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Alzheimer’s disease clinical trial update 2019–2021

  • Neurological Update
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Abstract

The current clinical trial landscape targeting Alzheimer’s disease (AD) is reviewed in the context of studies completed from 2019 to 2021. This review focuses on available data for observational and phase II/III clinical trial results, which will have the most impact on the field. ClinicalTrials.gov, the United States (US) comprehensive federal registry, was queried to identify completed trials. There are currently 226 interventional clinical trials and 51 observational studies completed, suspended, terminated, or withdrawn within our selected time frame. This review reveals that the role of biomarkers is expanding and although many lessons have been learned, many challenges remain when targeting disease modification of AD through amyloid and tau. In addition, to halt or slow clinical progression of AD, new clinical and observational trials are focusing on prevention as well as the role of more diverse biological processes known to influence AD pathology.

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References

  1. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu EC, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Elliott C, Masliah E, Ryan L, Silverberg N (2018) NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14:535–562. https://doi.org/10.1016/j.jalz.2018.02.018

    Article  PubMed  PubMed Central  Google Scholar 

  2. ten Kate M, Ingala S, Schwarz AJ, Fox NC, Chételat G, van Berckel BNM, Ewers M, Foley C, Gispert JD, Hill D, Irizarry MC, Lammertsma AA, Molinuevo JL, Ritchie C, Scheltens P, Schmidt ME, Visser PJ, Waldman A, Wardlaw J, Haller S, Barkhof F (2018) Secondary prevention of Alzheimer’s dementia: neuroimaging contributions. Alzheimer’s Res Ther 10:112. https://doi.org/10.1186/s13195-018-0438-z

    Article  CAS  Google Scholar 

  3. Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert M-O, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH (2021) Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Lancet Neurol 20:484–496. https://doi.org/10.1016/S1474-4422(21)00066-1

    Article  CAS  PubMed  Google Scholar 

  4. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM (2021) Alzheimer’s disease. Lancet 397:1577–1590. https://doi.org/10.1016/s0140-6736(20)32205-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rabinovici GD, Gatsonis C, Apgar C, Chaudhary K, Gareen I, Hanna L, Hendrix J, Hillner BE, Olson C, Lesman-Segev OH (2019) Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA 321:1286–1294

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hanseeuw BJ, Betensky RA, Jacobs HI, Schultz AP, Sepulcre J, Becker JA, Cosio DMO, Farrell M, Quiroz YT, Mormino EC (2019) Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol 76:915–924

    Article  PubMed  PubMed Central  Google Scholar 

  8. Guo T, Korman D, Baker SL, Landau SM, Jagust WJ, AsDN I (2021) Longitudinal cognitive and biomarker measurements support a unidirectional pathway in Alzheimer’s Disease pathophysiology. Biol Psychiat 89:786–794

    Article  CAS  PubMed  Google Scholar 

  9. Spallazzi M, Barocco F, Michelini G, Immovilli P, Taga A, Morelli N, Ruffini L, Caffarra P (2019) CSF biomarkers and amyloid PET: concordance and diagnostic accuracy in a MCI cohort. Acta Neurol Belg 119:445–452. https://doi.org/10.1007/s13760-019-01112-8

    Article  PubMed  Google Scholar 

  10. Levin F, Ferreira D, Lange C, Dyrba M, Westman E, Buchert R, Teipel SJ, Grothe MJ, For the Alzheimer’s Disease Neuroimaging I (2021) Data-driven FDG-PET subtypes of Alzheimer’s disease-related neurodegeneration. Alzheimer Res Ther 13:49. https://doi.org/10.1186/s13195-021-00785-9

    Article  CAS  Google Scholar 

  11. Chételat G, Arbizu J, Barthel H, Garibotto V, Law I, Morbelli S, van de Giessen E, Agosta F, Barkhof F, Brooks DJ, Carrillo MC, Dubois B, Fjell AM, Frisoni GB, Hansson O, Herholz K, Hutton BF, Jack CR, Lammertsma AA, Landau SM, Minoshima S, Nobili F, Nordberg A, Ossenkoppele R, Oyen WJG, Perani D, Rabinovici GD, Scheltens P, Villemagne VL, Zetterberg H, Drzezga A (2020) Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer’s disease and other dementias. Lancet Neurol 19:951–962. https://doi.org/10.1016/S1474-4422(20)30314-8

    Article  PubMed  Google Scholar 

  12. Zetterberg H, Bendlin BB (2021) Biomarkers for Alzheimer’s disease-preparing for a new era of disease-modifying therapies. Mol Psychiatry 26:296–308. https://doi.org/10.1038/s41380-020-0721-9

    Article  PubMed  Google Scholar 

  13. Zetterberg H, Blennow K (2021) Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegener 16:10. https://doi.org/10.1186/s13024-021-00430-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Budelier MM, Bateman RJ (2019) Biomarkers of Alzheimer disease. J Appl Lab Med 5:194–208. https://doi.org/10.1373/jalm.2019.030080

    Article  Google Scholar 

  15. Villemagne VL, Doré V, Bourgeat P, Burnham SC, Laws S, Salvado O, Masters CL, Rowe CC (2017) Aβ-amyloid and Tau Imaging in Dementia. Semin Nucl Med 47:75–88. https://doi.org/10.1053/j.semnuclmed.2016.09.006

    Article  PubMed  Google Scholar 

  16. van Waarde A, Marcolini S, de Deyn PP, Dierckx R (2021) PET agents in dementia: an overview. Semin Nucl Med 51:196–229. https://doi.org/10.1053/j.semnuclmed.2020.12.008

