurophysiol: Off J Int Fed Clin Neurophys 131(2):437–445
Sirin FB, Kumbul Doğuç D, Vural H, Eren I, Inanli I, Sütçü R, Delibaş N (2015) Plasma 8-isoPGF2α and serum melatonin levels in patients with minimal cognitive impairment and Alzheimer disease. Turk J Med Sci 45(5):1073–1077
Sjögren M, Blomberg M, Jonsson M, Wahlund L-O, Edman Å, Lind K, Rosengren L, Blennow K, Wallin A (2001) Neurofilament protein in cerebrospinal fluid: A marker of white matter changes. 66(3):510–516
Smailagic N, Lafortune L, Kelly S, Hyde C, Brayne C (2018) 18F-FDG PET for Prediction of Conversion to Alzheimer's Disease Dementia in People with Mild Cognitive Impairment: An Updated Systematic Review of Test Accuracy. Journal of Alzheimer's disease: JAD 64(4):1175–1194
Snider BJ, Fagan AM, Roe C, Shah AR, Grant EA, Xiong C, Morris JC, Holtzman DM (2009) Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol 66(5):638–645
Soldan A, Pettigrew C, Cai Q, Wang MC, Moghekar AR, O'Brien RJ, Selnes OA, Albert MS (2016) Hypothetical Preclinical Alzheimer Disease Groups and Longitudinal Cognitive Change. JAMA Neurol 73(6):698–705
Song A, Johnson N, Ayala A, Thompson AC (2021) Optical Coherence Tomography in Patients with Alzheimer's Disease: What Can It Tell Us? Eye Brain 13:1–20. https://doi.org/10.2147/EB.S235238
Song L, Lachno DR, Hanlon D, Shepro A, Jeromin A, Gemani D, Talbot JA, Racke MM, Dage JL, Dean RA (2016) A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1–42 peptide in human plasma with utility for studies of Alzheimer's disease therapeutics. Alzheimers Res Ther 8(1):58
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: J Alzheimer's Ass 7(3):280–292
Sperling RA, Donohue MC, Raman R, Sun C-K, Yaari R, Holdridge K, Siemers E, Johnson KA, Aisen PS, Team AS (2020) Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals. JAMA Neurol 77(6):735–745
Stomrud E, Hansson O, Zetterberg H, Blennow K, Minthon L, Londos E (2010) Correlation of Longitudinal Cerebrospinal Fluid Biomarkers With Cognitive Decline in Healthy Older Adults. Arch Neurol 67(2):217–223
Sutphen CL, McCue L, Herries EM, Xiong C, Ladenson JH, Holtzman DM, Fagan AM (2018) Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease. Alzheimers Dement 14(7):869–879
Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry 68(10):930–941
Swardfager W, Yu D, Scola G, Cogo-Moreira H, Chan P, Zou Y, Herrmann N, Lanctôt KL, Ramirez J, Gao F, Masellis M, Swartz RH, Sahlas DJ, Chan PC, Ojeda-Lopez C, Milan-Tomas A, Pettersen JA, Andreazza AC, Black SE (2017) Peripheral lipid oxidative stress markers are related to vascular risk factors and subcortical small vessel disease. Neurobiol Aging 59:91–97
Tagai K, Ono M, Kubota M, Kitamura S, Takahata K, Seki C, Takado Y, Shinotoh H, Sano Y, Yamamoto Y, Matsuoka K, Takuwa H, Shimojo M, Takahashi M, Kawamura K, Kikuchi T, Okada M, Akiyama H, Suzuki H, Onaya M, Takeda T, Arai K, Arai N, Araki N, Saito Y, Trojanowski JQ, Lee VMY, Mishra SK, Yamaguchi Y, Kimura Y, Ichise M, Tomita Y, Zhang M-R, Suhara T, Shigeta M, Sahara N, Higuchi M, Shimada H (2020) High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies. Neuron S0896627320307662
Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y (2009) gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 29(41):13042–13052
Tarkowski E, Blennow K, Wallin A, Tarkowski A (1999) Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 19(4):223–230
Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K (2003) Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull 61(3):255–260
Tato RE, Frank A, Hernanz A (1995) Tau protein concentrations in cerebrospinal fluid of patients with dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 59(3):280–283
