Skip to content
2000
Volume 25, Issue 8
  • ISSN: 1568-0266
  • E-ISSN: 1873-4294

Abstract

Alzheimer’s disease (AD) has been recognized as the most important cause of dementia, which is estimated to contribute more than 2 trillion USD in medical costs. AD patients encounter progressive neurodegenerative dementia associated with behavioural, linguistic, and visuospatial deficits. Although studies on the discovery of amyloid β (Aβ) and tau (the essential elements of plaques and tangles in AD) have shed light on the molecular pathological processes of AD, the exact cause of the condition is still largely unknown. The involvement of various proteins, such as amyloid-β, prion protein, tau, and α-synuclein has been linked to AD pathogenesis. The current AD treatments are mainly based on symptomatic management and restoration of neurotransmitters’ balance. There is a significant need to develop medications that can alter the underlying disease process and prevent its progression. The present manuscript provides a review of various hypotheses that have been proposed for AD pathogenesis. The manuscript has also explored the development of novel anti-AD drugs based on various pathogenic pathways, which are recently under various clinical trial phases.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ctmc/10.2174/0115680266274924231002110733
2023-10-05
2025-10-20

  • From This Site

    /content/journals/ctmc/10.2174/0115680266274924231002110733
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. KumarA. SidhuJ. GoyalA. TsaoJ. W. DoerrC. Alzheimer Disease (Nursing)StatPearlsTreasure Island (FL)2022
     [Google Scholar]
  2. LaneC.A. HardyJ. SchottJ.M. Alzheimer’s disease.Eur. J. Neurol.2018251597010.1111/ene.1343928872215
     [Google Scholar]
  3. PrinceM. AlbaneseE. GuerchetM. PrinaM. Dementia and risk reduction: An analysis of protective and modifiable risk factors.2014Available from: http://www.alz.co.uk/research/world-report-2014
    [Google Scholar]
  4. NandiA. CountsN. ChenS. SeligmanB. TortoriceD. VigoD. BloomD.E. Global and regional projections of the economic burden of Alzheimer’s disease and related dementias from 2019 to 2050: A value of statistical life approach.EClinicalMedicine20225110158010.1016/j.eclinm.2022.10158035898316
     [Google Scholar]
  5. Garre-OlmoJ. Epidemiology of Alzheimer’s disease and other dementiasRev. Neurol.2018661137738629790571
     [Google Scholar]
  6. LopezO.L. KullerL.H. Epidemiology of aging and associated cognitive disorders: Prevalence and incidence of Alzheimer’s disease and other dementias.Handb. Clin. Neurol.201916713914810.1016/B978‑0‑12‑804766‑8.00009‑131753130
     [Google Scholar]
  7. BrookmeyerR. AbdallaN. KawasC.H. CorradaM.M. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States.Alzheimers Dement.201814212112910.1016/j.jalz.2017.10.00929233480
     [Google Scholar]
  8. DeningT. SandilyanMB. Dementia: Definitions and types.Nurs Stand.20152937374210.7748/ns.29.37.37.e9405
     [Google Scholar]
  9. DuboisB. HampelH. FeldmanHH. ScheltensP. AisenP. AndrieuS. BakardjianH. BenaliH. BertramL. BlennowK. BroichK. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.Alzheimers Dement.201612329232310.1016/j.jalz.2016.02.002
     [Google Scholar]
  10. 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]
  11. KovacsG.G. Concepts and classification of neurodegenerative diseases.Handb. Clin. Neurol.201814530130710.1016/B978‑0‑12‑802395‑2.00021‑328987178
     [Google Scholar]
  12. DuggerB.N. DicksonD.W. Pathology of neurodegenerative diseases.Cold Spring Harb. Perspect. Biol.201797a02803510.1101/cshperspect.a02803528062563
     [Google Scholar]
  13. PalasíA. Gutiérrez-IglesiasB. AlegretM. PujadasF. OlabarrietaM. LiébanaD. QuintanaM. Álvarez-SabínJ. BoadaM. Differentiated clinical presentation of early and late-onset Alzheimer’s disease: Is 65 years of age providing a reliable threshold?J. Neurol.201526251238124610.1007/s00415‑015‑7698‑325791224
     [Google Scholar]
  14. Freudenberg-HuaY. LiW. DaviesP. The role of genetics in advancing precision medicine for Alzheimer’s disease—a narrative review.Front. Med.2018510810.3389/fmed.2018.0010829740579
     [Google Scholar]