    Article  PubMed  Google Scholar 

  17. Jie CV, Treyer V, Schibli R, Mu L (2021) TauvidTM: the First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer’s disease. Pharmaceuticals 14:110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ingala S, De Boer C, Masselink LA, Vergari I, Lorenzini L, Blennow K, Chételat G, Di Perri C, Ewers M, van der Flier WM, Fox NC, Gispert JD, Haller S, Molinuevo JL, Muniz-Terrera G, Mutsaerts HJ, Ritchie CW, Ritchie K, Schmidt M, Schwarz AJ, Vermunt L, Waldman AD, Wardlaw J, Wink AM, Wolz R, Wottschel V, Scheltens P, Visser PJ, Barkhof F (2021) Application of the ATN classification scheme in a population without dementia: findings from the EPAD cohort. Alzheimers Dement 17:1189–1204. https://doi.org/10.1002/alz.12292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schindler SE, Gray JD, Gordon BA, Xiong C, Batrla-Utermann R, Quan M, Wahl S, Benzinger TLS, Holtzman DM, Morris JC, Fagan AM (2018) Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement 14:1460–1469. https://doi.org/10.1016/j.jalz.2018.01.013

    Article  PubMed  PubMed Central  Google Scholar 

  20. Therriault J, Benedet AL, Pascoal TA, Savard M, Ashton NJ, Chamoun M, Tissot C, Lussier F, Kang MS, Bezgin G (2021) Determining Amyloid-β positivity using 18F-AZD4694 PET imaging. J Nucl Med 62:247–252

    Article  CAS  PubMed  Google Scholar 

  21. Baiardi S, Abu-Rumeileh S, Rossi M, Zenesini C, Bartoletti-Stella A, Polischi B, Capellari S, Parchi P (2019) Antemortem CSF Aβ42/Aβ40 ratio predicts Alzheimer’s disease pathology better than Aβ42 in rapidly progressive dementias. Ann Clin Transl Neurol 6:263–273. https://doi.org/10.1002/acn3.697

    Article  CAS  PubMed  Google Scholar 

  22. Mattke S, Cho SK, Bittner T, Hlávka J, Hanson M (2020) Blood-based biomarkers for Alzheimer’s pathology and the diagnostic process for a disease-modifying treatment: projecting the impact on the cost and wait times. Alzheimers Dement 12:e12081. https://doi.org/10.1002/dad2.12081

    Article  Google Scholar 

  23. West T, Kirmess KM, Meyer MR, Holubasch MS, Knapik SS, Hu Y, Contois JH, Jackson EN, Harpstrite SE, Bateman RJ, Holtzman DM, Verghese PB, Fogelman I, Braunstein JB, Yarasheski KE (2021) 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 16:30. https://doi.org/10.1186/s13024-021-00451-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. West T, Kirmess KM, Meyer MR, Holubasch MS, Knapik SS, Hu Y, Contois JH, Jackson EN, Harpstrite SE, Bateman RJ (2021) 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 16:1–12

    Article  Google Scholar 

  25. Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Li Y, Gordon BA, Holtzman DM, Morris JC, Benzinger TL, Xiong C (2019) High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology 93:e1647–e1659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE, Chai X, Proctor NK, Eichenlaub U, Zetterberg H, Blennow K, Reiman EM, Stomrud E, Dage JL, Hansson O (2020) Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med 26:379–386. https://doi.org/10.1038/s41591-020-0755-1

    Article  CAS  PubMed  Google Scholar 

  27. Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, Chamoun M, Savard M, Kang MS, Therriault J, Schöll M, Massarweh G, Soucy JP, Höglund K, Brinkmalm G, Mattsson N, Palmqvist S, Gauthier S, Stomrud E, Zetterberg H, Hansson O, Rosa-Neto P, Blennow K (2020) Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol 19:422–433. https://doi.org/10.1016/s1474-4422(20)30071-5

    Article  CAS  PubMed  Google Scholar 

  28. Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O (2020) Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324:772–781. https://doi.org/10.1001/jama.2020.12134

    Article  CAS  PubMed  Google Scholar 

  29. Palmqvist S, Tideman P, Cullen N, Zetterberg H, Blennow K, Dage JL, Stomrud E, Janelidze S, Mattsson-Carlgren N, Hansson O (2021) Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 27:1034–1042

    Article  CAS  PubMed  Google Scholar 

  30. Cullen NC, Leuzy A, Janelidze S, Palmqvist S, Svenningsson AL, Stomrud E, Dage JL, Mattsson-Carlgren N, Hansson O (2021) Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations. Nat Commun 12:3555. https://doi.org/10.1038/s41467-021-23746-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ashton NJ, Janelidze S, Al Khleifat A, Leuzy A, van der Ende EL, Karikari TK, Benedet AL, Pascoal TA, Lleó A, Parnetti L, Galimberti D, Bonanni L, Pilotto A, Padovani A, Lycke J, Novakova L, Axelsson M, Velayudhan L, Rabinovici GD, Miller B, Pariante C, Nikkheslat N, Resnick SM, Thambisetty M, Schöll M, Fernández-Eulate G, Gil-Bea FJ, López de Munain A, Al-Chalabi A, Rosa-Neto P, Strydom A, Svenningsson P, Stomrud E, Santillo A, Aarsland D, van Swieten JC, Palmqvist S, Zetterberg H, Blennow K, Hye A, Hansson O (2021) A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun 12:3400. https://doi.org/10.1038/s41467-021-23620-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dinkel F, Trujillo-Rodriguez D, Villegas A, Streffer J, Mercken M, Lopera F, Glatzel M, Sepulveda-Falla D (2020) Decreased deposition of beta-amyloid 1–38 and increased deposition of beta-amyloid 1–42 in brain tissue of presenilin-1 E280A familial Alzheimer’s disease patients. Front Aging Neurosci 12:220. https://doi.org/10.3389/fnagi.2020.00220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. De Strooper B, Annaert W (2010) Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol 26:235–260. https://doi.org/10.1146/annurev-cellbio-100109-104117

    Article  CAS  PubMed  Google Scholar 

  34. Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN (2017) Alzheimer’s-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions. Cell 170:443–456.e414

