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2000
Volume 20, Issue 3
  • ISSN: 1574-8871
  • E-ISSN: 1876-1038

Abstract

Alzheimer’s disease (AD) is a multifactorial pathology, responsible for neurodegenerative disorders which in more than 60% of patients evolve into dementia. Comprehension of the molecular mechanisms underlying the pathology and the development of reliable diagnostic methods have made new and more effective therapies possible. In recent years, in addition to the classic anticholinesterases (AChEs), which can control the clinical symptoms of the disease, compounds able to reduce deposits of amyloid-β (Aβ) and/or tau (τ) protein aggregates, which are disease-modifying therapeutics (DMTs), have been studied. The results have shown that symptomatic therapy works best when administered in the disease's mild to moderate clinical phase. On the other hand, treatment with DMTs has been found to be more effective in the preclinical stage of AD, when Aβ and τ protein neurofibrillary tangles have not yet been compromised and patients still have a normal quality of life. This innovative approach requires the identification of specific biomarkers predictive of the disease, detectable many years before clinical signs are evident. Biomarkers allow early diagnosis, give indications of the possible development of dementia in the future, and make it possible to study the evolution of the disease. New scenarios, involving different pathways and approaches, could emerge and provide effective therapies to treat the very early stages of the disease and hamper its progression. The specific biomarkers studied so far have been reported here.

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References

  1. LloretA. EsteveD. LloretM.A. FerriC.A. LopezB. NepomucenoM. MonllorP. When does Alzheimer′s disease really start? The role of biomarkers.Int. J. Mol. Sci.20192022553610.3390/ijms2022553631698826
     [Google Scholar]
  2. TierneyM.C. FisherR.H. LewisA.J. ZorzittoM.L. SnowW.G. ReidD.W. NieuwstratenP. The NINCDS-ADRDA Work Group criteria for the clinical diagnosis of probable Alzheimer’s disease.Neurology198838335936410.1212/WNL.38.3.3593347338
     [Google Scholar]
  3. Diagnostic and Statistical Manual of Mental Disorders Book.4th Ed.Washington, DCAmerican Psychiatric Association (APA)1994
     [Google Scholar]
  4. DuboisB. FeldmanH.H. JacovaC. DeKoskyS.T. GateauB.P. CummingsJ. DelacourteA. GalaskoD. GauthierS. JichaG. MeguroK. O’BrienJ. PasquierF. RobertP. RossorM. SallowayS. SternY. VisserP.J. ScheltensP. Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS–ADRDA criteria.Lancet Neurol.20076873474610.1016/S1474‑4422(07)70178‑317616482
     [Google Scholar]
  5. SperlingR.A. AisenP.S. BeckettL.A. BennettD.A. CraftS. FaganA.M. IwatsuboT. JackC.R.Jr KayeJ. MontineT.J. ParkD.C. ReimanE.M. RoweC.C. SiemersE. SternY. YaffeK. CarrilloM.C. ThiesB. BogoradM.M. WagsterM.V. PhelpsC.H. 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.Alzheimers Dement.20117328029210.1016/j.jalz.2011.03.00321514248
     [Google Scholar]
  6. JackC.R.Jr BennettD.A. BlennowK. CarrilloM.C. DunnB. HaeberleinS.B. HoltzmanD.M. JagustW. JessenF. KarlawishJ. LiuE. MolinuevoJ.L. MontineT. PhelpsC. RankinK.P. RoweC.C. ScheltensP. SiemersE. SnyderH.M. SperlingR. ElliottC. MasliahE. RyanL. SilverbergN. Contributors NIA-AA research framework: Toward a biological definition of Alzheimer’s disease.Alzheimers Dement.201814453556210.1016/j.jalz.2018.02.01829653606
     [Google Scholar]
  7. ChenZ.R. HuangJ.B. YangS.L. HongF.F. Role of cholinergic signaling in Alzheimer’s disease.Molecules2022276181610.3390/molecules2706181635335180
     [Google Scholar]
  8. VecchioI. SorrentinoL. PaolettiA. MarraR. ArbitrioM. The state of the art on acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease.J. Cent. Nerv. Syst. Dis.2021131179573521102911310.1177/1179573521102911334285627
     [Google Scholar]
  9. CummingsJ. LeeG. RitterA. SabbaghM. ZhongK. Alzheimer’s disease drug development pipeline: 2019.Alzheimers Dement.20195127229310.1016/j.trci.2019.05.00831334330
     [Google Scholar]
  10. CummingsJ. LeeG. RitterA. SabbaghM. ZhongK. Alzheimer’s disease drug development pipeline: 2020.Alzheimers Dement.202061e1205010.1002/trc2.1205032695874
     [Google Scholar]
  11. ScarpiniE GalimbertiD GhezziL. Disease-modifying drugs in Alzheimer's disease.Drug Des. Devel. Ther.20114420321610.2147/DDDT.S41431
     [Google Scholar]
  12. YiannopoulouK.G. PapageorgiouS.G. Current and future treatments in Alzheimer disease: An update.J. Cent. Nerv. Syst. Dis.20201211795735209073910.1177/117957352090739732165850
     [Google Scholar]
  13. RichardA. Current and evolving treatment strategies for the Alzheimer disease continuum.Am. J. Manag. Care.2020268 SupplS167S176
     [Google Scholar]
  14. HungA SchneiderM. Preclinical Alzheimer disease drug development.J. Manag. Care Spec. Pharm.202026710.18553
     [Google Scholar]
  15. WangJ. LogovinskyV. HendrixS.B. StanworthS.H. PerdomoC. XuL. DhaddaS. DoI. RabeM. LuthmanJ. CummingsJ. SatlinA. ADCOMS: A composite clinical outcome for prodromal Alzheimer’s disease trials.J. Neurol. Neurosurg. Psychiatry201687999399910.1136/jnnp‑2015‑31238327010616
     [Google Scholar]
  16. KovacsG.G. MilenkovicI. WöhrerA. HöftbergerR. GelpiE. HaberlerC. HönigschnablS. ConcinR.A. HeinzlH. JungwirthS. KramplaW. FischerP. BudkaH. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: A community-based autopsy series.Acta Neuropathol.2013126336538410.1007/s00401‑013‑1157‑y23900711
     [Google Scholar]
  17. JackC.R.Jr BennettD.A. BlennowK. CarrilloM.C. FeldmanH.H. FrisoniG.B. HampelH. JagustW.J. JohnsonK.A. KnopmanD.S. PetersenR.C. ScheltensP. SperlingR.A. DuboisB. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers.Neurology201687553954710.1212/WNL.000000000000292327371494
     [Google Scholar]
  18. FaganA.M. RoeC.M. XiongC. MintunM.A. MorrisJ.C. HoltzmanD.M. Cerebrospinal fluid tau/β-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.Arch. Neurol.200764334334910.1001/archneur.64.3.noc6012317210801
     [Google Scholar]
  19. VisserP.J. VerheyF. KnolD.L. ScheltensP. WahlundL.O. LeviF.Y. TsolakiM. MinthonL. WallinÅ.K. HampelH. BürgerK. PirttilaT. SoininenH. RikkertM.O. VerbeekM.M. SpiruL. BlennowK. Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: A prospective cohort study.Lancet Neurol.20098761962710.1016/S1474‑4422(09)70139‑519523877
     [Google Scholar]
  20. KlunkW.E. EnglerH. NordbergA. WangY. BlomqvistG. HoltD.P. BergströmM. SavitchevaI. HuangG.F. EstradaS. AusénB. DebnathM.L. BarlettaJ. PriceJ.C. SandellJ. LoprestiB.J. WallA. KoivistoP. AntoniG. MathisC.A. LångströmB. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B.Ann. Neurol.200455330631910.1002/ana.2000914991808
     [Google Scholar]
  21. VillainN. ChételatG. GrassiotB. BourgeatP. JonesG. EllisK.A. AmesD. MartinsR.N. EustacheF. SalvadoO. MastersC.L. RoweC.C. VillemagneV.L. Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: A voxelwise PiB–PET longitudinal study.Brain201213572126213910.1093/brain/aws12522628162
     [Google Scholar]
  22. MattssonN. ZetterbergH. HanssonO. AndreasenN. ParnettiL. JonssonM. HerukkaS.K. Flierd.v.W.M. BlankensteinM.A. EwersM. RichK. KaiserE. VerbeekM. TsolakiM. MulugetaE. RosénE. AarslandD. VisserP.J. SchröderJ. MarcussonJ. Leond.M. HampelH. ScheltensP. PirttiläT. WallinA. JönhagenM.E. MinthonL. WinbladB. BlennowK. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.JAMA2009302438539310.1001/jama.2009.106419622817
     [Google Scholar]
  23. BuergerK. EwersM. PirttiläT. ZinkowskiR. AlafuzoffI. TeipelS.J. DeBernardisJ. KerkmanD. McCullochC. SoininenH. HampelH. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease.Brain2006129113035304110.1093/brain/awl26917012293
     [Google Scholar]
  24. BrierM.R. GordonB. FriedrichsenK. McCarthyJ. SternA. ChristensenJ. OwenC. AldeaP. SuY. HassenstabJ. CairnsN.J. HoltzmanD.M. FaganA.M. MorrisJ.C. BenzingerT.L.S. AncesB.M. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease.Sci. Transl. Med.20168338338ra6610.1126/scitranslmed.aaf236227169802
     [Google Scholar]
  25. ChhatwalJ.P. SchultzA.P. MarshallG.A. BootB. IslaG.T. DumurgierJ. LaPointM. ScherzerC. RoeA.D. HymanB.T. SperlingR.A. JohnsonK.A. Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly.Neurology201687992092610.1212/WNL.000000000000305027473132
     [Google Scholar]