  15. Van CauwenbergheC. Van BroeckhovenC. SleegersK. The genetic landscape of Alzheimer disease: Clinical implications and perspectives.Genet. Med.201618542143010.1038/gim.2015.11726312828
     [Google Scholar]
  16. VerheijenJ. SleegersK. Understanding Alzheimer disease at the interface between genetics and transcriptomics.Trends Genet.201834643444710.1016/j.tig.2018.02.00729573818
     [Google Scholar]
  17. ScheltensP. De StrooperB. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. van der FlierW.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑433667416
     [Google Scholar]
  18. YiannopoulouK.G. PapageorgiouS.G. Current and future treatments in alzheimer disease: An update.J. Cent. Nerv. Syst. Dis.20201210.1177/117957352090739732165850
     [Google Scholar]
  19. ChangR. YeeK.L. SumbriaR.K. Tumor necrosis factor α Inhibition for Alzheimer’s Disease.J. Cent. Nerv. Syst. Dis.2017910.1177/117957351770927828579870
     [Google Scholar]
  20. TongB.C.K. WuA.J. LiM. CheungK.H. Calcium signaling in AD & therapies. Biochimica et Biophysica Acta (BBA)-. Molecular Cell Research20181865111745176010.1016/j.bbamcr.2018.07.01830059692
     [Google Scholar]
  21. Ghanbari-MamanA. Ghasemian-RoudsariF. AliakbariS. Gholami PourbadieH. KhodagholiF. ShaerzadehF. DaftariM. Calcium channel blockade ameliorates endoplasmic reticulum stress in the hippocampus induced by amyloidopathy in the entorhinal cortex.Iran. J. Pharm. Res.20191831466147610.22037/ijpr.2019.111532.1321632641955
     [Google Scholar]
  22. BergantinL.B. The interactions between AD and major depression: role of Ca2+ channel blockers and Ca2+/cAMP signalling.Curr. Drug Res. Rev.20211229710210.2174/258997751266620021709335632065096
     [Google Scholar]
  23. Sushma MondalA.C. Role of GPCR signaling and calcium dysregulation in Alzheimer’s disease.Mol. Cell. Neurosci.201910110341410.1016/j.mcn.2019.10341431655116
     [Google Scholar]
  24. JohnsonJ. KotermanskiS. Mechanism of action of memantine.Curr. Opin. Pharmacol.200661616710.1016/j.coph.2005.09.00716368266
     [Google Scholar]
  25. GuanP.P. CaoL.L. WangP. Elevating the levels of calcium ions exacerbate AD via inducing the production and aggregation of β-amyloid protein and phosphorylated tau.Int. J. Mol. Sci.20212211590010.3390/ijms2211590034072743
     [Google Scholar]
  26. ChappellA.S. GonzalesC. WilliamsJ. WitteM.M. MohsR.C. SperlingR. AMPA potentiator treatment of cognitive deficits in Alzheimer disease.Neurology200768131008101210.1212/01.wnl.0000260240.46070.7c17389305
     [Google Scholar]
  27. GeM. ZhangJ. ChenS. HuangY. ChenW. HeL. ZhangY. Role of calcium homeostasis in AD.Neuropsychiatr. Dis. Treat.20221848749810.2147/NDT.S35093935264851
     [Google Scholar]
  28. LacampagneA. LiuX. ReikenS. BussiereR. MeliA.C. LauritzenI. TeichA.F. ZalkR. SaintN. ArancioO. BauerC. DupratF. BriggsC.A. ChakrobortyS. StutzmannG.E. ShelanskiM.L. CheclerF. ChamiM. MarksA.R. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits.Acta Neuropathol.2017134574976710.1007/s00401‑017‑1733‑728631094
     [Google Scholar]
  29. YaoJ. ChenS.R.W. R-carvedilol, a potential new therapy for Alzheimer’s disease.Front. Pharmacol.202213106249510.3389/fphar.2022.106249536532759
     [Google Scholar]
  30. YaoJ. SunB. InstitorisA. ZhanX. GuoW. SongZ. LiuY. HiessF. BoyceA.K.J. NiM. WangR. ter KeursH. BackT.G. FillM. ThompsonR.J. TurnerR.W. GordonG.R. ChenS.R.W. Limiting RyR2 open time prevents Alzheimer’s disease-related neuronal hyperactivity and memory loss but not β-amyloid accumulation.Cell Rep.2020321210816910.1016/j.celrep.2020.10816932966798
     [Google Scholar]
  31. AtriA. Current and future treatments in AD.Semin. Neurol.201939222724010.1055/s‑0039‑167858130925615
     [Google Scholar]
  32. BlennowK. ZetterbergH. Biomarkers for Alzheimer’s disease: Current status and prospects for the future.J. Intern. Med.2018284664366310.1111/joim.1281630051512
     [Google Scholar]
  33. YangT.T. LiuC.G. GaoS.C. ZhangY. WangP.C. The serum exosome derived MicroRNA− 135a, − 193b, and− 384 were potential Alzheimer’s disease biomarkers.Biomed. Environ. Sci.2018312879610.3967/bes2018.01129606187
     [Google Scholar]