  35. Yakupova EI, Bobyleva LG, Shumeyko SA, Vikhlyantsev IM, Bobylev AG (2021) Amyloids: the history of toxicity and functionality. Biology. https://doi.org/10.3390/biology10050394

    Article  PubMed  PubMed Central  Google Scholar 

  36. Johannesson M, Sahlin C, Söderberg L, Basun H, Fälting J, Möller C, Zachrisson O, Sunnemark D, Svensson A, Odergren T, Lannfelt L (2021) Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer’s disease. Mol Cell Neurosci 114:103641. https://doi.org/10.1016/j.mcn.2021.103641

    Article  CAS  PubMed  Google Scholar 

  37. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB (1992) Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325

    Article  CAS  PubMed  Google Scholar 

  38. Kent SA, Spires-Jones TL, Durrant CS (2020) The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics. Acta Neuropathol 140:417–447. https://doi.org/10.1007/s00401-020-02196-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Finnie PS, Nader K (2020) Amyloid beta secreted during consolidation prevents memory malleability. Current Biology 30:1934–1940.e1934

  40. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, Visser PJ, Aalten P, Aarsland D, Alcolea D, Alexander M, Almdahl IS, Arnold SE, Baldeiras I, Barthel H, van Berckel BN, Bibeau K, Blennow K, Brooks DJ, van Buchem MA, Camus V, Cavedo E, Chen K, Chetelat G, Cohen AD, Drzezga A, Engelborghs S, Fagan AM, Fladby T, Fleisher AS, van der Flier WM, Ford L, Förster S, Fortea J, Foskett N, Frederiksen KS, Freund-Levi Y, Frisoni GB, Froelich L, Gabryelewicz T, Gill KD, Gkatzima O, Gómez-Tortosa E, Gordon MF, Grimmer T, Hampel H, Hausner L, Hellwig S, Herukka SK, Hildebrandt H, Ishihara L, Ivanoiu A, Jagust WJ, Johannsen P, Kandimalla R, Kapaki E, Klimkowicz-Mrowiec A, Klunk WE, Köhler S, Koglin N, Kornhuber J, Kramberger MG, Van Laere K, Landau SM, Lee DY, de Leon M, Lisetti V, Lleó A, Madsen K, Maier W, Marcusson J, Mattsson N, de Mendonça A, Meulenbroek O, Meyer PT, Mintun MA, Mok V, Molinuevo JL, Møllergård HM, Morris JC, Mroczko B, Van der Mussele S, Na DL, Newberg A, Nordberg A, Nordlund A, Novak GP, Paraskevas GP, Parnetti L, Perera G, Peters O, Popp J, Prabhakar S, Rabinovici GD, Ramakers IH, Rami L, Resende de Oliveira C, Rinne JO, Rodrigue KM, Rodríguez-Rodríguez E, Roe CM, Rot U, Rowe CC, Rüther E, Sabri O, Sanchez-Juan P, Santana I, Sarazin M, Schröder J, Schütte C, Seo SW, Soetewey F, Soininen H, Spiru L, Struyfs H, Teunissen CE, Tsolaki M, Vandenberghe R, Verbeek MM, Villemagne VL, Vos SJ, van Waalwijk van Doorn LJ, Waldemar G, Wallin A, Wallin Å K, Wiltfang J, Wolk DA, Zboch M, Zetterberg H, (2015) Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313:1924–1938. https://doi.org/10.1001/jama.2015.4668

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ossenkoppele R, Jansen WJ, Rabinovici GD, Knol DL, van der Flier WM, van Berckel BN, Scheltens P, Visser PJ, Verfaillie SC, Zwan MD, Adriaanse SM, Lammertsma AA, Barkhof F, Jagust WJ, Miller BL, Rosen HJ, Landau SM, Villemagne VL, Rowe CC, Lee DY, Na DL, Seo SW, Sarazin M, Roe CM, Sabri O, Barthel H, Koglin N, Hodges J, Leyton CE, Vandenberghe R, van Laere K, Drzezga A, Forster S, Grimmer T, Sánchez-Juan P, Carril JM, Mok V, Camus V, Klunk WE, Cohen AD, Meyer PT, Hellwig S, Newberg A, Frederiksen KS, Fleisher AS, Mintun MA, Wolk DA, Nordberg A, Rinne JO, Chételat G, Lleo A, Blesa R, Fortea J, Madsen K, Rodrigue KM, Brooks DJ (2015) Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 313:1939–1949. https://doi.org/10.1001/jama.2015.4669

    Article  PubMed  PubMed Central  Google Scholar 

  42. DeTure MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14:32. https://doi.org/10.1186/s13024-019-0333-5

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, Mayeda ER, Filshtein TJ, Power MC, Elahi FM, Brickman AM, Glymour MM (2021) Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ 372:n156. https://doi.org/10.1136/bmj.n156

    Article  PubMed  PubMed Central  Google Scholar 

  44. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Siemers E, Sethuraman G, Mohs R (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369:341–350. https://doi.org/10.1056/NEJMoa1210951

    Article  CAS  PubMed  Google Scholar 

  45. Miranda A, Montiel E, Ulrich H, Paz C (2021) Selective secretase targeting for Alzheimer’s disease therapy. J Alzheimers Dis 81:1–17. https://doi.org/10.3233/jad-201027

    Article  CAS  PubMed  Google Scholar 

  46. Sperling R, Henley D, Aisen PS, Raman R, Donohue MC, Ernstrom K, Rafii MS, Streffer J, Shi Y, Karcher K, Raghavan N, Tymofyeyev Y, Bogert J, Brashear HR, Novak G, Thipphawong J, Saad ZS, Kolb H, Rofael H, Sanga P, Romano G (2021) Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: a truncated randomized phase 2b/3 clinical trial. JAMA Neurol 78:293–301. https://doi.org/10.1001/jamaneurol.2020.4857