  26. AlawodeD.O.T. HeslegraveA.J. AshtonN.J. KarikariT.K. SimrénJ. GayaM.L. PanneeJ. O´ConnorA. WestonP.S.J. RodriguezL.J. KeshavanA. SnellmanA. GobomJ. PatersonR.W. SchottJ.M. BlennowK. FoxN.C. ZetterbergH. Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer’s disease.J. Intern. Med.2021290358360110.1111/joim.1333234021943
     [Google Scholar]
  27. BlennowK. HampelH. WeinerM. ZetterbergH. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.Nat. Rev. Neurol.20106313114410.1038/nrneurol.2010.420157306
     [Google Scholar]
  28. MontagneA. ZhaoZ. ZlokovicB.V. Alzheimer’s disease: A matter of blood–brain barrier dysfunction?J. Exp. Med.2017214113151316910.1084/jem.2017140629061693
     [Google Scholar]
  29. SeabJ.P. JagustW.J. WongS.T.S. RoosM.S. ReedB.R. BudingerT.F. Quantitative NMR measurements of hippocampal atrophy in Alzheimer’s disease.Magn. Reson. Med.19888220020810.1002/mrm.19100802103210957
     [Google Scholar]
  30. FoxN.C. CrumW.R. ScahillR.I. StevensJ.M. JanssenJ.C. RossorM.N. Imaging of onset and progression of Alzheimer’s disease with voxel-compression mapping of serial magnetic resonance images.Lancet2001358927720120510.1016/S0140‑6736(01)05408‑311476837
     [Google Scholar]
  31. MinoshimaS. GiordaniB. BerentS. FreyK.A. FosterN.L. KuhlD.E. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease.Ann. Neurol.1997421859410.1002/ana.4104201149225689
     [Google Scholar]
  32. BessonF.L. JoieL.R. DoeuvreL. GaubertM. MézengeF. EgretS. LandeauB. BarréL. AbbasA. IbazizeneM. SayetteL.d.V. DesgrangesB. EustacheF. ChételatG. Cognitive and brain profiles associated with current neuroimaging biomarkers of preclinical Alzheimer’s disease.J. Neurosci.20153529104021041110.1523/JNEUROSCI.0150‑15.201526203136
     [Google Scholar]
  33. DickersonB.C. BakkourA. SalatD.H. FeczkoE. PachecoJ. GreveD.N. GrodsteinF. WrightC.I. BlackerD. RosasH.D. SperlingR.A. AtriA. GrowdonJ.H. HymanB.T. MorrisJ.C. FischlB. BucknerR.L. The cortical signature of Alzheimer’s disease: Regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals.Cereb. Cortex200919349751010.1093/cercor/bhn11318632739
     [Google Scholar]
  34. KnopmanD.S. JackC.R.Jr WisteH.J. WeigandS.D. VemuriP. LoweV.J. KantarciK. GunterJ.L. SenjemM.L. MielkeM.M. RobertsR.O. BoeveB.F. PetersenR.C. Selective worsening of brain injury biomarker abnormalities in cognitively normal elderly persons with β-amyloidosis.JAMA Neurol.20137081030103810.1001/jamaneurol.2013.18223797806
     [Google Scholar]
  35. LandauS.M. HarveyD. MadisonC.M. KoeppeR.A. ReimanE.M. FosterN.L. WeinerM.W. JagustW.J. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI.Neurobiol. Aging20113271207121810.1016/j.neurobiolaging.2009.07.00219660834
     [Google Scholar]
  36. PerkovicN.M. PivacN. Genetic markers of Alzheimer’s disease.Adv. Exp. Med. Biol.20191192275210.1007/978‑981‑32‑9721‑0_3
     [Google Scholar]
  37. CacaceR. SleegersK. BroeckhovenV.C. Molecular genetics of early-onset Alzheimer’s disease revisited.Alzheimers Dement.201612673374810.1016/j.jalz.2016.01.01227016693
     [Google Scholar]
  38. ArberC. LovejoyC. HarrisL. WillumsenN. AlatzaA. CaseyJ.M. LinesG. KerinsC. MuellerA.K. ZetterbergH. HardyJ. RyanN.S. FoxN.C. LashleyT. WrayS. Familial Alzheimer’s disease mutations in PSEN1 lead to premature human stem cell neurogenesis.Cell Rep.202134210861510.1016/j.celrep.2020.10861533440141
     [Google Scholar]
  39. CanevelliM. PiscopoP. TalaricoG. VanacoreN. BlasimmeA. CrestiniA. TostoG. TroiliF. LenziG.L. ConfaloniA. BrunoG. Familial Alzheimer’s disease sustained by presenilin 2 mutations: Systematic review of literature and genotype–phenotype correlation.Neurosci. Biobehav. Rev.20144217017910.1016/j.neubiorev.2014.02.01024594196
     [Google Scholar]
  40. BlennowK. WallinA. Clinical heterogeneity of probable Alzheimer’s disease.J. Geriatr. Psychiatry Neurol.19925210611310.1177/0023830992005002081590911
     [Google Scholar]
  41. ZeccaC. BresciaV. PiccininniM. CapozzoR. BaroneR. BarulliM.R. LogroscinoG. Comparative evaluation of two immunoassays for cerebrospinal fluid β-Amyloid1–42 measurement.Clin. Chim. Acta201949310711110.1016/j.cca.2019.02.03330844363
     [Google Scholar]
  42. SeinoY. NakamuraT. HaradaT. NakahataN. KawarabayashiT. UedaT. TakatamaM. ShojiM. Quantitative measurement of cerebrospinal fluid amyloid-β species by mass spectrometry.J. Alzheimers Dis.202179257358410.3233/JAD‑20098733337370
     [Google Scholar]
  43. OlssonB. LautnerR. AndreassonU. ÖhrfeltA. PorteliusE. BjerkeM. HölttäM. RosénC. OlssonC. StrobelG. WuE. DakinK. PetzoldM. BlennowK. ZetterbergH. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis.Lancet Neurol.201615767368410.1016/S1474‑4422(16)00070‑327068280
     [Google Scholar]
  44. BjerkeM. EngelborghsS. Cerebrospinal fluid biomarkers for early and differential Alzheimer’s disease diagnosis.J. Alzheimers Dis.20186231199120910.3233/JAD‑170680
     [Google Scholar]
  45. MattssonN. ZetterbergH. Blennow Lessons from multicenter studies on CSF biomarkers for Alzheimer’s disease.Int. J. Alzheimers Dis.201020101510.4061/2010/61061320721354
     [Google Scholar]
  46. LeuzyA. CarlgrenM.N. PalmqvistS. JanelidzeS. DageJ.L. HanssonO. Blood-based biomarkers for Alzheimer’s disease.EMBO Mol. Med.2022141e1440810.15252/emmm.20211440834859598
     [Google Scholar]
  47. AshtonN.J. PascoalT.A. KarikariT.K. BenedetA.L. RodriguezL.J. BrinkmalmG. SnellmanA. SchöllM. TroakesC. HyeA. GauthierS. VanmechelenE. ZetterbergH. NetoR.P. BlennowK. Plasma p-tau231: A new biomarker for incipient Alzheimer’s disease pathology.Acta Neuropathol.2021141570972410.1007/s00401‑021‑02275‑633585983
     [Google Scholar]
  48. JanelidzeS. MattssonN. PalmqvistS. SmithR. BeachT.G. SerranoG.E. ChaiX. ProctorN.K. EichenlaubU. ZetterbergH. BlennowK. ReimanE.M. StomrudE. DageJ.L. HanssonO. Plasma P-tau181 in Alzheimer’s disease: Relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia.Nat. Med.202026337938610.1038/s41591‑020‑0755‑132123385
     [Google Scholar]
  49. MastersC.L. SimmsG. WeinmanN.A. MulthaupG. McDonaldB.L. BeyreutherK. Amyloid plaque core protein in Alzheimer disease and Down syndrome.Proc. Natl. Acad. Sci. USA198582124245424910.1073/pnas.82.12.42453159021
     [Google Scholar]
  50. MastersC.L. BatemanR. BlennowK. RoweC.C. SperlingR.A. CummingsJ.L. Alzheimer’s disease.Nat. Rev. Dis. Primers2015111505610.1038/nrdp.2015.5627188934
     [Google Scholar]
  51. SerneelsL. NarlawarR. BenitoP.L. MunicoyM. GuallarV. T’SyenD. DewildeM. BischoffF. FraipontsE. TresadernG. RoevensP.W.M. GijsenH.J.M. StrooperD.B. Selective inhibitors of the PSEN1–gamma-secretase complex.J. Biol. Chem.2023299610479410.1016/j.jbc.2023.10479437164155
     [Google Scholar]
  52. KangJ. LemaireH.G. UnterbeckA. SalbaumJ.M. MastersC.L. GrzeschikK.H. MulthaupG. BeyreutherK. HillM.B. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor.Nature1987325610673373610.1038/325733a02881207
     [Google Scholar]
  53. NakamuraT. ShojiM. HarigayaY. WatanabeM. HosodaK. CheungT.T. ShafferL.M. GoldeT.E. YounkinL.H. YounkinS.G. HiraiS. Amyloid β protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer’s disease.Ann. Neurol.199436690391110.1002/ana.4103606167998778
     [Google Scholar]
  54. IwatsuboT. OdakaA. SuzukiN. MizusawaH. NukinaN. IharaY. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: Evidence that an initially deposited species is Aβ42(43).Neuron1994131455310.1016/0896‑6273(94)90458‑88043280
     [Google Scholar]
  55. TamaokaA. SawamuraN. OdakaA. SuzukiN. MizusawaH. ShojiS. MoriH. Amyloid β protein 1–42/43 (Aβ 1–42/43) in cerebellar diffuse plaques: Enzyme-linked immunosorbent assay and immunocytochemical study.Brain Res.1995679115115610.1016/0006‑8993(95)00162‑J7648258
     [Google Scholar]
  56. MotterR. PelfreyV.C. KholodenkoD. BarbourR. WoodJ.K. GalaskoD. ChangL. MillerB. ClarkC. GreenR. OlsonD. SouthwickP. WolfertR. MunroeB. LieberburgI. SeubertP. SchenkD. Reduction of β-amyloid peptide 42 in the cerebrospinal fluid of patients with Alzheimer’s disease.Ann. Neurol.199538464364810.1002/ana.4103804137574461
     [Google Scholar]
  57. KuhlmannJ. AndreassonU. PanneeJ. BjerkeM. PorteliusE. LeinenbachA. BittnerT. KoreckaM. JenkinsR.G. VandersticheleH. StoopsE. LewczukP. ShawL.M. ZegersI. SchimmelH. ZetterbergH. BlennowK. CSF Aβ1–42 – An excellent but complicated Alzheimer’s biomarker – A75 route to standardisation.Clin. Chim. Acta2017467273310.1016/j.cca.2016.05.01427216941
     [Google Scholar]
  58. TapiolaT. AlafuzoffI. HerukkaS.K. ParkkinenL. HartikainenP. SoininenH. PirttiläT. Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain.Arch. Neurol.200966338238910.1001/archneurol.2008.59619273758
     [Google Scholar]