  34. MalikR. KalraS. BhatiaS. HarrasiA.A. SinghG. MohanS. MakeenH.A. AlbrattyM. MerayaA. BaharB. TambuwalaM.M. Overview of therapeutic targets in management of dementia.Biomed. Pharmacother.202215211316810.1016/j.biopha.2022.11316835701303
     [Google Scholar]
  35. FanL. MaoC. HuX. ZhangS. YangZ. HuZ. SunH. FanY. DongY. YangJ. ShiC. XuY. New insights into the pathogenesis of AD.Front. Neurol.202010131210.3389/fneur.2019.0131231998208
     [Google Scholar]
  36. AnY. ZhangC. HeS. YaoC. ZhangL. ZhangQ. Main hypotheses, concepts and theories in the study of AD.Life Sci. J.20085415
     [Google Scholar]
  37. FineA. HoyleC. MacleanC.J. LeVatteT.L. BakerH.F. RidleyR.M. Learning impairments following injection of a selective cholinergic immunotoxin, ME20.4 IgG-saporin, into the basal nucleus of Meynert in monkeys.Neuroscience199781233134310.1016/S0306‑4522(97)00208‑X9300425
     [Google Scholar]
  38. MirandaM.I. Bermúdez-RattoniF. Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories.Proc. Natl. Acad. Sci.199996116478648210.1073/pnas.96.11.647810339613
     [Google Scholar]
  39. ChenZ.R. HuangJ.B. YangS.L. HongF.F. Role of cholinergic signaling in Alzheimer’s disease.Molecules2022276181610.3390/molecules2706181635335180
     [Google Scholar]
  40. SimsN.R. BowenD.M. DavisonA.N. [14C]acetylcholine synthesis and [14C]carbon dioxide production from [U-14C]glucose by tissue prisms from human neocortex.Biochem. J.1981196386787610.1042/bj19608676797411
     [Google Scholar]
  41. GreenwaldB.S. DavisK.L. Experimental pharmacology of Alzheimer disease.Adv. Neurol.198338871026137135
     [Google Scholar]
  42. TerryA.V.Jr BuccafuscoJ.J. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development.J. Pharmacol. Exp. Ther.2003306382182710.1124/jpet.102.04161612805474
     [Google Scholar]
  43. StanciuG.D. LucaA. RusuR.N. BildV. Beschea ChiriacS.I. SolcanC. BildW. AbabeiD.C. Alzheimer’s disease pharmacotherapy in relation to cholinergic system involvement.Biomolecules20191014010.3390/biom1001004031888102
     [Google Scholar]
  44. GiacobiniE. Cholinesterases: New roles in brain function and in Alzheimer’s disease.Neurochem. Res.2003283/451552210.1023/A:102286922265212675140
     [Google Scholar]
  45. de los RíosC. Marco-ContellesJ. Tacrines for Alzheimer’s disease therapy. III. The PyridoTacrines.Eur. J. Med. Chem.201916638138910.1016/j.ejmech.2019.02.00530739821
     [Google Scholar]
  46. MufsonE.J. CountsS.E. GinsbergS.D. MahadyL. PerezS.E. MassaS.M. LongoF.M. IkonomovicM.D. Nerve growth factor pathobiology during the progression of Alzheimer’s disease.Front. Neurosci.20191353310.3389/fnins.2019.0053331312116
     [Google Scholar]
  47. RafiiM.S. TuszynskiM.H. ThomasR.G. BarbaD. BrewerJ.B. RissmanR.A. SiffertJ. AisenP.S. Adeno-associated viral vector (serotype 2)–nerve growth factor for patients with alzheimer disease: A randomized clinical trial.JAMA Neurol.201875783484110.1001/jamaneurol.2018.023329582053
     [Google Scholar]
  48. ButterfieldD.A. Boyd-KimballD. Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer’s disease.J. Alzheimers Dis.20186231345136710.3233/JAD‑17054329562527
     [Google Scholar]
  49. CheignonC. TomasM. Bonnefont-RousselotD. FallerP. HureauC. CollinF. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease.Redox Biol.20181445046410.1016/j.redox.2017.10.01429080524
     [Google Scholar]
  50. WangX. WangW. LiL. PerryG. LeeH. ZhuX. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease.Biochim. Biophys. Acta Mol. Basis Dis.2014184281240124710.1016/j.bbadis.2013.10.01524189435
     [Google Scholar]
  51. SultanaR. Boyd-KimballD. PoonH.F. CaiJ. PierceW.M. KleinJ.B. MerchantM. MarkesberyW.R. ButterfieldD.A. Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: An approach to understand pathological and biochemical alterations in AD.Neurobiol. Aging200627111564157610.1016/j.neurobiolaging.2005.09.02116271804
     [Google Scholar]
  52. ButterfieldD.A. StadtmanE.R. Protein oxidation processes in aging brain.Adv. Cell Aging Gerontol.1997216119110.1016/S1566‑3124(08)60057‑7
     [Google Scholar]
  53. PohankaM. Oxidative stress in Alzheimer disease as a target for therapy.Bratisl. Med. J.2018119953554310.4149/BLL_2018_09730226062