    Article  PubMed  Google Scholar 

  47. Knopman DS, Jones DT, Greicius MD (2021) Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement 17:696–701. https://doi.org/10.1002/alz.12213

    Article  PubMed  Google Scholar 

  48. Dunn B, Stein P, Cavazzoni P (2021) Approval of aducanumab for Alzheimer disease—the FDA’s perspective. JAMA Intern Med. https://doi.org/10.1001/jamainternmed.2021.4607

    Article  PubMed  Google Scholar 

  49. Salloway S, Cummings J (2021) Aducanumab, amyloid lowering, and slowing of Alzheimer disease. Neurology. https://doi.org/10.1212/wnl.0000000000012451

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A (2016) The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537:50–56. https://doi.org/10.1038/nature19323

    Article  CAS  PubMed  Google Scholar 

  51. Tucker S, Möller C, Tegerstedt K, Lord A, Laudon H, Sjödahl J, Söderberg L, Spens E, Sahlin C, Waara ER, Satlin A, Gellerfors P, Osswald G, Lannfelt L (2015) The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 43:575–588. https://doi.org/10.3233/jad-140741

    Article  CAS  PubMed  Google Scholar 

  52. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, Lannfelt L, Bradley H, Rabe M, Koyama A, Reyderman L, Berry DA, Berry S, Gordon R, Kramer LD, Cummings JL (2021) A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther 13:80. https://doi.org/10.1186/s13195-021-00813-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, Shcherbinin S, Sparks J, Sims JR, Brys M (2021) Donanemab in early Alzheimer’s disease. N Engl J Med 384:1691–1704

    Article  CAS  PubMed  Google Scholar 

  54. Cummings JL, Cohen S, van Dyck CH, Brody M, Curtis C, Cho W, Ward M, Friesenhahn M, Rabe C, Brunstein F, Quartino A, Honigberg LA, Fuji RN, Clayton D, Mortensen D, Ho C, Paul R (2018) ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 90:e1889–e1897. https://doi.org/10.1212/wnl.0000000000005550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schwarz AJ, Sundell KL, Charil A, Case MG, Jaeger RK, Scott D, Bracoud L, Oh J, Suhy J, Pontecorvo MJ (2019) Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv 5:328–337

    Article  Google Scholar 

  56. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H (2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378:321–330

    Article  CAS  PubMed  Google Scholar 

  57. Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, Ashford E, Retout S, Hofmann C, Delmar P, Klein G, Andjelkovic M, Dubois B, Boada M, Blennow K, Santarelli L, Fontoura P (2017) A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 9:95. https://doi.org/10.1186/s13195-017-0318-y

    Article  CAS  PubMed  Google Scholar 

  58. Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, Andjelkovic M, Ristic S, Wang G, Bateman R, Kerchner GA, Baudler M, Fontoura P, Doody R (2019) Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther 11:101. https://doi.org/10.1186/s13195-019-0559-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M (2009) Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 6:144–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lacosta AM, Pascual-Lucas M, Pesini P, Casabona D, Pérez-Grijalba V, Marcos-Campos I, Sarasa L, Canudas J, Badi H, Monleón I, San-José I, Munuera J, Rodríguez-Gómez O, Abdelnour C, Lafuente A, Buendía M, Boada M, Tárraga L, Ruiz A, Sarasa M (2018) Safety, tolerability and immunogenicity of an active anti-Aβ(40) vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res Ther 10:12. https://doi.org/10.1186/s13195-018-0340-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang CY, Wang PN, Chiu MJ, Finstad CL, Lin F, Lynn S, Tai YH, De Fang X, Zhao K, Hung CH, Tseng Y, Peng WJ, Wang J, Yu CC, Kuo BS, Frohna PA (2017) UB-311, a novel UBITh(®) amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement 3:262–272. https://doi.org/10.1016/j.trci.2017.03.005

    Article  Google Scholar 

  62. Zampar S, Wirths O (2020) Immunotherapy targeting Amyloid-β peptides in Alzheimer’s disease. In: Huang X (ed) Alzheimer’s disease: drug discovery. Exon Publications Brisbane, Australia, pp 23–42

    Chapter  Google Scholar 

  63. Belichenko PV, Madani R, Rey-Bellet L, Pihlgren M, Becker A, Plassard A, Vuillermot S, Giriens V, Nosheny RL, Kleschevnikov AM (2016) An anti-β-amyloid vaccine for treating cognitive deficits in a mouse model of down syndrome. PLoS ONE 11:e0152471

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wang T, Kuang W, Chen W, Xu W, Zhang L, Li Y, Li H, Peng Y, Chen Y, Wang B, Xiao J, Li H, Yan C, Du Y, Tang M, He Z, Chen H, Li W, Lin H, Shi S, Bi J, Zhou H, Cheng Y, Gao X, Guan Y, Huang Q, Chen K, Xin X, Ding J, Geng M, Xiao S (2020) A phase II randomized trial of sodium oligomannate in Alzheimer’s dementia. Alzheimers Res Ther 12:110. https://doi.org/10.1186/s13195-020-00678-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, Fillit H, Hey JA (2017) Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs 31:495–509. https://doi.org/10.1007/s40263-017-0434-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Abushakra S, Porsteinsson A, Vellas B, Cummings J, Gauthier S, Hey J, Power A, Hendrix S, Wang P, Shen L (2016) Clinical benefits of tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 alleles: the “APOE4 gene-dose effect.” J Prev Alz Dis 3:219–228

    CAS  Google Scholar 

  67. Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, Gauthier S, Hey JA, Power A, Wang P, Shen L, Tolar M (2017) Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer's disease suggest disease modification potential. J Prev Alzheimers Dis 4:149–156. https://doi.org/10.14283/jpad.2017.26