  59. FaganA.M. MintunM.A. MachR.H. LeeS.Y. DenceC.S. ShahA.R. LaRossaG.N. SpinnerM.L. KlunkW.E. MathisC.A. DeKoskyS.T. MorrisJ.C. HoltzmanD.M. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ 42 in humans.Ann. Neurol.200659351251910.1002/ana.2073016372280
     [Google Scholar]
  60. BatemanR.J. XiongC. BenzingerT.L.S. FaganA.M. GoateA. FoxN.C. MarcusD.S. CairnsN.J. XieX. BlazeyT.M. HoltzmanD.M. SantacruzA. BucklesV. OliverA. MoulderK. AisenP.S. GhettiB. KlunkW.E. McDadeE. MartinsR.N. MastersC.L. MayeuxR. RingmanJ.M. RossorM.N. SchofieldP.R. SperlingR.A. SallowayS. MorrisJ.C. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease.N. Engl. J. Med.2012367979580410.1056/NEJMoa120275322784036
     [Google Scholar]
  61. AbdelnourC. Steenovenv.I. LondosE. BlancF. AuestadB. KrambergerM.G. ZetterbergH. MollenhauerB. BoadaM. AarslandD. Alzheimer’s disease cerebrospinal fluid biomarkers predict cognitive decline in lewy body dementia.Mov. Disord.20163181203120810.1002/mds.2666827296778
     [Google Scholar]
  62. DuboisB. HampelH. FeldmanH.H. ScheltensP. AisenP. AndrieuS. BakardjianH. BenaliH. BertramL. BlennowK. BroichK. CavedoE. CrutchS. DartiguesJ.F. DuyckaertsC. EpelbaumS. FrisoniG.B. GauthierS. GenthonR. GouwA.A. HabertM.O. HoltzmanD.M. KivipeltoM. ListaS. MolinuevoJ.L. O’BryantS.E. RabinoviciG.D. RoweC. SallowayS. SchneiderL.S. SperlingR. TeichmannM. CarrilloM.C. CummingsJ. JackC.R.Jr Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria.Alzheimers Dement.201612329232310.1016/j.jalz.2016.02.00227012484
     [Google Scholar]
  63. BuchhaveP. MinthonL. ZetterbergH. WallinA.K. BlennowK. HanssonO. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia.Arch. Gen. Psychiatry20126919810610.1001/archgenpsychiatry.2011.15522213792
     [Google Scholar]
  64. BendlinB.B. CarlssonC.M. JohnsonS.C. CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer’s disease.PLoS One.201276e3772010.1371/journal.pone.0037720
     [Google Scholar]
  65. RingmanJ.M. YounkinS.G. PraticoD. SeltzerW. ColeG.M. GeschwindD.H. AgudeloR.Y. SchafferB. FeinJ. SokolowS. RosarioE.R. GylysK.H. VarpetianA. MedinaL.D. CummingsJ.L. Biochemical markers in persons with preclinical familial Alzheimer disease.Neurology2008712859210.1212/01.wnl.0000303973.71803.8118509095
     [Google Scholar]
  66. SchindlerS.E. BollingerJ.G. OvodV. MawuenyegaK.G. LiY. GordonB.A. HoltzmanD.M. MorrisJ.C. BenzingerT.L.S. XiongC. FaganA.M. BatemanR.J. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis.Neurology20199317e1647e165910.1212/WNL.000000000000808131371569
     [Google Scholar]
  67. NakamuraA. KanekoN. VillemagneV.L. KatoT. DoeckeJ. DoréV. FowlerC. LiQ.X. MartinsR. RoweC. TomitaT. MatsuzakiK. IshiiK. IshiiK. ArahataY. IwamotoS. ItoK. TanakaK. MastersC.L. YanagisawaK. High performance plasma amyloid-β biomarkers for Alzheimer’s disease.Nature2018554769124925410.1038/nature2545629420472
     [Google Scholar]
  68. HanssonO. MikulskisA. FaganA.M. TeunissenC. ZetterbergH. VandersticheleH. MolinuevoJ.L. ShawL.M. VandijckM. VerbeekM.M. SavageM. MattssonN. LewczukP. BatrlaR. RutzS. DeanR.A. BlennowK. The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer’s disease diagnosis: A review.Alzheimers Dement.201814101313133310.1016/j.jalz.2018.05.00829940161
     [Google Scholar]
  69. BaiardiS Abu-RumeilehS RossiM Antemortem csf a β 42/a β 40 ratio predicts Alzheimer's disease pathology better than a β 42 in rapidly progressive dementias.Ann. Clin. Transl. Neurol.20186226327310.1002/acn3.697
     [Google Scholar]
  70. SulikA. ToczylowskiK. PrzybikK.A. MroczkoB. Amyloid and tau protein concentrations in children with meningitis and encephalitis.Viruses202214472510.3390/v1404072535458457
     [Google Scholar]
  71. LewczukP. MatzenA. BlennowK. Cerebrospinal fluid Aβ42/40 corresponds better than Aβ42 to amyloid PET in Alzheimer’s disease.J Alzheimer’s Dis.201655281382210.3233/JAD‑160722
     [Google Scholar]
  72. CummingsJ. The role of biomarkers in Alzheimer’s disease drug development.Adv. Exp. Med. Biol.2019296110.1007/978‑3‑030‑05542‑4_2
     [Google Scholar]
  73. SperlingR.A. DonohueM.C. RamanR. SunC.K. YaariR. HoldridgeK. SiemersE. JohnsonK.A. AisenP.S. A4 Study Team Association of factors with elevated amyloid burden in clinically normal older individuals.JAMA Neurol.202077673574510.1001/jamaneurol.2020.038732250387
     [Google Scholar]
  74. SongF. PoljakA. ValenzuelaM. MayeuxR. SmytheG.A. SachdevP.S. Meta-analysis of plasma amyloid-β levels in Alzheimer’s disease.J. Alzheimers Dis.201126236537510.3233/JAD‑2011‑10197721709378
     [Google Scholar]
  75. ToledoJ.B. ShawL.M. TrojanowskiJ.Q. Plasma amyloid beta measurements - A desired but elusive Alzheimer’s disease biomarker.Alzheimers Res. Ther.201352810.1186/alzrt16223470128
     [Google Scholar]
  76. JanelidzeS. StomrudE. PalmqvistS. ZetterbergH. Westenv.D. JerominA. SongL. HanlonD. HehirT.C.A. BakerD. BlennowK. HanssonO. Plasma β-amyloid in Alzheimer’s disease and vascular disease.Sci. Rep.2016612680110.1038/srep2680127241045
     [Google Scholar]
  77. VerberkI.M.W. SlotR.E. VerfaillieS.C.J. HeijstH. PrinsN.D. Berckelv.B.N.M. ScheltensP. TeunissenC.E. Flierd.v.W.M. Plasma amyloid as prescreener for the earliest Alzheimer pathological changes.Ann. Neurol.201884564865810.1002/ana.2533430196548
     [Google Scholar]
  78. PalmqvistS. JanelidzeS. StomrudE. ZetterbergH. KarlJ. ZinkK. BittnerT. MattssonN. EichenlaubU. BlennowK. HanssonO. Performance of fully automated plasma assays as screening tests for Alzheimer disease–related β-amyloid status.JAMA Neurol.20197691060106910.1001/jamaneurol.2019.163231233127
     [Google Scholar]
  79. JanelidzeS. TeunissenC.E. ZetterbergH. AlluéJ.A. SarasaL. EichenlaubU. BittnerT. OvodV. VerberkI.M.W. TobaK. NakamuraA. BatemanR.J. BlennowK. HanssonO. Head-to-head comparison of 8 plasma amyloid-β 42/40 assays in Alzheimer disease.JAMA Neurol.202178111375138210.1001/jamaneurol.2021.318034542571
     [Google Scholar]
  80. KuoY.M. EmmerlingM.R. LampertH.C. HempelmanS.R. KokjohnT.A. WoodsA.S. CotterR.J. RoherA.E. High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer’s disease.Biochem. Biophys. Res. Commun.1999257378779110.1006/bbrc.1999.055210208861
     [Google Scholar]
  81. RózgaM. BittnerT. BatrlaR. KarlJ. Preanalytical sample handling recommendations for Alzheimer’s disease plasma biomarkers.Alzheimers Dement.20191129130010.1016/j.dadm.2019.02.002
     [Google Scholar]
  82. ParkJ.C. HanS.H. LeeH. JeongH. ByunM.S. BaeJ. KimH. LeeD.Y. YiD. ShinS.A. KimY.K. HwangD. LeeS.W. JungM.I. Prognostic plasma protein panel for Aβ deposition in the brain in Alzheimer’s disease.Prog. Neurobiol.201918310169010.1016/j.pneurobio.2019.10169031605717
     [Google Scholar]
  83. JangH. KimJ.S. LeeH.J. KimC.H. NaD.L. KimH.J. AlluéJ.A. SarasaL. CastilloS. PesiniP. GallacherJ. SeoS.W. DPUK Performance of the plasma Aβ42/Aβ40 ratio, measured with a novel HPLC-MS/MS method, as a biomarker of amyloid PET status in a DPUK-KOREAN cohort.Alzheimers Res. Ther.202113117910.1186/s13195‑021‑00911‑734686209
     [Google Scholar]
  84. OvodV. RamseyK.N. MawuenyegaK.G. BollingerJ.G. HicksT. SchneiderT. SullivanM. PaumierK. HoltzmanD.M. MorrisJ.C. BenzingerT. FaganA.M. PattersonB.W. BatemanR.J. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.Alzheimers Dement.201713884184910.1016/j.jalz.2017.06.226628734653
     [Google Scholar]
  85. WestT. KirmessK.M. MeyerM.R. HolubaschM.S. KnapikS.S. HuY. ContoisJ.H. JacksonE.N. HarpstriteS.E. BatemanR.J. HoltzmanD.M. VergheseP.B. FogelmanI. BraunsteinJ.B. YarasheskiK.E. A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: Findings from a multi cohort validity analysis.Mol. Neurodegener.20211613010.1186/s13024‑021‑00451‑633933117
     [Google Scholar]
  86. PalmqvistS. InselP.S. ZetterbergH. BlennowK. BrixB. StomrudE. MattssonN. HanssonO. Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer’s disease: Cross-validation study of practical algorithms.Alzheimers Dement.201915219420410.1016/j.jalz.2018.08.01430365928
     [Google Scholar]
  87. EbbesenS.U. HøghP. ZibrandtsenI. Plasma Aβ biomarker for early diagnosis and prognosis of Alzheimer’s disease - A systematic review.Dan. Med. J.2023706A0722044637341353
     [Google Scholar]
  88. ZhangK. MizumaH. ZhangX. TakahashiK. JinC. SongF. GaoY. KanayamaY. WuY. LiY. MaL. TianM. ZhangH. WatanabeY. PET imaging of neural activity, β-amyloid, and tau in normal brain aging.Eur. J. Nucl. Med. Mol. Imaging202148123859387110.1007/s00259‑021‑05230‑533674892
     [Google Scholar]