     [Google Scholar]
  54. ButterfieldD.A. KanskiJ. Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer’s amyloid β-peptide 1–42.Peptides20022371299130910.1016/S0196‑9781(02)00066‑912128086
     [Google Scholar]
  55. Di MeoS. ReedT.T. VendittiP. VictorV.M. Role of ROS and RNS sources in physiological and pathological conditions.Oxid. Med. Cell. Longev.2016201614410.1155/2016/124504927478531
     [Google Scholar]
  56. AbolhassaniN. LeonJ. ShengZ. OkaS. HamasakiH. IwakiT. NakabeppuY. Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer’s disease brain.Mech. Ageing Dev.2017161Pt A9510410.1016/j.mad.2016.05.00527233446
     [Google Scholar]
  57. BedseG. Di DomenicoF. ServiddioG. CassanoT. Aberrant insulin signaling in Alzheimer’s disease: Current knowledge.Front. Neurosci.2015920410.3389/fnins.2015.0020426136647
     [Google Scholar]
  58. 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]
  59. PrakashA. DhaliwalG.K. KumarP. MajeedA.B.A. Brain biometals and Alzheimer’s disease – boon or bane?Int. J. Neurosci.201712729910810.3109/00207454.2016.117411827044501
     [Google Scholar]
  60. FasaeK.D. AbolajiA.O. FaloyeT.R. OdunsiA.Y. OyetayoB.O. EnyaJ.I. RotimiJ.A. AkinyemiR.O. WhitworthA.J. AschnerM. Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: Limitations, and current and future perspectives.J. Trace Elem. Med. Biol.20216712677910.1016/j.jtemb.2021.12677934034029
     [Google Scholar]
  61. CristóvãoJ.S. SantosR. GomesC.M. Metals and neuronal metal binding proteins implicated in Alzheimer’s disease.Oxid. Med. Cell. Longev.2016201611310.1155/2016/981217826881049
     [Google Scholar]
  62. AytonS. LeiP. BushA.I. Metallostasis in Alzheimer’s disease.Free Radic. Biol. Med.201362768910.1016/j.freeradbiomed.2012.10.55823142767
     [Google Scholar]
  63. HanJ. DuZ. LimM.H. Mechanistic insight into the design of chemical tools to control multiple pathogenic features in AD.Acc. Chem. Res.202154203930394010.1021/acs.accounts.1c0045734606227
     [Google Scholar]
  64. ZhaoZ. Iron and oxidizing species in oxidative stress and Alzheimer’s disease.Aging Med.201922828710.1002/agm2.1207431942516
     [Google Scholar]
  65. JuszczykG. MikulskaJ. KasperekK. PietrzakD. MrozekW. HerbetM. Chronic stress and oxidative stress as common factors of the pathogenesis of depression and AD: The role of antioxidants in prevention and treatment.Antioxidants2021109143910.3390/antiox1009143934573069
     [Google Scholar]
  66. SimunkovaM. AlwaselS.H. AlhazzaI.M. JomovaK. KollarV. RuskoM. ValkoM. Management of oxidative stress and other pathologies in Alzheimer’s disease.Arch. Toxicol.20199392491251310.1007/s00204‑019‑02538‑y31440798
     [Google Scholar]
  67. CastellaniR.J. Plascencia-VillaG. PerryG. The amyloid cascade and Alzheimer’s disease therapeutics: Theory versus observation.Lab. Invest.201999795897010.1038/s41374‑019‑0231‑z30760863
     [Google Scholar]
  68. GravinaS.A. HoL. EckmanC.B. LongK.E. OtvosL.Jr YounkinL.H. SuzukiN. YounkinS.G. Amyloid β protein (A β) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A β 40 or A β 42(43).J. Biol. Chem.1995270137013701610.1074/jbc.270.13.70137706234
     [Google Scholar]
  69. SelkoeD.J. HardyJ. The amyloid hypothesis of Alzheimer’s disease at 25 years.EMBO Mol. Med.20168659560810.15252/emmm.20160621027025652
     [Google Scholar]
  70. MannD.M. EsiriM.M. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome.J Neurol Sci.1989892-316917910.1016/0022‑510X(89)90019‑1
     [Google Scholar]
  71. SunX. ChenW.D. WangY.D. β-Amyloid: The key peptide in the pathogenesis of AD. Frontiers in pharmacology, Sec. Experimental Pharmacology and Drug Discovery2015622110.3389/fphar.2015.0022126483691
     [Google Scholar]
  72. BurdickD. SoreghanB. KwonM. KosmoskiJ. KnauerM. HenschenA. YatesJ. CotmanC. GlabeC. Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs.J. Biol. Chem.1992267154655410.1016/S0021‑9258(18)48529‑81730616
     [Google Scholar]
  73. ScheunerD. EckmanC. JensenM. SongX. CitronM. SuzukiN. BirdT.D. HardyJ. HuttonM. KukullW. LarsonE. Levy-LahadL. ViitanenM. PeskindE. PoorkajP. SchellenbergG. TanziR. WascoW. LannfeltL. SelkoeD. YounkinS. Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease.Nat. Med.19962886487010.1038/nm0896‑8648705854