  68. Tolar M, Abushakra S, Sabbagh M (2020) The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement 16:1553–1560. https://doi.org/10.1016/j.jalz.2019.09.075

    Article  PubMed  Google Scholar 

  69. Sabbagh MN (2017) Clinical effects of oral tramiprosate in APOE4/4 homozygous patients with mild Alzheimer's disease suggest disease modification. J Prev Alzheimers Dis 4:136–137. https://doi.org/10.14283/jpad.2017.24

  70. Manzano S, Agüera L, Aguilar M, Olazarán J (2020) A Review on tramiprosate (homotaurine) in Alzheimer’s disease and other neurocognitive disorders. Front Neurol 11:614. https://doi.org/10.3389/fneur.2020.00614

    Article  PubMed  PubMed Central  Google Scholar 

  71. Mather M, Harley CW (2016) The Locus Coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cognit Sci 20:214–226. https://doi.org/10.1016/j.tics.2016.01.001

    Article  Google Scholar 

  72. Van Hoesen GW, Hyman BT, Damasio AR (1991) Entorhinal cortex pathology in Alzheimer’s disease. Hippocampus 1:1–8. https://doi.org/10.1002/hipo.450010102

    Article  PubMed  Google Scholar 

  73. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278. https://doi.org/10.1016/0197-4580(95)00021-6 (Discussion 278–284)

    Article  CAS  PubMed  Google Scholar 

  74. Jones DT, Graff-Radford J, Lowe VJ, Wiste HJ, Gunter JL, Senjem ML, Botha H, Kantarci K, Boeve BF, Knopman DS, Petersen RC, Jack CR Jr (2017) Tau, amyloid, and cascading network failure across the Alzheimer’s disease spectrum. Cortex 97:143–159. https://doi.org/10.1016/j.cortex.2017.09.018

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC, Miller TM, Grinberg LT, Seeley WW, Diamond MI (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–1288. https://doi.org/10.1016/j.neuron.2014.04.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Raj A, LoCastro E, Kuceyeski A, Tosun D, Relkin N, Weiner M (2015) Network diffusion model of progression predicts longitudinal patterns of atrophy and metabolism in Alzheimer’s disease. Cell Rep 10:359–369. https://doi.org/10.1016/j.celrep.2014.12.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA, Rawal B, Parisi JE, Petersen RC, Kantarci K, Ross OA, Duara R, Knopman DS, Jack CR Jr, Dickson DW (2015) Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain 138:1370–1381. https://doi.org/10.1093/brain/awv050

    Article  PubMed  PubMed Central  Google Scholar 

  78. Hoenig MC, Bischof GN, Seemiller J, Hammes J, Kukolja J, Onur ÖA, Jessen F, Fliessbach K, Neumaier B, Fink GR, van Eimeren T, Drzezga A (2018) Networks of tau distribution in Alzheimer’s disease. Brain 141:568–581. https://doi.org/10.1093/brain/awx353

    Article  PubMed  Google Scholar 

  79. Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O (2021) Four distinct trajectories of tau deposition identified in Alzheimer’s disease. Nat Med 27:871–881. https://doi.org/10.1038/s41591-021-01309-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H (2009) Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 70:922–931

    Article  CAS  PubMed  Google Scholar 

  81. Forlenza OV, Radanovic M, Talib LL, Gattaz WF (2019) Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry 215:668–674. https://doi.org/10.1192/bjp.2019.76

    Article  PubMed  Google Scholar 

  82. van Dyck CH, Nygaard HB, Chen K, Donohue MC, Raman R, Rissman RA, Brewer JB, Koeppe RA, Chow TW, Rafii MS, Gessert D, Choi J, Turner RS, Kaye JA, Gale SA, Reiman EM, Aisen PS, Strittmatter SM (2019) Effect of AZD0530 on cerebral metabolic decline in Alzheimer disease: a randomized clinical trial. JAMA Neurol 76:1219–1229. https://doi.org/10.1001/jamaneurol.2019.2050

    Article  PubMed  PubMed Central  Google Scholar 

  83. Turner RS, Hebron ML, Lawler A, Mundel EE, Yusuf N, Starr JN, Anjum M, Pagan F, Torres-Yaghi Y, Shi W, Mulki S, Ferrante D, Matar S, Liu X, Esposito G, Berkowitz F, Jiang X, Ahn J, Moussa C (2020) Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease. Ann Neurol 88:183–194. https://doi.org/10.1002/ana.25775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17:5–21. https://doi.org/10.1038/nrn.2015.1

    Article  CAS  PubMed  Google Scholar 

  85. Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, Sohn PD, Schilling B, Cong X, Ellerby L, Gibson BW, Johnson J, Krogan N, Shamloo M, Gestwicki J, Masliah E, Verdin E, Gan L (2015) Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21:1154–1162. https://doi.org/10.1038/nm.3951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tsai RM, Miller Z, Koestler M, Rojas JC, Ljubenkov PA, Rosen HJ, Rabinovici GD, Fagan AM, Cobigo Y, Brown JA, Jung JI, Hare E, Geldmacher DS, Natelson-Love M, McKinley EC, Luong PN, Chuu EL, Powers R, Mumford P, Wolf A, Wang P, Shamloo M, Miller BL, Roberson ED, Boxer AL (2020) Reactions to multiple ascending doses of the microtubule sabilizer TPI-287 in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome: a randomized clinical trial. JAMA Neurol 77:215–224. https://doi.org/10.1001/jamaneurol.2019.3812

    Article  PubMed  Google Scholar 

  87. Qiang L, Sun X, Austin TO, Muralidharan H, Jean DC, Liu M, Yu W, Baas PW (2018) Tau does not stabilize axonal microtubules but rather enables them to have long labile domains. Curr Biol 28:2181-2189.e2184. https://doi.org/10.1016/j.cub.2018.05.045