  89. Wilded.A. ReimandJ. TeunissenC.E. ZwanM. WindhorstA.D. BoellaardR. Flierd.v.W.M. ScheltensP. Berckelv.B.N.M. BouwmanF. OssenkoppeleR. Discordant amyloid-β PET and CSF biomarkers and its clinical consequences.Alzheimers Res. Ther.20191117810.1186/s13195‑019‑0532‑x31511058
     [Google Scholar]
  90. ReimandJ. BoonB.D.C. CollijL.E. TeunissenC.E. RozemullerA.J.M. Berckelv.B.N.M. ScheltensP. OssenkoppeleR. BouwmanF. Amyloid-β PET and CSF in an autopsy-confirmed cohort.Ann. Clin. Transl. Neurol.20207112150216010.1002/acn3.5119533080124
     [Google Scholar]
  91. PalmqvistS. SchöllM. StrandbergO. MattssonN. StomrudE. ZetterbergH. BlennowK. LandauS. JagustW. HanssonO. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity.Nat. Commun.201781121410.1038/s41467‑017‑01150‑x29089479
     [Google Scholar]
  92. VlassenkoA.G. McCueL. JasielecM.S. SuY. GordonB.A. XiongC. HoltzmanD.M. BenzingerT.L.S. MorrisJ.C. FaganA.M. Imaging and cerebrospinal fluid biomarkers in early preclinical Alzheimer disease.Ann. Neurol.201680337938710.1002/ana.2471927398953
     [Google Scholar]
  93. HanssonO. SeibylJ. StomrudE. ZetterbergH. TrojanowskiJ.Q. BittnerT. LifkeV. CorradiniV. EichenlaubU. BatrlaR. BuckK. ZinkK. RabeC. BlennowK. ShawL.M. CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts.Alzheimers Dement.201814111470148110.1016/j.jalz.2018.01.01029499171
     [Google Scholar]
  94. BouterC. VogelgsangJ. WiltfangJ. Comparison between amyloid-PET and CSF amyloid-β biomarkers in a clinical cohort with memory deficits.Clin. Chim. Acta2019492626810.1016/j.cca.2019.02.00530735665
     [Google Scholar]
  95. ChiasseuM. MartinezA.L. BelforteN. QuinteroH. DotignyF. DestroismaisonsL. VeldeV.C. PanayiF. LouisC. PoloD.A. Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease.Mol. Neurodegener.20171215810.1186/s13024‑017‑0199‑328774322
     [Google Scholar]
  96. GrimaldiA. BrighiC. PeruzziG. RagozzinoD. BonanniV. LimatolaC. RuoccoG. AngelantonioD.S. Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer’s disease in the 3xTg-AD mouse model.Cell Death Dis.20189668510.1038/s41419‑018‑0740‑529880901
     [Google Scholar]
  97. Wijngaardenv.P. HadouxX. AlwanM. KeelS. DiraniM. Emerging ocular biomarkers of Alzheimer disease.Clin. Exp. Ophthalmol.2017451546110.1111/ceo.1287228147442
     [Google Scholar]
  98. SinghA. VermaS. Use of ocular biomarkers as a potential tool for early diagnosis of Alzheimer’s disease.Indian J. Ophthalmol.202068455556110.4103/ijo.IJO_999_1932174567
     [Google Scholar]
  99. KoronyoY. SalumbidesB.C. BlackK.L. HamaouiK.M. Alzheimer’s disease in the retina: Imaging retinal aβ plaques for early diagnosis and therapy assessment.Neurodegener. Dis.2012101-428529310.1159/00033515422343730
     [Google Scholar]
  100. MoreS.S. VinceR. Hyperspectral imaging signatures detect amyloidopathy in Alzheimer’s mouse retina well before onset of cognitive decline.ACS Chem. Neurosci.20156230631510.1021/cn500242z25354367
     [Google Scholar]
  101. ShiH. KoronyoY. FuchsD.T. SheynJ. JallowO. MandaliaK. GrahamS.L. GuptaV.K. MirzaeiM. KramerovA.A. LjubimovA.V. HawesD. MillerC.A. BlackK.L. CarareR.O. HamaouiK.M. Retinal arterial Aβ 40 deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients.Alzheimers Dement.202319115185519710.1002/alz.1308637166032
     [Google Scholar]
  102. ChoiS. LeeB. WooJ.H. JeongJ.B. JunI. KimE.K. APP processing and metabolism in corneal fibroblasts and epithelium as a potential biomarker for Alzheimer’s disease.Exp. Eye Res.201918216717410.1016/j.exer.2019.03.01230930125
     [Google Scholar]
  103. RodaM. CiavarellaC. GiannaccareG. VersuraP. Biomarkers in Tears and Ocular Surface: A Window for Neurodegenerative Diseases.Eye Contact Lens2020462Suppl. 2S129S13410.1097/ICL.000000000000066331658175
     [Google Scholar]
  104. PreteD.S. MarascoD. SabettaR. PreteD.A. MarinoF.Z. FrancoR. TroisiS. TroisiM. CennamoG. Tear liquid for predictive diagnosis of Alzheimer’s disease.Reports2021432610.3390/reports4030026
     [Google Scholar]
  105. GijsM. RamakersI.H.G.B. VisserP.J. VerheyF.R.J. Waarenburgd.v.M.P.H. SchalkwijkC.G. NuijtsR.M.M.A. WebersC.A.B. Association of tear fluid amyloid and tau levels with disease severity and neurodegeneration.Sci. Rep.20211112267510.1038/s41598‑021‑01993‑x34811435
     [Google Scholar]
  106. GharbiyaM. VisioliG. TrebbastoniA. AlbaneseG.M. ColardoM. D’AntonioF. SegattoM. LambiaseA. Beta-amyloid peptide in tears: An early diagnostic marker of Alzheimer’s disease correlated with choroidal thickness.Int. J. Mol. Sci.2023243259010.3390/ijms2403259036768913
     [Google Scholar]
  107. ShipJ.A. PuckettS.A. Longitudinal study on oral health in subjects with Alzheimer’s disease.J. Am. Geriatr. Soc.1994421576310.1111/j.1532‑5415.1994.tb06074.x8277117
     [Google Scholar]
  108. ShipJ.A. DecarliC. FriedlandR.P. BaumB.J. Diminished submandibular salivary flow in dementia of the Alzheimer type.J. Gerontol.1990452M61M6610.1093/geronj/45.2.M612313044
     [Google Scholar]
  109. SabbaghM.N. ShiJ. LeeM. ArnoldL. HasanA.Y. HeimJ. McGeerP. Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer’s disease dementia from normal controls: Preliminary findings.BMC Neurol.201818115510.1186/s12883‑018‑1160‑y30257642
     [Google Scholar]
  110. LeeM. GuoJ.P. KennedyK. McGeerE.G. McGeerP.L. A method for diagnosing Alzheimer’s disease based on salivary amyloid-β protein 42 levels.J. Alzheimers Dis.20165531175118210.3233/JAD‑16074827792013
     [Google Scholar]
  111. IqbalG.I. IqbalK. TungY.C. QuinlanM. WisniewskiH.M. BinderL.I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.Proc. Natl. Acad. Sci. USA198683134913491710.1073/pnas.83.13.49133088567
     [Google Scholar]
  112. MeredithJ.E.Jr SankaranarayananS. GussV. Characterization of novel csf tau and ptau biomarkers for Alzheimer’s disease.PLoS One.2013810e7652310.1371/journal.pone.0076523
     [Google Scholar]
  113. RussellC.L. MitraV. HanssonK. Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates.J. Alzheimers Dis.201655130331310.3233/JAD‑160633
     [Google Scholar]
  114. CalvetS.M. KarikariT.K. AshtonN.J. RodríguezL.J. AlomàM.M. GispertJ.D. SalvadóG. MinguillonC. FauriaK. ShekariM. RiveraG.O. UrquijoA.E.M. VilaS.A. BenavidesS.G. González-de-EchávarriJ.M. KollmorgenG. StoopsE. VanmechelenE. ZetterbergH. BlennowK. MolinuevoJ.L. BetetaA. CacciagliaR. CañasA. DeulofeuC. CumplidoI. DominguezR. EmilioM. FalconC. FuentesS. HernandezL. HuesaG. HuguetJ. MarneP. MenchónT. OpertoG. PoloA. PradasS. SoterasA. VilanovaM. TejedorV.N. ALFA Study Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected.EMBO Mol. Med.20201212e1292110.15252/emmm.20201292133169916
     [Google Scholar]
  115. BlennowK. WallinA. ÅgrenH. SpengerC. SiegfriedJ. VanmechelenE. tau protein in cerebrospinal fluid.Mol. Chem. Neuropathol.199526323124510.1007/BF028151408748926
     [Google Scholar]
  116. ZetterbergH. Review: Tau in biofluids – relation to pathology, imaging and clinical features.Neuropathol. Appl. Neurobiol.201743319419910.1111/nan.1237828054371
     [Google Scholar]
  117. SeppäläT.T. NergO. KoivistoA.M. RummukainenJ. PuliL. ZetterbergH. PyykköO.T. HelisalmiS. AlafuzoffI. HiltunenM. JääskeläinenJ.E. RinneJ. SoininenH. LeinonenV. HerukkaS.K. CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings.Neurology201278201568157510.1212/WNL.0b013e3182563bd022517093
     [Google Scholar]
  118. FaganA.M. MintunM.A. ShahA.R. AldeaP. RoeC.M. MachR.H. MarcusD. MorrisJ.C. HoltzmanD.M. Cerebrospinal fluid tau and ptau 181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer’s disease.EMBO Mol. Med.200918-937138010.1002/emmm.20090004820049742
     [Google Scholar]
  119. JanelidzeS. StomrudE. SmithR. PalmqvistS. MattssonN. AireyD.C. ProctorN.K. ChaiX. ShcherbininS. SimsJ.R. BaltzerG. TheunisC. SlemmonR. MerckenM. KolbH. DageJ.L. HanssonO. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease.Nat. Commun.2020111168310.1038/s41467‑020‑15436‑032246036
     [Google Scholar]
  120. BarthélemyN.R. BatemanR.J. HirtzC. MarinP. BecherF. SatoC. GabelleA. LehmannS. 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.20201212610.1186/s13195‑020‑00596‑432183883
     [Google Scholar]
  121. KarikariT.K. EmeršičA. VrillonA. RodriguezLJ. AshtonN.J. KrambergerM.G. DumurgierJ. HourregueC. ČučnikS. BrinkmalmG. RotU. ZetterbergH. PaquetC. BlennowK. Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer’s disease diagnosis.Alzheimers Dement.202117575576710.1002/alz.1223633252199
     [Google Scholar]