     [Google Scholar]
  74. HachiyaN. FułekM. ZajączkowskaK. KurpasD. TrypkaE. LeszekJ. Cellular prion protein and amyloid – β oligomers in AD – there are connections?Preprints2021202105003210.20944/preprints202105.0032.v1
     [Google Scholar]
  75. LuoJ. WärmländerS.K.T.S. GräslundA. AbrahamsJ.P. Cross-interactions between the Alzheimer disease amyloid-β peptide and other amyloid proteins: A further aspect of the amyloid cascade hypothesis.J. Biol. Chem.201629132164851649310.1074/jbc.R116.71457627325705
     [Google Scholar]
  76. RushworthJ.V. GriffithsH.H. WattN.T. HooperN.M. Prion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1.J. Biol. Chem.2013288138935895110.1074/jbc.M112.40035823386614
     [Google Scholar]
  77. ZetterbergH. Review: Tau in biofluids - relation to pathology, imaging and clinical features.Neuropathol. Appl. Neurobiol.201743319419910.1111/nan.1237828054371
     [Google Scholar]
  78. ThalD.R. ToméS.O. The central role of tau in Alzheimer’s disease: From neurofibrillary tangle maturation to the induction of cell death.Brain Res. Bull.202219020421710.1016/j.brainresbull.2022.10.00636244581
     [Google Scholar]
  79. GuoT. NobleW. HangerD.P. Roles of tau protein in health and disease.Acta Neuropathol.2017133566570410.1007/s00401‑017‑1707‑928386764
     [Google Scholar]
  80. TacikP. Sanchez-ContrerasM. RademakersR. DicksonD.W. WszolekZ.K. Genetic disorders with tau pathology: A review of the literature and report of two patients with tauopathy and positive family histories.Neurodegener. Dis.2016161-2122110.1159/00044084026550830
     [Google Scholar]
  81. NeveR.L. HarrisP. KosikK.S. KurnitD.M. DonlonT.A. Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2.Brain Res. Mol. Brain Res.19861327128010.1016/0169‑328X(86)90033‑13103857
     [Google Scholar]
  82. MoloneyC.M. LiuC.C. WicklandD.P. LesserE.R. KachergusJ. Van BlitterswijkM.M. Graff-RadfordN.R. DicksonD.W. ThompsonE.A. MurrayM.E. Investigation of differentially expressed proteins through neurofibrillary tangle maturation in Alzheimer’s disease using NanoString’s GeoMx Digital Spatial Profiler.Alzheimers Dement.202218S3e06666810.1002/alz.066668
     [Google Scholar]
  83. MoloneyC.M. LoweV.J. MurrayM.E. Visualization of neurofibrillary tangle maturity in Alzheimer’s disease: A clinicopathologic perspective for biomarker research.Alzheimers Dement.20211791554157410.1002/alz.1232133797838
     [Google Scholar]
  84. MurrayM.E. KouriN. LinW.L. JackC.R.Jr DicksonD.W. VemuriP. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias.Alzheimers Res. Ther.2014611310.1186/alzrt23124382028
     [Google Scholar]
  85. ChienD.T. BahriS. SzardeningsA.K. WalshJ.C. MuF. SuM.Y. ShankleW.R. ElizarovA. KolbH.C. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807.J. Alzheimers Dis.201334245746810.3233/JAD‑12205923234879
     [Google Scholar]
  86. KrothH. OdenF. MoletteJ. SchiefersteinH. CapotostiF. MuellerA. BerndtM. Schmitt-WillichH. DarmencyV. GabellieriE. BoudouC. JuergensT. VariscoY. VokaliE. HickmanD.T. TamagnanG. PfeiferA. DinkelborgL. MuhsA. StephensA. Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer’s disease and other tauopathies.Eur. J. Nucl. Med. Mol. Imaging201946102178218910.1007/s00259‑019‑04397‑231264169
     [Google Scholar]
  87. ReillyP. WinstonC.N. BaronK.R. TrejoM. RockensteinE.M. AkersJ.C. KfouryN. DiamondM. MasliahE. RissmanR.A. YuanS.H. Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation.Neurobiol. Dis.201710622223410.1016/j.nbd.2017.06.00528610892
     [Google Scholar]
  88. FanL. MaoC. HuX. ZhangS. YangZ. HuZ. SunH. FanY. DongY. YangJ. ShiC. XuY. New insights into the pathogenesis of Alzheimer’s disease.Front. Neurol.202010131210.3389/fneur.2019.0131231998208
     [Google Scholar]
  89. Serrano-PozoA. QianJ. MonsellS.E. BetenskyR.A. HymanB.T. APOE ε2 is associated with milder clinical and pathological Alzheimer disease.Ann. Neurol.201577691792910.1002/ana.2436925623662
     [Google Scholar]
  90. HuangS. ZhangZ. CaoJ. YuY. PeiG. Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer’s tau pathology.Signal Transduct. Target. Ther.20227117610.1038/s41392‑022‑01006‑x35691989