    Article  CAS  PubMed  Google Scholar 

  88. Wilcock GK, Gauthier S, Frisoni GB, Jia J, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Schelter BO, Wischik DJ, Davis CS, Staff RT, Vuksanovic V, Ahearn T, Bracoud L, Shamsi K, Marek K, Seibyl J, Riedel G, Storey JMD, Harrington CR, Wischik CM (2018) Potential of low dose leuco-methylthioninium bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary outcome in a phase III clinical trial. J Alzheimers Dis 61:435–457. https://doi.org/10.3233/jad-170560

    Article  CAS  PubMed  Google Scholar 

  89. Gibbons GS, Lee VMY, Trojanowski JQ (2019) Mechanisms of cell-to-cell transmission of pathological tau: a review. JAMA Neurol 76:101–108. https://doi.org/10.1001/jamaneurol.2018.2505

    Article  PubMed  PubMed Central  Google Scholar 

  90. Calsolaro V, Edison P (2016) Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimers Dement 12:719–732. https://doi.org/10.1016/j.jalz.2016.02.010

    Article  PubMed  Google Scholar 

  91. Butterfield DA (2002) Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36:1307–1313. https://doi.org/10.1080/1071576021000049890

    Article  CAS  PubMed  Google Scholar 

  92. Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 57:1041–1048. https://doi.org/10.3233/jad-160763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Edwin TH, Henjum K, Nilsson LNG, Watne LO, Persson K, Eldholm RS, Saltvedt I, Halaas NB, Selbæk G, Engedal K, Strand BH, Knapskog AB (2020) A high cerebrospinal fluid soluble TREM2 level is associated with slow clinical progression of Alzheimer’s disease. Alzheimers Dement 12:e12128. https://doi.org/10.1002/dad2.12128

    Article  Google Scholar 

  94. Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, Colonna M (2020) Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med. https://doi.org/10.1084/jem.20200785

    Article  PubMed  PubMed Central  Google Scholar 

  95. Estus S, Shaw BC, Devanney N, Katsumata Y, Press EE, Fardo DW (2019) Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol 138:187–199. https://doi.org/10.1007/s00401-019-02000-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hori Y, Takeda S, Cho H, Wegmann S, Shoup TM, Takahashi K, Irimia D, Elmaleh DR, Hyman BT, Hudry E (2015) A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer disease. J Biol Chem 290:1966–1978. https://doi.org/10.1074/jbc.M114.586602

    Article  CAS  PubMed  Google Scholar 

  97. Brazier D, Perry R, Keane J, Barrett K, Elmaleh DR (2017) Pharmacokinetics of cromolyn and ibuprofen in healthy elderly volunteers. Clin Drug Investig 37:1025–1034. https://doi.org/10.1007/s40261-017-0549-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Burns L, Wang HY (2017) Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease. NN 4:263

    Article  CAS  PubMed  Google Scholar 

  99. Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 163:55–72. https://doi.org/10.1016/j.neuroscience.2009.05.071

    Article  CAS  PubMed  Google Scholar 

  100. Potter H, Woodcock JH, Boyd TD, Coughlan CM, O’Shaughnessy JR, Borges MT, Thaker AA, Raj BA, Adamszuk K, Scott D, Adame V, Anton P, Chial HJ, Gray H, Daniels J, Stocker ME, Sillau SH (2021) Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer’s disease. Alzheimers Dement 7:e12158. https://doi.org/10.1002/trc2.12158

    Article  Google Scholar 

  101. Howard R, Zubko O, Bradley R, Harper E, Pank L, O’Brien J, Fox C, Tabet N, Livingston G, Bentham P, McShane R, Burns A, Ritchie C, Reeves S, Lovestone S, Ballard C, Noble W, Nilforooshan R, Wilcock G, Gray R (2020) Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA Neurol 77:164–174. https://doi.org/10.1001/jamaneurol.2019.3762

    Article  PubMed  Google Scholar 

  102. Decourt B, Drumm-Gurnee D, Wilson J, Jacobson S, Belden C, Sirrel S, Ahmadi M, Shill H, Powell J, Walker A, Gonzales A, Macias M, Sabbagh MN (2017) Poor safety and tolerability hamper reaching a potentially therapeutic dose in the use of thalidomide for Alzheimer’s disease: results from a double-blind, placebo-controlled trial. Curr Alzheimer Res 14:403–411. https://doi.org/10.2174/1567205014666170117141330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Decourt B, Lahiri DK, Sabbagh MN (2017) Targeting tumor necrosis factor alpha for Alzheimer’s disease. Curr Alzheimer Res 14:412–425. https://doi.org/10.2174/1567205013666160930110551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Decourt B, Wilson J, Ritter A, Dardis C, DiFilippo FP, Zhuang X, Cordes D, Lee G, Fulkerson ND, St Rose T, Hartley K, Sabbagh MN (2020) MCLENA-1: a phase II clinical trial for the assessment of safety, tolerability, and efficacy of lenalidomide in patients with mild cognitive impairment due to Alzheimer’s disease. Open Access J Clin Trials 12:1–13. https://doi.org/10.2147/oajct.s221914

    Article  PubMed  PubMed Central  Google Scholar 

  105. Boada M, López OL, Olazarán J, Núñez L, Pfeffer M, Paricio M, Lorites J, Piñol-Ripoll G, Gámez JE, Anaya F, Kiprov D, Lima J, Grifols C, Torres M, Costa M, Bozzo J, Szczepiorkowski ZM, Hendrix S, Páez A (2020) A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease: primary results of the AMBAR Study. Alzheimers Dement 16:1412–1425. https://doi.org/10.1002/alz.12137

    Article  PubMed  PubMed Central  Google Scholar 

  106. Cerovic M, Forloni G, Balducci C (2019) Neuroinflammation and the gut microbiota: possible alternative therapeutic targets to counteract Alzheimer’s disease? Front Aging Neurosci 11:284. https://doi.org/10.3389/fnagi.2019.00284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RLM, Curtis MA, Dragunow M, Potempa J (2019) Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5:eaau3333. https://doi.org/10.1126/sciadv.aau3333

