Table Info

Table 5.

Drugs targeting non-cognitive symptoms of Alzheimer’s disease

Drug name	Target and rationale	Status on clinical trial (start date–end date)	AD stage	Results	Clinical trial identifier (NCT number)
Methylphenidate	Block DAT. And increase the dopamine level	Completed phase 3, (2016–2020)	Apathy in AD	Mild improvement of apathy, measured at 6 months compared to placebo	02346201
Prazosin	Antagonist of alpha1-adrenergic receptor	Completed (2018–2022)	Moderate to severe disruptive behavior	Non-significant improvement of agitation	03710642
Pimavanserin (Nuplazid)	Inverse agonist and antagonist of 5-HT2A in neurotransmission	Completed phase 2 (2017–2019)	Probable AD who has symptoms of agitation and aggression	(1) Promising reduction of psychosis score in AD, also see [74] and (2) delay in psychosis relapse (p < 0.05) and a lower risk of relapse with the continuation of the drug [75]	03118947 03325556
ITI-007 (Lumateperone)	5-HT2A serotonin receptor antagonist	Terminated phase 3 (2019) due to pre-specified interim analysis indicating futility	Probably AD	Terminated	02817906
Lemborexant (Dayvigo)	Orexin receptor antagonist	Completed (2016–2020)	Mild-moderate	Approved for insomnia, lower nighttime activity, and improved circadian rhythmicity	03001557
Suvorexant (Belsomra, MK-4305)	Orexin receptor antagonist	Completed (2016–2018)	Mild-moderate	Approved for insomnia in AD, lengthened total night sleep time	02750306

AD: Alzheimer’s disease; DAT: dopamine transporter; 5-HT2A: 5-hydroxytryptamine 2A

Declarations

Acknowledgments

The authors would like to thank Dr. Lisa Glickstein (Regis College, Weston, MA) for editing the manuscript.

Author contributions

DX: Conceptualization, Funding acquisition, Investigation, Writing—original draft, Writing—review & editing. CZ: Conceptualization, Funding acquisition, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work is supported by a Sabbatical Grant (2023) from Regis College, Weston, USA 02493, and a grant from the Chinese Institutes for Medical Research, Beijing [CX23YZ03]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky ST, et al.; Synaptic Health Endpoints Working Group. The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease. Alzheimers Res Ther. 2020;12:21. [DOI] [PubMed] [PMC]

Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules. 2020;25:5789. [DOI] [PubMed] [PMC]

Collaborators G2CoD. Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403:2100–32. [DOI] [PubMed] [PMC]

Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol. 2018;25:59–70. [DOI] [PubMed]

Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet. 2011;377:1019–31. [DOI] [PubMed]

Giri M, Zhang M, Lü Y. Genes associated with Alzheimer's disease: an overview and current status. Clin Interv Aging. 2016;11:665–81. [DOI] [PubMed] [PMC]

Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43–51. [DOI] [PubMed] [PMC]

Lanfranco MF, Ng CA, Rebeck GW. ApoE Lipidation as a Therapeutic Target in Alzheimer’s Disease. Int J Mol Sci. 2020;21:6336. [DOI] [PubMed] [PMC]

Athar T, Balushi KA, Khan SA. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Mol Biol Rep. 2021;48:5629–5645. [DOI] [PubMed] [PMC]

10.

Passeri E, Elkhoury K, Morsink M, Broersen K, Linder M, Tamayol A, et al. Alzheimer's Disease: Treatment Strategies and Their Limitations. Int J Mol Sci. 2022;23:13954. [DOI] [PubMed] [PMC]

11.

Weller J, Budson A. Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Res. 2018;7:F1000 Faculty Rev–1161. [DOI] [PubMed] [PMC]

12.

Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and Management of Dementia: Review. JAMA. 2019;322:1589–99. [DOI] [PubMed] [PMC]

13.

Nguyen K, Hoffman H, Chakkamparambil B, Grossberg GT. Evaluation of rivastigmine in Alzheimer’s disease. Neurodegener Dis Manag. 2021;11:35–48. [DOI] [PubMed]

14.

Cummings J, Osse AML, Cammann D, Powell J, Chen J. Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease. BioDrugs. 2024;38:5–22. [DOI] [PubMed] [PMC]

15.

Perneczky R, Dom G, Chan A, Falkai P, Bassetti C. Anti-amyloid antibody treatments for Alzheimer’s disease. Eur J Neurol. 2024;31:e16049. [DOI]

16.

Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. [DOI] [PubMed] [PMC]

17.

Sun X, Li L, Dong Q, Zhu J, Huang Y, Hou S, et al. Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J Neuroinflammation. 2021;18:131. [DOI] [PubMed] [PMC]

18.

Heneka MT. ApoE4 makes microglia trem²bling. Neuron. 2023;111:142–4. [DOI] [PubMed]

19.