     [Google Scholar]
  91. WangC. XiongM. GratuzeM. BaoX. ShiY. AndheyP.S. ManisM. SchroederC. YinZ. MadoreC. ButovskyO. ArtyomovM. UlrichJ.D. HoltzmanD.M. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.Neuron20211091016571674.e710.1016/j.neuron.2021.03.02433831349
     [Google Scholar]
  92. LeeK.S. HuhS. LeeS. WuZ. KimA.K. KangH.Y. LuB. Altered ER–mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.Proc. Natl. Acad. Sci.201811538E8844E885310.1073/pnas.172113611530185553
     [Google Scholar]
  93. PchitskayaE. PopugaevaE. BezprozvannyI. Calcium signaling and molecular mechanisms underlying neurodegenerative diseases.Cell Calcium201870879410.1016/j.ceca.2017.06.00828728834
     [Google Scholar]
  94. Area-GomezE. SchonE.A. On the pathogenesis of AD: the MAM hypothesis.FASEB J.201731386486710.1096/fj.20160130928246299
     [Google Scholar]
  95. LiuY. ZhuX. Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases.Transl. Neurodegener.2017612110.1186/s40035‑017‑0092‑628852477
     [Google Scholar]
  96. Area-GomezE. SchonE.A. Mitochondria-associated ER membranes and Alzheimer disease.Curr. Opin. Genet. Dev.201638909610.1016/j.gde.2016.04.00627235807
     [Google Scholar]
  97. MüllerM. Ahumada-CastroU. SanhuezaM. Gonzalez-BillaultC. CourtF.A. CárdenasC. Mitochondria and calcium regulation as basis of neurodegeneration associated with aging.Front. Neurosci.20181247010.3389/fnins.2018.0047030057523
     [Google Scholar]
  98. PopugaevaE. PchitskayaE. BezprozvannyI. Dysregulation of neuronal calcium homeostasis in Alzheimer’s disease – A therapeutic opportunity?Biochem. Biophys. Res. Commun.20174834998100410.1016/j.bbrc.2016.09.05327641664
     [Google Scholar]
  99. WangY. ShiY. WeiH. Calcium dysregulation in AD: A target for new drug development.J. Alzheimers Dis. Parkinsonism20177537410.4172/2161‑0460.100037429214114
     [Google Scholar]
  100. DemuroA. ParkerI. Cytotoxicity of intracellular Aβ42 amyloid oligomers involves Ca2+ release from the ER by stimulated production of inositol trisphosphate.J. Neurosci.20133393824383310.1523/JNEUROSCI.4367‑12.201323447594
     [Google Scholar]
  101. AfewerkyH.K. LuY. ZhangT. LiH. Roles of sodium-calcium exchanger isoform-3 toward calcium ion regulation in alzheimers disease.J. Alzheimers Dis. Parkinsonism20166729110.4172/2161‑0460.1000291
     [Google Scholar]
  102. LiaoJ. LiH. ZengW. SauerD.B. BelmaresR. JiangY. Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger.Science2012335606968669010.1126/science.121575922323814
     [Google Scholar]
  103. PannaccioneA. PiccialliI. SecondoA. CicconeR. MolinaroP. BosciaF. AnnunziatoL. The Na+/Ca2+exchanger in Alzheimer’s disease.Cell Calcium20208710219010.1016/j.ceca.2020.10219032199208
     [Google Scholar]
  104. Calvo-RodriguezM. KharitonovaE.K. BacskaiB.J. Therapeutic strategies to target calcium dysregulation in Alzheimer’s Disease.Cells2020911251310.3390/cells911251333233678
     [Google Scholar]
  105. TrzepaczP.T. CummingsJ. KonechnikT. ForresterT.D. ChangC. DennehyE.B. WillisB.A. ShulerC. TabasL.B. LyketsosC. Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer’s disease.Int. Psychogeriatr.201325570771910.1017/S104161021200214123257314
     [Google Scholar]
  106. CalsolaroV. EdisonP. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement.201612671973210.1016/j.jalz.2016.02.010
     [Google Scholar]
  107. GuerrieroF. SgarlataC. FrancisM. MauriziN. FaragliA. PernaS. RondanelliM. RolloneM. RicevutiG. Neuroinflammation, immune system and Alzheimer disease: Searching for the missing link.Aging Clin. Exp. Res.201729582183110.1007/s40520‑016‑0637‑z27718173
     [Google Scholar]
  108. RegenF. Hellmann-RegenJ. CostantiniE. RealeM. Neuroinflammation and AD: Implications for microglial activation.Curr. Alzheimer Res.201714111140114810.2174/156720501466617020314171728164764
     [Google Scholar]
  109. LueL. WalkerD.G. RogersJ. Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures.Neurobiol. Aging200122694595610.1016/S0197‑4580(01)00311‑611755003
     [Google Scholar]
  110. FengY.S. TanZ.X. WuL.Y. DongF. ZhangF. The involvement of NLRP3 inflammasome in the treatment of Alzheimer’s disease.Ageing Res. Rev.20206410119210.1016/j.arr.2020.10119233059089