  108. Costa MJF, de Araújo IDT, da Rocha AL, da Silva RL, Dos Santos CP, Borges BCD, de Aquino Martins ARL, de Vasconcelos Gurgel BC, Lins R (2021) Relationship of porphyromonas gingivalis and Alzheimer’s disease: a systematic review of pre-clinical studies. Clin Oral Investig 25:797–806. https://doi.org/10.1007/s00784-020-03764-w

    Article  PubMed  Google Scholar 

  109. Devanand DP, Andrews H, Kreisl WC, Razlighi Q, Gershon A, Stern Y, Mintz A, Wisniewski T, Acosta E, Pollina J, Katsikoumbas M, Bell KL, Pelton GH, Deliyannides D, Prasad KM, Huey ED (2020) Antiviral therapy: Valacyclovir Treatment of Alzheimer’s Disease (VALAD) Trial: protocol for a randomised, double-blind, placebo-controlled, treatment trial. BMJ Open 10:e032112. https://doi.org/10.1136/bmjopen-2019-032112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Swerdlow RH (2020) The mitochondrial hypothesis: dysfunction, bioenergetic defects, and the metabolic link to Alzheimer’s disease. Int Rev Neurobiol 154:207–233. https://doi.org/10.1016/bs.irn.2020.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Swerdlow RH (2018) Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis 62:1403–1416. https://doi.org/10.3233/jad-170585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Swerdlow RH, Koppel S, Weidling I, Hayley C, Ji Y, Wilkins HM (2017) Mitochondria, cybrids, aging, and Alzheimer’s disease. Prog Mol Biol Transl Sci 146:259–302. https://doi.org/10.1016/bs.pmbts.2016.12.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH (2018) Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement 4:28–36. https://doi.org/10.1016/j.trci.2017.11.002

    Article  Google Scholar 

  114. Koppel SJ, Swerdlow RH (2018) Neuroketotherapeutics: a modern review of a century-old therapy. Neurochem Int 117:114–125. https://doi.org/10.1016/j.neuint.2017.05.019

    Article  CAS  PubMed  Google Scholar 

  115. Ballard C, Nørgaard CH, Friedrich S, Mørch LS, Gerds T, Møller DV, Knudsen LB, Kvist K, Zinman B, Holm E, Torp-Pedersen C, Hansen CT (2020) Liraglutide and semaglutide: Pooled post hoc analysis to evaluate risk of dementia in patients with type 2 diabetes. Alzheimers Dement 16:e042909. https://doi.org/10.1002/alz.042909

    Article  Google Scholar 

  116. Femminella GD, Frangou E, Love SB, Busza G, Holmes C, Ritchie C, Lawrence R, McFarlane B, Tadros G, Ridha BH, Bannister C, Walker Z, Archer H, Coulthard E, Underwood BR, Prasanna A, Koranteng P, Karim S, Junaid K, McGuinness B, Nilforooshan R, Macharouthu A, Donaldson A, Thacker S, Russell G, Malik N, Mate V, Knight L, Kshemendran S, Harrison J, Hölscher C, Brooks DJ, Passmore AP, Ballard C, Edison P (2019) Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study). Trials 20:191. https://doi.org/10.1186/s13063-019-3259-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E (2018) Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis 65:1225–1236. https://doi.org/10.3233/jad-180263

    Article  PubMed  PubMed Central  Google Scholar 

  118. Bar-Am O, Amit T, Weinreb O, Youdim MB, Mandel S (2010) Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation. J Alzheimers Dis 21:361–371. https://doi.org/10.3233/jad-2010-100150

    Article  CAS  PubMed  Google Scholar 

  119. Jenner P, Langston JW (2011) Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline. Mov Disord 26:2316–2323. https://doi.org/10.1002/mds.23926

    Article  PubMed  Google Scholar 

  120. Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K (2020) Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement 6:e12050–e12050. https://doi.org/10.1002/trc2.12050

    Article  Google Scholar 

  121. Matthews DC, Ritter A, Thomas RG, Andrews RD, Lukic AS, Revta C, Kinney JW, Tousi B, Leverenz JB, Fillit H, Zhong K, Feldman HH, Cummings J (2021) Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer’s dementia. Alzheimers Dement 7:e12106. https://doi.org/10.1002/trc2.12106

    Article  Google Scholar 

  122. Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, Andrews RD, Lukic AS, Lee J, Hampilos N, Shafiian N, Sano M, David Mozley P, Fillit H, McEwen BS, Shungu DC, Pereira AC (2021) Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease. Brain. https://doi.org/10.1093/brain/awab222

    Article  PubMed  PubMed Central  Google Scholar 

  123. Mallo SC, Ismail Z, Pereiro AX, Facal D, Lojo-Seoane C, Campos-Magdaleno M, Juncos-Rabadán O (2019) Assessing mild behavioral impairment with the mild behavioral impairment checklist in people with subjective cognitive decline. Int Psychogeriatr 31:231–239. https://doi.org/10.1017/s1041610218000698

    Article  PubMed  Google Scholar 

  124. Johansson M, Stomrud E, Insel PS, Leuzy A, Johansson PM, Smith R, Ismail Z, Janelidze S, Palmqvist S, van Westen D, Mattsson-Carlgren N, Hansson O (2021) Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer’s disease. Transl Psychiatry 11:76. https://doi.org/10.1038/s41398-021-01206-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sheline YI, Snider BJ, Beer JC, Seok D, Fagan AM, Suckow RF, Lee JM, Waligorska T, Korecka M, Aselcioglu I, Morris JC, Shaw LM, Cirrito JR (2020) Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: a controlled clinical trial. Neurology 95:e2658–e2665. https://doi.org/10.1212/wnl.0000000000010725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ballard C, Banister C, Khan Z, Cummings J, Demos G, Coate B, Youakim JM, Owen R, Stankovic S (2018) Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 17:213–222. https://doi.org/10.1016/s1474-4422(18)30039-5