  122. JohanssonM. StomrudE. InselP.S. LeuzyA. JohanssonP.M. SmithR. IsmailZ. JanelidzeS. PalmqvistS. Westenv.D. CarlgrenM.N. HanssonO. Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer’s disease.Transl. Psychiatry20211117610.1038/s41398‑021‑01206‑z33500386
     [Google Scholar]
  123. BuckleyR.F. MorminoE.C. RabinJ.S. HohmanT.J. LandauS. HanseeuwB.J. JacobsH.I.L. PappK.V. AmariglioR.E. ProperziM.J. SchultzA.P. KirnD. ScottM.R. HeddenT. FarrellM. PriceJ. ChhatwalJ. RentzD.M. VillemagneV.L. JohnsonK.A. SperlingR.A. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults.JAMA Neurol.201976554255110.1001/jamaneurol.2018.469330715078
     [Google Scholar]
  124. FilonJ.R. IntorciaA.J. SueL.I. ArreolaV.E. WilsonJ. DavisK.J. SabbaghM.N. BeldenC.M. CaselliR.J. AdlerC.H. WoodruffB.K. RapscakS.Z. AhernG.L. BurkeA.D. JacobsonS. ShillH.A. DunckleyD.E. ChenK. ReimanE.M. BeachT.G. SerranoG.E. Gender differences in Alzheimer disease: Brain atrophy, histopathology burden, and cognition.J. Neuropathol. Exp. Neurol.201675874875410.1093/jnen/nlw04727297671
     [Google Scholar]
  125. BlennowK VanmechelenE HampelH. CSF total tau, aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease.Mol. Neurobiol.2001241-3879710.1385/MN:24:1‑3:087
     [Google Scholar]
  126. AugustinackJ.C. SchneiderA. MandelkowE.M. HymanB.T. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease.Acta Neuropathol.20021031263510.1007/s00401010042311837744
     [Google Scholar]
  127. MuñozL.J. SierraG.F. FalcónV. MenéndezI. MacíasC.L. MenaR. Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer’s disease.J. Alzheimers Dis.200581294110.3233/JAD‑2005‑810416155347
     [Google Scholar]
  128. MuñozL.J. MacíasC.L. SierraG.F. MenaR. Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease.J. Alzheimers Dis.200712436537510.3233/JAD‑2007‑1241018198423
     [Google Scholar]
  129. GordonB.A. BlazeyT.M. ChristensenJ. DincerA. FloresS. KeefeS. ChenC. SuY. McDadeE.M. WangG. LiY. HassenstabJ. AschenbrennerA. HornbeckR. JackC.R.Jr AncesB.M. BermanS.B. BroschJ.R. GalaskoD. GauthierS. LahJ.J. MasellisM. Dyckv.C.H. MintunM.A. KleinG. RisticS. CairnsN.J. MarcusD.S. XiongC. HoltzmanD.M. RaichleM.E. MorrisJ.C. BatemanR.J. BenzingerT.L.S. Tau PET in autosomal dominant Alzheimer’s disease: Relationship with cognition, dementia and other biomarkers.Brain201914241063107610.1093/brain/awz01930753379
     [Google Scholar]
  130. MattssonN. InselP.S. DonohueM. JögiJ. OssenkoppeleR. OlssonT. SchöllM. SmithR. HanssonO. Predicting diagnosis and cognition with 18 F-AV-1451 tau PET and structural MRI in Alzheimer’s disease.Alzheimers Dement.201915457058010.1016/j.jalz.2018.12.00130639421
     [Google Scholar]
  131. BarthélemyN.R. LiY. MathurinJ.N. GordonB.A. HassenstabJ. BenzingerT.L.S. BucklesV. FaganA.M. PerrinR.J. GoateA.M. MorrisJ.C. KarchC.M. XiongC. AllegriR. MendezP.C. BermanS.B. IkeuchiT. MoriH. ShimadaH. ShojiM. SuzukiK. NobleJ. FarlowM. ChhatwalJ. RadfordG.N.R. SallowayS. SchofieldP.R. MastersC.L. MartinsR.N. O’ConnorA. FoxN.C. LevinJ. JuckerM. GabelleA. LehmannS. SatoC. BatemanR.J. McDadeE. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease.Nat. Med.202026339840710.1038/s41591‑020‑0781‑z32161412
     [Google Scholar]
  132. MaiaL.F. KaeserS.A. ReichwaldJ. HruschaM. MartusP. StaufenbielM. JuckerM. Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein.Sci. Transl. Med.20135194194re210.1126/scitranslmed.300644623863834
     [Google Scholar]
  133. CarlgrenM.N. AnderssonE. JanelidzeS. OssenkoppeleR. InselP. StrandbergO. ZetterbergH. RosenH.J. RabinoviciG. ChaiX. BlennowK. DageJ.L. StomrudE. SmithR. PalmqvistS. HanssonO. Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease.Sci. Adv.2020616eaaz238710.1126/sciadv.aaz238732426454
     [Google Scholar]
  134. At CTAD Tau PET Emerges as Favored Outcome Biomarker for Trials.2017Available from: https//www.alzforum.org/news/conference-coverage/ctad-tau-pet-emerges-favored-outcome-biomarker-trials
  135. SatoC. BarthélemyN.R. MawuenyegaK.G. PattersonB.W. GordonB.A. BalsarottiJ.J. SullivanM. CrispM.J. KastenT. KirmessK.M. KanaanN.M. YarasheskiK.E. NighB.A. BenzingerT.L.S. MillerT.M. KarchC.M. BatemanR.J. Tau kinetics in neurons and the human central nervous system.Neuron201897612841298.e710.1016/j.neuron.2018.02.01529566794
     [Google Scholar]
  136. TatebeH. KasaiT. OhmichiT. KishiY. KakeyaT. WaragaiM. KondoM. AllsopD. TokudaT. Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: Pilot case-control studies including patients with Alzheimer’s disease and down syndrome.Mol. Neurodegener.20171216310.1186/s13024‑017‑0206‑828866979
     [Google Scholar]
  137. ThijssenE.H. JoieL.R. StromA. FonsecaC. IaccarinoL. WolfA. SpinaS. AllenI.E. CobigoY. HeuerH. VandeVredeL. ProctorN.K. LagoA.L. BakerS. SivasankaranR. KielochA. KinhikarA. YuL. ValentinM.A. JerominA. ZetterbergH. HanssonO. CarlgrenM.N. GrahamD. BlennowK. KramerJ.H. GrinbergL.T. SeeleyW.W. RosenH. BoeveB.F. MillerB.L. TeunissenC.E. RabinoviciG.D. RojasJ.C. DageJ.L. BoxerA.L. 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.202120973975210.1016/S1474‑4422(21)00214‑334418401
     [Google Scholar]
  138. WesselingH. MairW. KumarM. SchlaffnerC.N. TangS. BeerepootP. FatouB. GuiseA.J. ChengL. TakedaS. MuntelJ. RotunnoM.S. DujardinS. DaviesP. KosikK.S. MillerB.L. BerrettaS. HedreenJ.C. GrinbergL.T. SeeleyW.W. HymanB.T. SteenH. SteenJ.A. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease.Cell2020183616991713.e1310.1016/j.cell.2020.10.02933188775
     [Google Scholar]
  139. BarthélemyN.R. HorieK. SatoC. BatemanR.J. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease.J. Exp. Med.202021711e2020086110.1084/jem.2020086132725127
     [Google Scholar]
  140. CarlgrenM.N. JanelidzeS. PalmqvistS. CullenN. SvenningssonA.L. StrandbergO. MengelD. WalshD.M. StomrudE. DageJ.L. HanssonO. Longitudinal plasma p-tau217 is increased in early stages of Alzheimer’s disease.Brain2020143113234324110.1093/brain/awaa28633068398
     [Google Scholar]
  141. CullenN.C. LeuzyA. PalmqvistS. JanelidzeS. StomrudE. PesiniP. SarasaL. AlluéJ.A. ProctorN.K. ZetterbergH. DageJ.L. BlennowK. CarlgrenM.N. HanssonO. Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations.Nature Aging20201111412310.1038/s43587‑020‑00003‑537117993
     [Google Scholar]
  142. BayoumyS. VerberkI.M.W. Dulkd.B. HussainaliZ. ZwanM. Flierd.v.W.M. AshtonN.J. ZetterbergH. BlennowK. VanbrabantJ. StoopsE. VanmechelenE. DageJ.L. TeunissenC.E. Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231.Alzheimers Res. Ther.202113119810.1186/s13195‑021‑00939‑934863295
     [Google Scholar]
  143. RoyS. BanerjeeD. ChatterjeeI. NatarajanD. MathewJ.C. The role of 18F-flortaucipir (av-1451) in the diagnosis of neurodegenerative disorders.Cureus2021137e1664410.7759/cureus.1664434458044
     [Google Scholar]
  144. ChiotisK. SavitchevaI. PoulakisK. AubertS.L. WallA. AntoniG. NordbergA. [18F]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer’s disease.Mol. Psychiatry202126105875588710.1038/s41380‑020‑0815‑432616831
     [Google Scholar]
  145. JeongH.J. LeeH. LeeS.Y. SeoS. ParkK.H. LeeY.B. ShinD.J. KangJ.M. YeonB.K. KangS.G. ChoJ. SeongJ.K. OkamuraN. VillemagneV.L. NaD.L. NohY. [ 18 F]THK5351 PET imaging in patients with mild cognitive impairment.J. Clin. Neurol.202016220221410.3988/jcn.2020.16.2.20232319236
     [Google Scholar]
  146. TagaiK. OnoM. KubotaM. KitamuraS. TakahataK. SekiC. TakadoY. ShinotohH. SanoY. YamamotoY. MatsuokaK. TakuwaH. ShimojoM. TakahashiM. KawamuraK. KikuchiT. OkadaM. AkiyamaH. SuzukiH. OnayaM. TakedaT. AraiK. AraiN. ArakiN. SaitoY. TrojanowskiJ.Q. LeeV.M.Y. MishraS.K. YamaguchiY. KimuraY. IchiseM. TomitaY. ZhangM.R. SuharaT. ShigetaM. SaharaN. HiguchiM. ShimadaH. High contrast in vivo imaging of tau pathologies in Alzheimer’s and non-Alzheimer’s disease tauopathies.Neuron202110914258.e810.1016/j.neuron.2020.09.04233125873
     [Google Scholar]
  147. AubertS.L. LemoineL. ChiotisK. LeuzyA. VieitezR.E. NordbergA. Tau PET imaging: Present and future directions.Mol. Neurodegener.20171211910.1186/s13024‑017‑0162‑328219440
     [Google Scholar]
  148. MorminoE.C. TouegT.N. AzevedoC. CastilloJ.B. GuoW. NadiadwalaA. CorsoN.K. HallJ.N. FanA. TrelleA.N. HarrisonM.B. HuntM.P. ShaS.J. DeutschG. JamesM. FredericksC.A. KoranM.E. ZeinehM. PostonK. GreiciusM.D. KhalighiM. DavidzonG.A. ShenB. ZaharchukG. WagnerA.D. ChinF.T. Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases.Eur. J. Nucl. Med. Mol. Imaging20214872233224410.1007/s00259‑020‑04923‑732572562
     [Google Scholar]