     [Google Scholar]
  111. de Brito ToscanoE.C. RochaN.P. LopesB.N.A. SuemotoC.K. TeixeiraA.L. Neuroinflammation in AD: focus on NLRP1 and NLRP3 inflammasomes.Curr. Protein Pept. Sci.202122858459810.2174/138920372266621091614143634530705
     [Google Scholar]
  112. BaiH. ZhangQ. Activation of NLRP3 inflammasome and onset of AD.Front. Immunol.20211270128210.3389/fimmu.2021.70128234381452
     [Google Scholar]
  113. ChenD. GaoH. PengC. PeiS. DaiA. YuX. ZhouP. WangY. CaiB. Quinones as preventive agents in Alzheimer’s diseases: Focus on NLRP3 inflammasomes.J. Pharm. Pharmacol.202072111481149010.1111/jphp.1333232667050
     [Google Scholar]
  114. HwangJu Dong-YoungC. MiH.P. JinTH. NF-κB as a key mediator of brain inflammation in alzheimer's disease.CNS Neurol Disord Drug Targets.201918131010.2174/1871527316666170807130011
     [Google Scholar]
  115. SunE. MotolaniA. CamposL. LuT. The pivotal role of NF-kB in the pathogenesis and therapeutics of Alzheimer’s Disease.Int. J. Mol. Sci.20222316897210.3390/ijms2316897236012242
     [Google Scholar]
  116. JhaN.K. JhaS.K. KarR. NandP. SwatiK. GoswamiV.K. Nuclear factor-kappa β as a therapeutic target for Alzheimer’s disease.J. Neurochem.2019150211313710.1111/jnc.1468730802950
     [Google Scholar]
  117. YuanJ. AminP. OfengeimD. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases.Nat. Rev. Neurosci.2019201193310.1038/s41583‑018‑0093‑130467385
     [Google Scholar]
  118. JayaramanA. HtikeT.T. JamesR. PiconC. ReynoldsR. TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus.Acta Neuropathol. Commun.20219115910.1186/s40478‑021‑01264‑w34625123
     [Google Scholar]
  119. Stojić-VukanićZ. HadžibegovićS. NicoleO. Nacka-AleksićM. LeštarevićS. LeposavićG. CD8+ T Cell-mediated mechanisms contribute to the progression of neurocognitive impairment in both multiple sclerosis and AD?Front. Immunol.20201156622510.3389/fimmu.2020.56622533329528
     [Google Scholar]
  120. SwerdlowR.H. Mitochondria and mitochondrial cascades in AD.J. Alzheimers Dis.20186231403141610.3233/JAD‑17058529036828
     [Google Scholar]
  121. SwerdlowR.H. The mitochondrial hypothesis: Dysfunction, bioenergetic defects, and the metabolic link to Alzheimer’s disease.Int. Rev. Neurobiol.202015420723310.1016/bs.irn.2020.01.00832739005
     [Google Scholar]
  122. SharmaC. KimS. NamY. JungU.J. KimS.R. Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer’s Disease.Int. J. Mol. Sci.2021229485010.3390/ijms2209485034063708
     [Google Scholar]
  123. IvannikovM.V. SugimoriM. LlinásR.R. Calcium clearance and its energy requirements in cerebellar neurons.Cell Calcium201047650751310.1016/j.ceca.2010.04.00420510449
     [Google Scholar]
  124. SupnetC. BezprozvannyI. The dysregulation of intracellular calcium in Alzheimer disease.Cell Calcium201047218318910.1016/j.ceca.2009.12.01420080301
     [Google Scholar]
  125. JadiyaP. KolmetzkyD.W. TomarD. Di MecoA. LombardiA.A. LambertJ.P. LuongoT.S. LudtmannM.H. PraticòD. ElrodJ.W. Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease.Nat. Commun.2019101388510.1038/s41467‑019‑11813‑631467276
     [Google Scholar]
  126. CalabròM. RinaldiC. SantoroG. CrisafulliC. The biological pathways of Alzheimer disease: a review.AIMS Neurosci.2021818613210.3934/Neuroscience.202100533490374
     [Google Scholar]
  127. SwerdlowR.H. KhanS.M. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease.Med. Hypotheses200463182010.1016/j.mehy.2003.12.04515193340
     [Google Scholar]
  128. SilvaD.F. EstevesA.R. OliveiraC.R. CardosoS.M. Mitochondria: the common upstream driver of amyloid-β and tau pathology in Alzheimer’s disease.Curr. Alzheimer Res.20118556357210.2174/15672051179639187221244356
     [Google Scholar]
  129. WongK.Y. RoyJ. FungM.L. HengB.C. ZhangC. LimL.W. Relationships between mitochondrial dysfunction and neurotransmission failure in alzheimer’s disease.Aging Dis.20201151291131610.14336/AD.2019.112533014538
     [Google Scholar]
  130. Area-GomezE. de GroofA. BonillaE. MontesinosJ. TanjiK. BoldoghI. PonL. SchonE.A. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease.Cell Death Dis.20189333510.1038/s41419‑017‑0215‑029491396
     [Google Scholar]