    Article  CAS  PubMed  Google Scholar 

  127. Cummings J (2021) New approaches to symptomatic treatments for Alzheimer’s disease. Mol Neurodegener 16:2. https://doi.org/10.1186/s13024-021-00424-9

    Article  PubMed  PubMed Central  Google Scholar 

  128. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N (2020) Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396:413–446. https://doi.org/10.1016/S0140-6736(20)30367-6

    Article  PubMed  PubMed Central  Google Scholar 

  129. Evans IEM, Martyr A, Collins R, Brayne C, Clare L (2019) Social isolation and cognitive function in later life: a systematic review and meta-analysis. J Alzheimers Dis 70:S119-s144. https://doi.org/10.3233/jad-180501

    Article  PubMed  PubMed Central  Google Scholar 

  130. Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, Cheung AK, Cleveland ML, Coker LH, Crowe MG, Cushman WC, Cutler JA, Davatzikos C, Desiderio L, Erus G, Fine LJ, Gaussoin SA, Harris D, Hsieh MK, Johnson KC, Kimmel PL, Tamura MK, Launer LJ, Lerner AJ, Lewis CE, Martindale-Adams J, Moy CS, Nasrallah IM, Nichols LO, Oparil S, Ogrocki PK, Rahman M, Rapp SR, Reboussin DM, Rocco MV, Sachs BC, Sink KM, Still CH, Supiano MA, Snyder JK, Wadley VG, Walker J, Weiner DE, Whelton PK, Wilson VM, Woolard N, Wright JT Jr, Wright CB (2019) Effect of intensive vs standard blood pressure control on probable Dementia: a randomized clinical trial. JAMA 321:553–561. https://doi.org/10.1001/jama.2018.21442

    Article  PubMed  PubMed Central  Google Scholar 

  131. Vidoni ED, Morris JK, Watts A, Perry M, Clutton J, Van Sciver A, Kamat AS, Mahnken J, Hunt SL, Townley R, Honea R, Shaw AR, Johnson DK, Vacek J, Burns JM (2021) Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer’s: a 1-year randomized controlled trial. PLoS ONE 16:e0244893–e0244893. https://doi.org/10.1371/journal.pone.0244893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kaufman CS, Honea RA, Pleen J, Lepping RJ, Watts A, Morris JK, Billinger SA, Burns JM, Vidoni ED (2021) Aerobic exercise improves hippocampal blood flow for hypertensive Apolipoprotein E4 carriers. J Cereb Blood Flow Metab: 271678x21990342 https://doi.org/10.1177/0271678x21990342

  133. Buchman AS, Yu L, Wilson RS, Lim A, Dawe RJ, Gaiteri C, Leurgans SE, Schneider JA, Bennett DA (2019) Physical activity, common brain pathologies, and cognition in community-dwelling older adults. Neurology 92:e811–e822. https://doi.org/10.1212/wnl.0000000000006954

    Article  PubMed  PubMed Central  Google Scholar 

  134. Dawe RJ, Yu L, Leurgans SE, James BD, Poole VN, Arfanakis K, Schneider JA, Bennett DA, Buchman AS (2021) Physical activity, brain tissue microstructure, and cognition in older adults. PLoS ONE 16:e0253484. https://doi.org/10.1371/journal.pone.0253484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. André C, Rehel S, Kuhn E, Landeau B, Moulinet I, Touron E, Ourry V, Le Du G, Mézenge F, Tomadesso C, de Flores R, Bejanin A, Sherif S, Delcroix N, Manrique A, Abbas A, Marchant NL, Lutz A, Klimecki OM, Collette F, Arenaza-Urquijo EM, Poisnel G, Vivien D, Bertran F, de la Sayette V, Chételat G, Rauchs G (2020) Association of sleep-disordered breathing with Alzheimer disease biomarkers in community-dwelling older adults: a secondary analysis of a randomized clinical trial. JAMA Neurol 77:716–724. https://doi.org/10.1001/jamaneurol.2020.0311

    Article  PubMed  Google Scholar 

  136. Dunietz GL, Chervin RD, Burke JF, Conceicao AS, Braley TJ (2021) Obstructive sleep apnea treatment and dementia risk in older adults. Sleep. https://doi.org/10.1093/sleep/zsab076

    Article  PubMed  PubMed Central  Google Scholar 

  137. Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J, Paul Vonsattel J, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Keene CD, Kamboh MI, Kofler JK, Duque L, Gilbert JR, Gwirtsman HE, Buxbaum JD, Dickson DW, Frosch MP, Ghetti BF, Lunetta KL, Wang LS, Hyman BT, Kukull WA, Foroud T, Haines JL, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Farrer LA, Schellenberg GD, Beecham GW, Montine TJ, Jun GR (2020) Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun 11:667. https://doi.org/10.1038/s41467-019-14279-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, University of Kansas Alzheimer’s Disease Center, University of Kansas Medical Center, Kansas City, KS, USA

    Joseph Pleen & Ryan Townley

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  1. Joseph Pleen
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This was an invited review. Dr. JP performed the literature search and data analysis. Dr. JP and Dr. RT, drafted and critically revised the work.

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Correspondence to Ryan Townley.

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Conflicts of interest

Dr. Townley is a site principal investigator for the following related studies: AHEAD 3-45, TRC-PAD, and Vaccinex SIGNAL-AD. Dr. Pleen has nothing to disclose and no conflict of interest.

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Pleen, J., Townley, R. Alzheimer’s disease clinical trial update 2019–2021. J Neurol 269, 1038–1051 (2022). https://doi.org/10.1007/s00415-021-10790-5

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