  149. PascoalT.A. TherriaultJ. BenedetA.L. SavardM. LussierF.Z. ChamounM. TissotC. QureshiM.N.I. KangM.S. MathotaarachchiS. StevensonJ. HopewellR. MassarwehG. SoucyJ.P. GauthierS. NetoR.P. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles.Brain202014392818283010.1093/brain/awaa18032671408
     [Google Scholar]
  150. LeuzyA. ChiotisK. LemoineL. GillbergP.G. AlmkvistO. VieitezR.E. NordbergA. Tau PET imaging in neurodegenerative tauopathies—still a challenge.Mol. Psychiatry20192481112113410.1038/s41380‑018‑0342‑830635637
     [Google Scholar]
  151. ChoH. ChoiJ.Y. HwangM.S. KimY.J. LeeH.M. LeeH.S. LeeJ.H. RyuY.H. LeeM.S. LyooC.H. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum.Ann. Neurol.201680224725810.1002/ana.2471127323247
     [Google Scholar]
  152. ScheltensP. StrooperD.B. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. Flierd.v.W.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑433667416
     [Google Scholar]
  153. BraakH. AlafuzoffI. ArzbergerT. KretzschmarH. TrediciD.K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry.Acta Neuropathol.2006112438940410.1007/s00401‑006‑0127‑z16906426
     [Google Scholar]
  154. AschenbrennerA.J. GordonB.A. BenzingerT.L.S. MorrisJ.C. HassenstabJ.J. Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease.Neurology2018919e859e86610.1212/WNL.000000000000607530068637
     [Google Scholar]
  155. JoieL.R. VisaniA.V. BakerS.L. BrownJ.A. BourakovaV. ChaJ. ChaudharyK. EdwardsL. IaccarinoL. JanabiM. SegevL.O.H. MillerZ.A. PerryD.C. O’NeilJ.P. PhamJ. RojasJ.C. RosenH.J. SeeleyW.W. TsaiR.M. MillerB.L. JagustW.J. RabinoviciG.D. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET.Sci. Transl. Med.202012524eaau573210.1126/scitranslmed.aau573231894103
     [Google Scholar]
  156. FranzmeierN. NeitzelJ. RubinskiA. SmithR. StrandbergO. OssenkoppeleR. HanssonO. EwersM. WeinerM. AisenP. PetersenR. JackC.R.Jr JagustW. TrojanowkiJ.Q. TogaA.W. BeckettL. GreenR.C. SaykinA.J. MorrisJ. ShawL.M. LiuE. MontineT. ThomasR.G. DonohueM. WalterS. GessertD. SatherT. JiminezG. HarveyD. DonohueM. BernsteinM. FoxN. ThompsonP. SchuffN. DeCArliC. BorowskiB. GunterJ. SenjemM. VemuriP. JonesD. KantarciK. WardC. KoeppeR.A. FosterN. ReimanE.M. ChenK. MathisC. LandauS. CairnsN.J. HouseholderE. ReinwaldL.T. LeeV. KoreckaM. FigurskiM. CrawfordK. NeuS. ForoudT.M. PotkinS. ShenL. KelleyF. KimS. NhoK. KachaturianZ. FrankR. SnyderP.J. MolchanS. KayeJ. QuinnJ. LindB. CarterR. DolenS. SchneiderL.S. PawluczykS. BecceraM. TeodoroL. SpannB.M. BrewerJ. VanderswagH. FleisherA. HeidebrinkJ.L. LordJ.L. PetersenR. MasonS.S. AlbersC.S. KnopmanD. JohnsonK. DoodyR.S. MeyerJ.V. ChowdhuryM. RountreeS. DangM. SternY. HonigL.S. BellK.L. AncesB. MorrisJ.C. CarrollM. LeonS. HouseholderE. MintunM.A. SchneiderS. OliverNGA. GriffithR. ClarkD. GeldmacherD. BrockingtonJ. RobersonE. GrossmanH. MitsisE. Morrelld.L. ShahR.C. DuaraR. VaronD. GreigM.T. RobertsP. AlbertM. OnyikeC. D’AgostinoD.II KielbS. GalvinJ.E. PogorelecD.M. CerboneB. MichelC.A. RusinekH. Leond.M.J. GlodzikL. SantiD.S. DoraiswamyP.M. PetrellaJ.R. WongT.Z. ArnoldS.E. KarlawishJ.H. WolkD. SmithC.D. JichaG. HardyP. SinhaP. OatesE. ConradG. LopezO.L. OakleyM.A. SimpsonD.M. PorsteinssonA.P. GoldsteinB.S. MartinK. MakinoK.M. IsmailM.S. BrandC. MulnardR.A. ThaiG. OrtizC.M.A. WomackK. MathewsD. QuicenoM. ArrastiaR.D. KingR. WeinerM. CookK.M. DeVousM. LeveyA.I. LahJ.J. CellarJ.S. BurnsJ.M. AndersonH.S. SwerdlowR.H. ApostolovaL. TingusK. WooE. SilvermanD.H.S. LuP.H. BartzokisG. RadfordN.R.G. ParfittHF. KendallT. JohnsonH. FarlowM.R. HakeA.M. MatthewsB.R. HerringS. HuntC. Dyckv.C.H. CarsonR.E. MacAvoyM.G. ChertkowH. BergmanH. HoseinC. BlackS. StefanovicB. CaldwellC. HsiungG.Y.R. FeldmanH. MudgeB. PastM.A. KerteszA. RogersJ. TrostD. BernickC. MunicD. KerwinD. MesulamM.M. LipowskiK. WuC.K. JohnsonN. SadowskyC. MartinezW. VillenaT. TurnerR.S. JohnsonK. ReynoldsB. SperlingR.A. JohnsonK.A. MarshallG. FreyM. YesavageJ. TaylorJ.L. LaneB. RosenA. TinklenbergJ. SabbaghM.N. BeldenC.M. JacobsonS.A. SirrelS.A. KowallN. KillianyR. BudsonA.E. NorbashA. JohnsonP.L. ObisesanT.O. WoldayS. AllardJ. LernerA. OgrockiP. HudsonL. FletcherE. CarmichaelO. OlichneyJ. DeCarliC. KitturS. BorrieM. LeeT.Y. BarthaR. JohnsonS. AsthanaS. CarlssonC.M. PotkinS.G. PredaA. NguyenD. TariotP. FleisherA. ReederS. BatesV. CapoteH. RainkaM. ScharreD.W. KatakiM. AdeliA. ZimmermanE.A. CelminsD. BrownA.D. PearlsonG.D. BlankK. AndersonK. SantulliR.B. KitzmillerT.J. SchwartzE.S. SinkSK.M. WilliamsonJ.D. GargP. WatkinsF. OttB.R. QuerfurthH. TremontG. SallowayS. MalloyP. CorreiaS. RosenH.J. MillerB.L. MintzerJ. SpicerK. BachmanD. FingerE. PasternakS. RachinskyI. RogersJ. KerteszA. DrostD. PomaraN. HernandoR. SarraelA. SchultzS.K. PontoL.L.B. ShimH. SmithK.E. RelkinN. ChaingG. RaudinL. SmithA. FargherK. RajB.A. Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease.Nat. Commun.202011134710.1038/s41467‑019‑14159‑131953405
     [Google Scholar]
  157. JackC.R.Jr WisteH.J. SchwarzC.G. LoweV.J. SenjemM.L. VemuriP. WeigandS.D. TherneauT.M. KnopmanD.S. GunterJ.L. JonesD.T. RadfordG.J. KantarciK. RobertsR.O. MielkeM.M. MachuldaM.M. PetersenR.C. Longitudinal tau PET in ageing and Alzheimer’s disease.Brain201814151517152810.1093/brain/awy05929538647
     [Google Scholar]
  158. WangL. BenzingerT.L. SuY. ChristensenJ. FriedrichsenK. AldeaP. McConathyJ. CairnsN.J. FaganA.M. MorrisJ.C. AncesB.M. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy.JAMA Neurol.20167391070107710.1001/jamaneurol.2016.207827454922
     [Google Scholar]
  159. HardyJA HigginsGA Alzheimer’s disease: The amyloid cascade hypothesis.Science1992256505418418510.1126/science.1566067
     [Google Scholar]
  160. UddinM.S. KabirM.T. RahmanM.S. BehlT. JeandetP. AshrafG.M. NajdaA. JumahB.M.N. SeediE.H.R. DaimA.M.M. Revisiting the amyloid cascade hypothesis: From anti-Aβ therapeutics to auspicious new ways for Alzheimer’s disease.Int. J. Mol. Sci.20202116585810.3390/ijms2116585832824102
     [Google Scholar]
  161. ChoH. LeeH.S. ChoiJ.Y. LeeJ.H. RyuY.H. LeeM.S. LyooC.H. Predicted sequence of cortical tau and amyloid-β deposition in Alzheimer disease spectrum.Neurobiol. Aging201868768410.1016/j.neurobiolaging.2018.04.00729751288
     [Google Scholar]
  162. BucciM. ChiotisK. NordbergA. Alzheimer’s disease profiled by fluid and imaging markers: Tau PET best predicts cognitive decline.Mol. Psychiatry202126105888589810.1038/s41380‑021‑01263‑234593971
     [Google Scholar]
  163. HanseeuwB.J. BetenskyR.A. JacobsH.I.L. SchultzA.P. SepulcreJ. BeckerJ.A. CosioD.M.O. FarrellM. QuirozY.T. MorminoE.C. BuckleyR.F. PappK.V. AmariglioR.A. DewachterI. IvanoiuA. HuijbersW. HeddenT. MarshallG.A. ChhatwalJ.P. RentzD.M. SperlingR.A. JohnsonK. Association of amyloid and tau with cognition in preclinical Alzheimer disease.JAMA Neurol.201976891592410.1001/jamaneurol.2019.142431157827
     [Google Scholar]
  164. SchönC. HoffmannN.A. OchsS.M. Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice.PLoS One.2012712e5354710.1371/journal.pone.0053547
     [Google Scholar]
  165. Haand.J. VerbraakF.D. VisserP.J. BouwmanF.H. Retinal thickness in Alzheimer’s disease: A systematic review and meta-analysis.Alzheimers Dement.20176116217010.1016/j.dadm.2016.12.01428275698
     [Google Scholar]
  166. ChopraN. WangR. MaloneyB. NhoK. BeckJ.S. PourshafieN. NiculescuA. SaykinA.J. RinaldiC. CountsS.E. LahiriD.K. MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties.Mol. Psychiatry202126105636565710.1038/s41380‑019‑0610‑231942037
     [Google Scholar]
  167. HoW.L. LeungY. TsangA.W. SoK.F. ChiuK. ChangR.C. Review: Tauopathy in the retina and optic nerve: Does it shadow pathological changes in the brain?Mol. Vis.2012182700271023170062
     [Google Scholar]
  168. ConradC. ViannaC. FreemanM. DaviesP. A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer’s disease.Proc. Natl. Acad. Sci. USA200299117751775610.1073/pnas.11219459912032355
     [Google Scholar]
  169. AshtonN.J. IdeM. SchöllM. BlennowK. LovestoneS. HyeA. ZetterbergH. No association of salivary total tau concentration with Alzheimer’s disease.Neurobiol. Aging20187012512710.1016/j.neurobiolaging.2018.06.01430007161
     [Google Scholar]
  170. PekelesH. QureshiH.Y. PaudelH.K. SchipperH.M. GornistkyM. ChertkowH. Development and validation of a salivary tau biomarker in Alzheimer’s disease.Alzheimers Dement.2018101536010.1016/j.dadm.2018.03.00330623019
     [Google Scholar]
  171. FrisoniG.B. FoxN.C. JackC.R.Jr ScheltensP. ThompsonP.M. The clinical use of structural MRI in Alzheimer disease.Nat. Rev. Neurol.201062677710.1038/nrneurol.2009.21520139996
     [Google Scholar]