Tcw J, Goate AM (2017) Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease. Cold Spring Harb Perspect Med 7(6)
te Velde AA, Huijbens RJ, Heije K, de Vries JE, Figdor CG (1990) Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood 76(7):1392–1397
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580
Therriault, J., A. Benedet, T. A. Pascoal, M. Savard, N. Ashton, M. Chamoun, C. Tissot, F. Lussier, M. S. P. Kang, G. Bezgin, T. Wang, J. Fernandez-Arias, G. Massarweh, P. Vitali, H. Zetterberg, K. Blennow, P. Saha-Chaudhuri, J.-P. Soucy, S. Gauthier and P. Rosa-Neto (2020). "Determining Amyloid-β positivity using [18F]AZD4694 PET imaging." Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Tiepolt S, Patt M, Aghakhanyan G, Meyer PM, Hesse S, Barthel H, Sabri O (2019) Current radiotracers to image neurodegenerative diseases. EJNMMI Radiopharm Chem 4(1):17
Toledo JB, Xie SX, Trojanowski JQ, Shaw LM (2013) Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol 126(5):659–670
Valcarcel-Nazco C, Perestelo-Perez L, Molinuevo J, Mar J, Castilla Rodríguez I, Aguilar P (2014) Cost-Effectiveness of the Use of Biomarkers in Cerebrospinal Fluid for Alzheimer's Disease. J Alzheimer's Disease : JAD 42
van der Velpen V, Teav T, Gallart-Ayala H, Mehl F, Konz I, Clark C, Oikonomidi A, Peyratout G, Henry H, Delorenzi M, Ivanisevic J, Popp J (2019) Systemic and central nervous system metabolic alterations in Alzheimer’s disease. Alzheimer's Res Therapy 11(1):93
Vandermeeren M, Mercken M, Vanmechelen E, Six J, van de Voorde A, Martin JJ, Cras P (1993) Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 61(5):1828–1834
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741
Vella LJ, Hill AF, Cheng L (2016) Focus on Extracellular Vesicles: Exosomes and Their Role in Protein Trafficking and Biomarker Potential in Alzheimer's and Parkinson's Disease. Int J Mol Sci 17(2):173
Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer's disease. Neurotherapeutics 7(4):399–412
Vermunt L, Sikkes SAM, van den Hout A, Handels R, Bos I, van der Flier WM, Kern S, Ousset PJ, Maruff P, Skoog I, Verhey FRJ, Freund-Levi Y, Tsolaki M, Wallin KÅ, Rikkert MO, Soininen H, Spiru L, Zetterberg H, Blennow K, Scheltens P, Muniz-Terrera G, Visser PJ (2019) Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement 15(7):888–898
Villemagne VL, Klunk WE, Mathis CA, Rowe CC, Brooks DJ, Hyman BT, Ikonomovic MD, Ishii K, Jack CR, Jagust WJ, Johnson KA, Koeppe RA, Lowe VJ, Masters CL, Montine TJ, Morris JC, Nordberg A, Petersen RC, Reiman EM, Selkoe DJ, Sperling RA, Van Laere K, Weiner MW, Drzezga A (2012) Aβ Imaging: feasible, pertinent, and vital to progress in Alzheimer's disease. Eur J Nucl Med Mole Imaging 39(2):209–219
von Einem B, Schwanzar D, Rehn F, Beyer A-S, Weber P, Wagner M, Schneckenburger H, von Arnim CAF (2010) The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1. Exper Neurol 225(1):85–93
Walji AM, Hostetler ED, Selnick H, Zeng Z, Miller P, Bennacef I, Salinas C, Connolly B, Gantert L, Holahan M, O'Malley S, Purcell M, Riffel K, Li J, Balsells J, Obrien JA, Melquist S, Soriano A, Zhang X, Ogawa A, Xu S, Joshi E, Della Rocca J, Hess FJ, Schachter J, Hesk D, Schenk D, Struyk A, Babaoglu K, Lohith TG, Wang Y, Yang K, Fu J, Evelhoch JL, Coleman PJ (2016) Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18)F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs). J Med Chem 59(10):4778–4789
Watson LS, Hamlett ED, Stone TD, Sims-Robinson C (2019) Neuronally derived extracellular vesicles: an emerging tool for understanding Alzheimer’s disease. Mole Neurodegeneration 14(1):22
Wildburger, N. C., F. Gyngard, C. Guillermier, B. W. Patterson, D. Elbert, K. G. Mawuenyega, T. Schneider, K. Green, R. Roth, R. E. Schmidt, N. J. Cairns, T. L. S. Benzinger, M. L. Steinhauser and R. J. Bateman (2018). "Amyloid-β Plaques in Clinical Alzheimer’s Disease Brain Incorporate Stable Isotope Tracer In Vivo and Exhibit Nanoscale Heterogeneity." 9(169)
Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, Revesz T (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain: A J Neurol 130(Pt 6):1566–1576
Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont V, Ravert HT, Dannals RF, Nandi A, Brasić JR, Ye W, Hilton J, Lyketsos C, Kung HF, Joshi AD, Skovronsky DM, Pontecorvo MJ (2010) In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). J Nucl Med: Off Publ, Soc Nucl Med 51(6):913–920
Woollacott IOC, Nicholas JM, Heslegrave A, Heller C, Foiani MS, Dick KM, Russell LL, Paterson RW, Keshavan A, Fox NC, Warren JD, Schott JM, Zetterberg H, Rohrer JD (2018) Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup. Alzheimers Res Ther 10(1):79
Yamao T, Miwa K, Matsuda H, Akamatsu G, Wagatsuma K, Takano H (2019) <strong>Feasibility of <sup>18</sup>F-THK5351 PET quantitation using the Centiloid scale</strong>. J Nucl Med, supplement 1 60:1182
Yan LJ, Xiao M, Chen R, Cai Z (2013) Metabolic Dysfunction of Astrocyte: An Initiating Factor in Beta-amyloid Pathology? Aging Neurodegener 1(1):7–14
Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402(6761):533–537
Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M (2016) TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron 91(2):328–340
Yılmaz ŞGEM, Özge AA, Sungur MA (2016) Can Peripheral MicroRNA Expression Data Serve as Epigenomic (Upstream) Biomarkers of Alzheimer's Disease? 20(8):456–461
Yuan L, Liu J, Ma W, Dong L, Wang W, Che R, Xiao R (2016) Dietary pattern and antioxidants in plasma and erythrocyte in patients with mild cognitive impairment from China. Nutrition 32(2):193–198
Zakharova NV, Bugrova AE, Kononikhin AS, Indeykina MI, Popov IA, Nikolaev EN (2018) Mass spectrometry analysis of the diversity of Aβ peptides: difficulties and future perspectives for AD biomarker discovery. Expert Review of Proteomics 15(10):773–775
Zetterberg H, Skillbäck T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, Weiner MW, Blennow K, f. t. A. s. D. N. Initiative (2016) Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. JAMA Neurol 73(1):60–67
Zhao M, Cribbs DH, Anderson AJ, Cummings BJ, Su JH, Wasserman AJ, Cotman CW (2003) The induction of the TNFalpha death domain signaling pathway in Alzheimer's disease brain. Neurochem Res 28(2):307–318
Zhao Y, Bhattacharjee S, Jones BM, Hill J, Dua P, Lukiw WJ (2014) Regulation of Neurotropic Signaling by the Inducible, NF-kB-Sensitive miRNA-125b in Alzheimer's Disease (AD) and in Primary Human Neuronal-Glial (HNG) Cells. Molecular Neurobiology 50(1):97–106
Zhong L, Chen X-F (2019) The Emerging Roles and Therapeutic Potential of Soluble TREM2 in Alzheimer’s Disease. 11(328)
Zulfiqar S, Garg P, Nieweg K (2019) Contribution of astrocytes to metabolic dysfunction in the Alzheimer's disease brain. Biol Chem 400(9):1113–1127
Funding
This study was partially supported by an award to MGS from Alzheimer’s Association to (AARF-17-504724).
Author information
Authors and Affiliations
Contributions
JZ wrote AD fluid biomarkers section and MB wrote AD imaging biomarkers sections of this manuscript. JZ and MB edited and organized this manuscript. MGS developed the idea, wrote introductory sections and revised this manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The author declares no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhou, J., Benoit, M. & Sharoar, M.G. Recent advances in pre-clinical diagnosis of Alzheimer’s disease. Metab Brain Dis 37, 1703–1725 (2022). https://doi.org/10.1007/s11011-021-00733-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-021-00733-4