  131. PeraM. LarreaD. Guardia-LaguartaC. MontesinosJ. VelascoK.R. AgrawalR.R. XuY. ChanR.B. Di PaoloG. MehlerM.F. PerumalG.S. MacalusoF.P. FreybergZ.Z. Acin-PerezR. EnriquezJ.A. SchonE.A. Area-GomezE. Increased localization of APP -C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.EMBO J.201736223356337110.15252/embj.20179679729018038
     [Google Scholar]
  132. van Echten-DeckertG. WalterJ. Sphingolipids: Critical players in Alzheimer’s disease.Prog. Lipid Res.201251437839310.1016/j.plipres.2012.07.00122835784
     [Google Scholar]
  133. GrimmM.O.W. GrösgenS. RothhaarT.L. BurgV.K. HundsdörferB. HaupenthalV.J. FriessP. MüllerU. FassbenderK. RiemenschneiderM. GrimmH.S. HartmannT. Intracellular APP domain regulates serine-palmitoyl-CoA transferase expression and is affected in Alzheimer’s disease.Int. J. Alzheimers Dis.201120111810.4061/2011/69541321660213
     [Google Scholar]
  134. FilippovV. SongM.A. ZhangK. VintersH.V. TungS. KirschW.M. YangJ. Duerksen-HughesP.J. Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases.J. Alzheimers Dis.201229353754710.3233/JAD‑2011‑11120222258513
     [Google Scholar]
  135. KennedyM.A. MoffatT.C. GableK. GanesanS. Niewola-StaszkowskaK. JohnstonA. NislowC. GiaeverG. HarrisL.J. LoewithR. ZarembergV. HarperM.E. DunnT. BennettS.A.L. BaetzK. A signaling lipid associated with Alzheimer’s disease promotes mitochondrial dysfunction.Sci. Rep.2016611933210.1038/srep1933226757638
     [Google Scholar]
  136. AdavS.S. ParkJ.E. SzeS.K. Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer’s disease.Mol. Brain2019121810.1186/s13041‑019‑0430‑y30691479
     [Google Scholar]
  137. Van BulckM. Sierra-MagroA. Alarcon-GilJ. Perez-CastilloA. Morales-GarciaJ. Novel approaches for the treatment of alzheimer’s and parkinson’s disease.Int. J. Mol. Sci.201920371910.3390/ijms2003071930743990
     [Google Scholar]
  138. HungS.Y. FuW.M. Drug candidates in clinical trials for Alzheimer’s disease.J. Biomed. Sci.20172414710.1186/s12929‑017‑0355‑728720101
     [Google Scholar]
  139. GodyńJ. JończykJ. PanekD. MalawskaB. Therapeutic strategies for Alzheimer’s disease in clinical trials.Pharmacol. Rep.201668112713810.1016/j.pharep.2015.07.00626721364
     [Google Scholar]
  140. CummingsJ. LeeG. NahedP. KambarM.E.Z.N. ZhongK. FonsecaJ. TaghvaK. Alzheimer’s disease drug development pipeline: 2022.Alzheimers Dement.202281e1229510.1002/trc2.1229535516416
     [Google Scholar]
  141. CummingsJ. ZhouY. LeeG. ZhongK. FonsecaJ. ChengF. Alzheimer’s disease drug development pipeline: 2023.Alzheimers Dement.202392e1238510.1002/trc2.1238537251912
     [Google Scholar]
  142. AkhtarA. AndleebA. WarisT.S. BazzarM. MoradiA.R. AwanN.R. YarM. Neurodegenerative diseases and effective drug delivery: A review of challenges and novel therapeutics.J Control Release20213301152116710.1016/j.jconrel.2020.11.021
     [Google Scholar]
  143. AtharT. Al BalushiK. KhanS.A. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease.Mol. Biol. Rep.20214875629564510.1007/s11033‑021‑06512‑934181171
     [Google Scholar]
  144. CaoJ. HouJ. PingJ. CaiD. Advances in developing novel therapeutic strategies for Alzheimer’s disease.Mol. Neurodegener.20181316410.1186/s13024‑018‑0299‑830541602
     [Google Scholar]
  145. HuangL.K. ChaoS.P. HuC.J. Clinical trials of new drugs for Alzheimer disease.J. Biomed. Sci.20202711810.1186/s12929‑019‑0609‑731906949
     [Google Scholar]
  146. DrummondE. GoñiF. LiuS. PrelliF. ScholtzovaH. WisniewskiT. Potential novel approaches to understand the pathogenesis and treat AD.J. Alzheimers Dis.201864s1S299S31210.3233/JAD‑17990929562516
     [Google Scholar]
/content/journals/ctmc/10.2174/0115680266274924231002110733
Loading
Targeting Various Pathogenic Pathways for the Development of Anti-alzheimer’s Drugs: An Update
Curr. Top. Med. Chem. 25, 826 (2025); https://doi.org/10.2174/0115680266274924231002110733
/content/journals/ctmc/10.2174/0115680266274924231002110733
/content/journals/ctmc/10.2174/0115680266274924231002110733
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): Alzheimer’s disease; Amyloid beta; Clinical trial; Drug discovery; Neurofibrillary tangles; Tau

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test