  172. VogtN.M. HuntJ.F. AdluruN. DeanD.C.III JohnsonS.C. AsthanaS. YuJ.P.J. AlexanderA.L. BendlinB.B. Cortical microstructural alterations in mild cognitive impairment and Alzheimer’s disease dementia.Cereb. Cortex20203052948296010.1093/cercor/bhz28631833550
     [Google Scholar]
  173. FoxN.C. WarringtonE.K. RossorM.N. Serial magnetic resonance imaging of cerebral atrophy in preclinical Alzheimer’s disease.Lancet19993539170212510.1016/S0140‑6736(99)00496‑110382699
     [Google Scholar]
  174. DickersonB.C. StoubT.R. ShahR.C. SperlingR.A. KillianyR.J. AlbertM.S. HymanB.T. BlackerD. Morrelld.L. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults.Neurology201176161395140210.1212/WNL.0b013e3182166e9621490323
     [Google Scholar]
  175. ArmstrongR.A. SyedA.B. Alzheimer’s disease and the eye.Ophthalmic Physiol. Opt.199616Suppl. 1S2S810.1111/j.1475‑1313.1996.95001344.x8796193
     [Google Scholar]
  176. MorgiaL.C. CisnerosR.F.N. KoronyoY. HannibalJ. GallassiR. CantalupoG. SambatiL. PanB.X. TozerK.R. BarboniP. ProviniF. AvanziniP. CarbonelliM. PelosiA. ChuiH. LiguoriR. BaruzziA. HamaouiK.M. SadunA.A. CarelliV. Melanopsin retinal ganglion cell loss in Alzheimer disease.Ann. Neurol.20167919010910.1002/ana.2454826505992
     [Google Scholar]
  177. KhalilM. TeunissenC.E. OttoM. PiehlF. SormaniM.P. GattringerT. BarroC. KapposL. ComabellaM. FazekasF. PetzoldA. BlennowK. ZetterbergH. KuhleJ. Neurofilaments as biomarkers in neurological disorders.Nat. Rev. Neurol.2018141057758910.1038/s41582‑018‑0058‑z30171200
     [Google Scholar]
  178. YuanA. RaoM.V. Veeranna NixonR.A. Neurofilaments and neurofilament proteins in health and disease.Cold Spring Harb. Perspect. Biol.201794a01830910.1101/cshperspect.a01830928373358
     [Google Scholar]
  179. KhalilM. PirpamerL. HoferE. VoortmanM.M. BarroC. LeppertD. BenkertP. RopeleS. EnzingerC. FazekasF. SchmidtR. KuhleJ. Serum neurofilament light levels in normal aging and their association with morphologic brain changes.Nat. Commun.202011181210.1038/s41467‑020‑14612‑632041951
     [Google Scholar]
  180. ZetterbergH. SkillbäckT. MattssonN. TrojanowskiJ.Q. PorteliusE. ShawL.M. WeinerM.W. BlennowK. Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression.JAMA Neurol.2016731606710.1001/jamaneurol.2015.303726524180
     [Google Scholar]
  181. MattssonN. AndreassonU. ZetterbergH. BlennowK. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease.JAMA Neurol.201774555756610.1001/jamaneurol.2016.611728346578
     [Google Scholar]
  182. GleerupH.S. SimonsenA.H. HøghP. The added value of cerebrospinal fluid neurofilament light chain to existing diagnostic methods and biomarkers in a mixed memory clinic cohort of consecutive patients.J. Alzheimers Dis. Rep.20226112112710.3233/ADR‑21004735530115
     [Google Scholar]
  183. BridelC. Wieringenv.W.N. ZetterbergH. TijmsB.M. TeunissenC.E. CermeñoA.J.C. AndreassonU. AxelssonM. BäckströmD.C. BartosA. BjerkeM. BlennowK. BoxerA. BrundinL. BurmanJ. ChristensenT. FialováL. ForsgrenL. FrederiksenJ.L. GisslénM. GrayE. GunnarssonM. HallS. HanssonO. HerbertM.K. JakobssonJ. KrutJ.J. JanelidzeS. JohannssonG. JonssonM. KapposL. KhademiM. KhalilM. KuhleJ. LandénM. LeinonenV. LogroscinoG. LuC.H. LyckeJ. MagdalinouN.K. MalaspinaA. MattssonN. MeeterL.H. MehtaS.R. ModvigS. OlssonT. PatersonR.W. SantiagoP.J. PiehlF. PijnenburgY.A.L. PyykköO.T. RagnarssonO. RojasJ.C. ChristensenR.J. SandbergL. ScherlingC.S. SchottJ.M. SellebjergF.T. SimoneI.L. SkillbäckT. StilundM. SundströmP. SvenningssonA. TortelliR. TortorellaC. TrentiniA. TroianoM. TurnerM.R. Swietenv.J.C. VågbergM. VerbeekM.M. VillarL.M. VisserP.J. WallinA. WeissA. WikkelsøC. WildE.J. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology.JAMA Neurol.20197691035104810.1001/jamaneurol.2019.153431206160
     [Google Scholar]
  184. GalaI.I. LleoA. KarydasA. StaffaroniA.M. ZetterbergH. SivasankaranR. GrinbergL.T. SpinaS. KramerJ.H. RamosE.M. CoppolaG. JoieL.R. RabinoviciG.D. PerryD.C. TempiniG.M.L. SeeleyW.W. MillerB.L. RosenH.J. BlennowK. BoxerA.L. RojasJ.C. Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer disease.Neurology2021965e671e68310.1212/WNL.000000000001122633199433
     [Google Scholar]
  185. AshtonN.J. LeuzyA. LimY.M. TroakesC. HortobágyiT. HöglundK. AarslandD. LovestoneS. SchöllM. BlennowK. ZetterbergH. HyeA. Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration.Acta Neuropathol. Commun.201971510.1186/s40478‑018‑0649‑330626432
     [Google Scholar]
  186. PreischeO. SchultzS.A. ApelA. KuhleJ. KaeserS.A. BarroC. GräberS. BulettaK.E. LaFougereC. LaskeC. VögleinJ. LevinJ. MastersC.L. MartinsR. SchofieldP.R. RossorM.N. RadfordG.N.R. SallowayS. GhettiB. RingmanJ.M. NobleJ.M. ChhatwalJ. GoateA.M. BenzingerT.L.S. MorrisJ.C. BatemanR.J. WangG. FaganA.M. McDadeE.M. GordonB.A. JuckerM. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease.Nat. Med.201925227728310.1038/s41591‑018‑0304‑330664784
     [Google Scholar]
  187. MinoshimaS. MosciK. CrossD. ThientunyakitT. Brain [F-18]FDG PET for clinical dementia workup: Differential diagnosis of Alzheimer’s disease and other types of dementing disorders.Semin. Nucl. Med.202151323024010.1053/j.semnuclmed.2021.01.00233546814
     [Google Scholar]
  188. ZetterbergH. BendlinB.B. Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies.Mol. Psychiatry202126129630810.1038/s41380‑020‑0721‑932251378
     [Google Scholar]
  189. ChenM.K. MeccaA.P. NaganawaM. FinnemaS.J. ToyonagaT. LinS. NajafzadehS. RopchanJ. LuY. McDonaldJ.W. MichalakH.R. NabulsiN.B. ArnstenA.F.T. HuangY. CarsonR.E. Dyckv.C.H. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2a positron emission tomographic imaging.JAMA Neurol.201875101215122410.1001/jamaneurol.2018.183630014145
     [Google Scholar]
  190. LiS. CaiZ. ZhangW. HoldenD. LinS. FinnemaS.J. ShiraliA. RopchanJ. CarreS. MercierJ. CarsonR.E. NabulsiN. HuangY. Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A).Eur. J. Nucl. Med. Mol. Imaging20194691952196510.1007/s00259‑019‑04357‑w31175396
     [Google Scholar]
  191. ConstantinescuC.C. TresseC. ZhengM. GouasmatA. CarrollV.M. MisticoL. AlagilleD. SandiegoC.M. PapinC. MarekK. SeibylJ.P. TamagnanG.D. BarretO. Development and in vivo preclinical imaging of fluorine-18-labeled synaptic vesicle protein 2a (SV2A) pet tracers.Mol. Imaging Biol.201921350951810.1007/s11307‑018‑1260‑530084043
     [Google Scholar]
  192. PorteliusE. OlssonB. HöglundK. CullenN.C. KvartsbergH. AndreassonU. ZetterbergH. SandeliusÅ. ShawL.M. LeeV.M.Y. IrwinD.J. GrossmanM. WeintraubD. PlotkinC.A. WolkD.A. McCluskeyL. ElmanL. McBrideJ. ToledoJ.B. TrojanowskiJ.Q. BlennowK. Cerebrospinal fluid neurogranin concentration in neurodegeneration: Relation to clinical phenotypes and neuropathology.Acta Neuropathol.2018136336337610.1007/s00401‑018‑1851‑x29700597
     [Google Scholar]
  193. KvartsbergH. DuitsF.H. IngelssonM. AndreasenN. ÖhrfeltA. AnderssonK. BrinkmalmG. LannfeltL. MinthonL. HanssonO. AndreassonU. TeunissenC.E. ScheltensP. Flierd.V.W.M. ZetterbergH. PorteliusE. BlennowK. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer’s disease.Alzheimers Dement.201511101180119010.1016/j.jalz.2014.10.00925533203
     [Google Scholar]
  194. VosD.A. JacobsD. StruyfsH. FransenE. AnderssonK. PorteliusE. AndreassonU. SurgelooseD.D. HernalsteenD. SleegersK. RobberechtC. BroeckhovenV.C. ZetterbergH. BlennowK. EngelborghsS. VanmechelenE. C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease.Alzheimers Dement.201511121461146910.1016/j.jalz.2015.05.01226092348
     [Google Scholar]
  195. BălașaA.F. ChircovC. GrumezescuA.M. Body fluid biomarkers for Alzheimer’s disease—an up-to-date overview.Biomedicines202081042110.3390/biomedicines810042133076333
     [Google Scholar]
  196. Król-GrzymałaA. Sienkiewicz-SzłapkaE. FiedorowiczE. RozmusD. CieślińskaA. GrzybowskiA. Tear biomarkers in Alzheimer’s and parkinson’s diseases, and multiple sclerosis: Implications for diagnosis (systematic review).Int. J. Mol. Sci.202223171012310.3390/ijms23171012336077520
     [Google Scholar]
  197. KallóG. EmriM. VargaZ. Changes in the chemical barrier composition of tears in Alzheimer’s disease reveal potential tear diagnostic biomarkers.PLoS One.2016116e015800010.1371/journal.pone.0158000
     [Google Scholar]
  198. CarroE. BartoloméF. ParejaB.F. GalendeA. MolinaJ.A. OrtizP. CaleroM. RabanoA. CanteroJ.L. OriveG. Early diagnosis of mild cognitive impairment and Alzheimer’s disease based on salivary lactoferrin.Alzheimers Dement.20178113113810.1016/j.dadm.2017.04.00228649597
     [Google Scholar]
  199. BakhtiariS. Can salivary acetylcholinesterase be a diagnostic biomarker for Alzheimer?J. Clin. Diagn. Res.111ZC58ZC6010.7860/JCDR/2017/21715.9192
     [Google Scholar]
  200. BlancoG.A. BautistaP.C. OgerC. VigorC. GalanoJ.M. DurandT. IbáñezM.N. BaqueroM. VentoM. PericásC.C. Reliable determination of new lipid peroxidation compounds as potential early Alzheimer Disease biomarkers.Talanta201818419320110.1016/j.talanta.2018.03.00229674032
     [Google Scholar]
  201. LeeH.S. KimI. ChungC.B. Increased urinary level of oxidized nucleosides in patients with mild-to-moderate Alzheimer’s disease.Clin. Biochem.20074013-1493693810.1016/j.clinbiochem.2006.11.02117692303
     [Google Scholar]
  202. BautistaP.C. TirleT. NoguerolesL.M. VentoM. BaqueroM. PericásC.C. Oxidative damage of DNA as early marker of Alzheimer’s disease.Int. J. Mol. Sci.20192024613610.3390/ijms2024613631817451
     [Google Scholar]
  203. MonteL.d.S.M. WandsJ.R. The AD7c-NTP neuronal thread protein biomarker for detecting Alzheimer’s disease.J. Alzheimers Dis.20013334535310.3233/JAD‑2001‑331012214056
     [Google Scholar]
  204. LvS. ZhouX. LiY. ZhangS. WangY. JiaS. NiuX. WangL. PengD. The association between plasma α-synuclein (α-syn) protein, urinary Alzheimer-associated neuronal thread protein (ad7c-ntp), and apolipoprotein epsilon 4 (apoe ε4) alleles and cognitive decline in 60 patients with Alzheimer’s disease compared with 28 age-matched normal individuals.Med. Sci. Monit.202127e93299810.12659/MSM.93299834312362
     [Google Scholar]
  205. TakaeK. HataJ. OharaT. YoshidaD. ShibataM. MukaiN. HirakawaY. KishimotoH. TsuruyaK. KitazonoT. KiyoharaY. NinomiyaT. Albuminuria increases the risks for both Alzheimer disease and vascular dementia in community-dwelling japanese elderly: The hisayama study.J. Am. Heart Assoc.201872e00669310.1161/JAHA.117.00669329353232
     [Google Scholar]
  206. YangW. ChauhanA. MehtaS. MehtaP. GuF. ChauhanV. Trichostatin A increases the levels of plasma gelsolin and amyloid beta-protein in a transgenic mouse model of Alzheimer’s disease.Life Sci.2014991-2313610.1016/j.lfs.2014.01.06424486299
     [Google Scholar]
  207. AgbemenyahH.Y. BalboaA.R.C. BurkhardtS. DelalleI. FischerA. Insulin growth factor binding protein 7 is a novel target to treat dementia.Neurobiol. Dis.20146213514310.1016/j.nbd.2013.09.01124075854
     [Google Scholar]
  208. RentsendorjA. SheynJ. FuchsD.T. DaleyD. SalumbidesB.C. SchubloomH.E. HartN.J. LiS. HaydenE.Y. TeplowD.B. BlackK.L. KoronyoY. HamaouiK.M. A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer’s models.Brain Behav. Immun.20186716318010.1016/j.bbi.2017.08.01928860067
     [Google Scholar]
  209. MusunuriS. KhoonsariP.E. MikusM. Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain.J. Alzheimers Dis.20165441671168610.3233/JAD‑16027127636840
     [Google Scholar]
  210. BadhwarA. HaqqaniA.S. Biomarker potential of brain-secreted extracellular vesicles in blood in Alzheimer’s disease.Alzheimers Dement.2020121e1200110.1002/dad2.1200132211497
     [Google Scholar]
  211. Haard.v.H.J. BurgmansS. JansenJ.F.A. Oschv.M.J.P. Buchemv.M.A. MullerM. HofmanP.A.M. VerheyF.R.J. BackesW.H. Blood brain barrier leakage in patients with early Alzheimer disease.Radiology2016281252753510.1148/radiol.201615224427243267
     [Google Scholar]
  212. SadikN. CruzL. GurtnerA. Extracellular RNAS: A new awareness of old perspectives.Methods Mol. Biol.2018174011510.1007/978‑1‑4939‑7652‑2_1
     [Google Scholar]
  213. YanZ. ZhouZ. WuQ. ChenZ.B. KooE.H. ZhongS. Presymptomatic increase of an extracellular RNA in blood plasma associates with the development of Alzheimer’s disease.Curr. Biol.2020301017711782.e310.1016/j.cub.2020.02.08432220323
     [Google Scholar]
  214. EbertM.S. SharpP.A. Roles for microRNAs in conferring robustness to biological processes.Cell2012149351552410.1016/j.cell.2012.04.00522541426
     [Google Scholar]
  215. DongH. LiJ. HuangL. ChenX. LiD. WangT. HuC. XuJ. ZhangC. ZenK. XiaoS. YanQ. WangC. ZhangC.Y. Serum MicroRNA profiles serve as novel biomarkers for the diagnosis of Alzheimer’s disease.Dis. Markers2015201511110.1155/2015/62565926078483
     [Google Scholar]
  216. KennyA. McArdleH. CaleroM. RabanoA. MaddenS. AdamsonK. ForsterR. SpainE. PrehnJ. HenshallD. MedinaM. MateosJ.E. EngelT. Elevated plasma microRNA-206 levels predict cognitive decline and progression to dementia from mild cognitive impairment.Biomolecules201991173410.3390/biom911073431766231
     [Google Scholar]
  217. GratuzeM. LeynsC.E.G. HoltzmanD.M. New insights into the role of TREM2 in Alzheimer’s disease.Mol. Neurodegener.20181316610.1186/s13024‑018‑0298‑930572908
     [Google Scholar]
  218. MolinuevoJ.L. AytonS. BatrlaR. BednarM.M. BittnerT. CummingsJ. FaganA.M. HampelH. MielkeM.M. MikulskisA. O’BryantS. ScheltensP. SevignyJ. ShawL.M. SoaresH.D. TongG. TrojanowskiJ.Q. ZetterbergH. BlennowK. Current state of Alzheimer’s fluid biomarkers.Acta Neuropathol.2018136682185310.1007/s00401‑018‑1932‑x30488277
     [Google Scholar]
  219. CalvetS.M. KleinbergerG. CaballeroA.M.Á. BrendelM. RomingerA. AlcoleaD. ForteaJ. LleóA. BlesaR. GispertJ.D. ValleS.R. AntonellA. RamiL. MolinuevoJ.L. BrosseronF. TraschützA. HenekaM.T. StruyfsH. EngelborghsS. SleegersK. BroeckhovenV.C. ZetterbergH. NellgårdB. BlennowK. CrispinA. EwersM. HaassC. sTREM 2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers.EMBO Mol. Med.20168546647610.15252/emmm.20150612326941262
     [Google Scholar]
  220. ElahiF.M. CasalettoK.B. JoieL.R. WaltersS.M. HarveyD. WolfA. EdwardsL. ContrerasR.W. KarydasA. CobigoY. RosenH.J. DeCarliC. MillerB.L. RabinoviciG.D. KramerJ.H. Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer’s disease.Alzheimers Dement.202016468169510.1016/j.jalz.2019.09.00431879236
     [Google Scholar]
  221. ShenX.N. NiuL.D. WangY.J. CaoX.P. LiuQ. TanL. ZhangC. YuJ.T. Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: A meta-analysis and systematic review of 170 studies.J. Neurol. Neurosurg. Psychiatry201990559059810.1136/jnnp‑2018‑31914830630955
     [Google Scholar]
  222. ZhouR. JiB. KongY. QinL. RenW. GuanY. NiR. PET imaging of neuroinflammation in Alzheimer’s disease.Front. Immunol.20211273913010.3389/fimmu.2021.73913034603323
     [Google Scholar]
  223. BuccellatoF.R. D’AncaM. FenoglioC. ScarpiniE. GalimbertiD. Role of oxidative damage in Alzheimer’s disease and neurodegeneration: From pathogenic mechanisms to biomarker discovery.Antioxidants2021109135310.3390/antiox1009135334572985
     [Google Scholar]
  224. CalvaniR. PiccaA. GuerraF. JuniorC.H. BucciC. MarzettiE. Circulating extracellular vesicles: Friends and foes in neurodegeneration.Neural Regen. Res.202217353454210.4103/1673‑5374.32097234380883
     [Google Scholar]
  225. JiaL. QiuQ. ZhangH. ChuL. DuY. ZhangJ. ZhouC. LiangF. ShiS. WangS. QinW. WangQ. LiF. WangQ. LiY. ShenL. WeiY. JiaJ. Concordance between the assessment of Aβ42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid.Alzheimers Dement.20191581071108010.1016/j.jalz.2019.05.00231422798
     [Google Scholar]
  226. MikułaE. Recent advancements in electrochemical biosensors for Alzheimers disease biomarkers detection.Curr. Med. Chem.202128204049407310.2174/1875533XMTExqMzkj033176635
     [Google Scholar]
  227. GaubertS. RaimondoF. HouotM. CorsiM.C. NaccacheL. SittD.J. HermannB. OudietteD. GagliardiG. HabertM.O. DuboisB. FallaniV.D.F. BakardjianH. EpelbaumS. EEG evidence of compensatory mechanisms in preclinical Alzheimer’s disease.Brain201914272096211210.1093/brain/awz15031211359
     [Google Scholar]
  228. BlennowK. ZetterbergH. The past and the future of Alzheimer’s disease fluid biomarkers.J. Alzheimers Dis.20186231125114010.3233/JAD‑170773
     [Google Scholar]
  229. TeunissenC.E. VerberkI.M.W. ThijssenE.H. VermuntL. HanssonO. ZetterbergH. Flierd.v.W.M. MielkeM.M. Campod.M. Blood-based biomarkers for Alzheimer’s disease: Towards clinical implementation.Lancet Neurol.2022211667710.1016/S1474‑4422(21)00361‑634838239
     [Google Scholar]
/content/journals/rrct/10.2174/0115748871331138250114052615
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New Research on Biomarkers in Alzheimer’s Continuum
Rev. Recent Clin. Trials 20, 211 (2025); https://doi.org/10.2174/0115748871331138250114052615
/content/journals/rrct/10.2174/0115748871331138250114052615
/content/journals/rrct/10.2174/0115748871331138250114052615
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  • Article Type:     Review Article
Keyword(s): Alzheimer’s continuum; amyloid-β; anticholinesterases; disease-modifying therapeutics; multifactorial pathology; τ protein

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