Macdonald R, Barnes K, Hastings C, Mortiboys H. Mitochondrial abnormalities in Parkinson’s disease and Alzheimer’s disease: can mitochondria be targeted therapeutically? Biochem Soc Trans. 2018;46:891–909. [DOI] [PubMed]

20.

Wunderlich G, Blahova Z, Garcia M, Jessen F. Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimer’s dementia: a randomized controlled trial. Alzheimers Res Ther. 2023;15:24. [DOI] [PubMed] [PMC]

21.

Hajjar I, Okafor M, McDaniel D, Obideen M, Dee E, Shokouhi M, et al. Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment: A Randomized Clinical Trial. JAMA Netw Open. 2020;3:e2012252. [DOI] [PubMed] [PMC]

22.

Chase TN, Farlow MR, Clarence-Smith K. Donepezil Plus Solifenacin (CPC-201) Treatment for Alzheimer's Disease. Neurotherapeutics. 2017;14:405–16. [DOI] [PubMed] [PMC]

23.

Ostrowitzki S, Bittner T, Sink KM, Mackey H, Rabe C, Honig LS, et al. Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials. JAMA Neurol. 2022;79:1113–1121. [DOI] [PubMed] [PMC]

24.

Yu HJ, Dickson SP, Wang P, Chiu M, Huang C, Chang C, et al. Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 2a study. EBioMedicine. 2023;94:104665. [DOI] [PubMed] [PMC]

25.

Lon HK, Mendonca N, Goss S, Othman AA, Locke C, Jin Z, et al. Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies. Clin Pharmacol Drug Dev. 2019;8:290–303. [DOI] [PubMed]

26.

Novak P, Schmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16:123–34. [DOI]

27.

Novak P, Kovacech B, Katina S, Schmidt R, Scheltens P, Kontsekova E, et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat Aging. 2021;1:521–34. [DOI] [PubMed]

28.

Cummings JL, Tong G, Ballard C. Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options. J Alzheimers Dis. 2019;67:779–94. [DOI] [PubMed] [PMC]

29.

Malar DS, Thitilertdecha P, Ruckvongacheep KS, Brimson S, Tencomnao T, Brimson JM. Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders. CNS Drugs. 2023;37:399–440. [DOI] [PubMed] [PMC]

30.

Hampel H, Williams C, Etcheto A, Goodsaid F, Parmentier F, Sallantin J, et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study. Alzheimers Dement (N Y). 2020;6:e12013. [DOI] [PubMed] [PMC]

31.

Wessels AM, Lines C, Stern RA, Kost J, Voss T, Mozley LH, et al. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer’s disease. Alzheimers Dement. 2020;16:1483–92. [DOI] [PubMed]

32.

Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8:101–12. [DOI] [PubMed]

33.

Pluta R, Barcikowska M, Misicka A, Lipkowski AW, Spisacka S, Januszewski S. Ischemic rats as a model in the study of the neurobiological role of human beta-amyloid peptide. Neuroreport. 1999;10:3615–9. [DOI] [PubMed]

34.

Yadollahikhales G, Rojas JC. Anti-Amyloid Immunotherapies for Alzheimer’s Disease: A 2023 Clinical Update. Neurotherapeutics. 2023;20:914–931. [DOI] [PubMed] [PMC]

35.

Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al.; Bapineuzumab 3000 and 3001 Clinical Study Investigators. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8:18. [DOI] [PubMed] [PMC]

36.

Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med. 2018;378:321–30. [DOI]

37.

Asher S, Priefer R. Alzheimer’s disease failed clinical trials. Life Sci. 2022;306:120861. [DOI] [PubMed]

38.

Tagliapietra, M. Aducanumab for the treatment of Alzheimer’s disease. Drugs Today (Barc). 2022;58:465–77. [DOI] [PubMed]

39.

Jorfi M, Maaser-Hecker A, Tanzi RE. The neuroimmune axis of Alzheimer’s disease. Genome Med. 2023;15:6. [DOI] [PubMed] [PMC]

40.

Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al.; TRAILBLAZER-ALZ 2 Investigators. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330:512–27. [DOI] [PubMed] [PMC]

41.

Pontecorvo MJ, Lu M, Burnham SC, Schade AE, Dage JL, Shcherbinin S, et al. Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurol. 2022;79:1250–9. [DOI] [PubMed] [PMC]

42.

Reardon, S. Alzheimer’s drug donanemab helps most when taken at earliest disease stage, study finds. Nature. 2023;619:682–3. [DOI]

43.

van Dyck CH, Sabbagh M, Cohen S. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388:9–21. [DOI] [PubMed]

44.

Reiman EM, Pruzin JJ, Rios-Romenets S, Brown C, Giraldo M, Acosta-Baena N, et al.; API ADAD Colombia Trial Group. A public resource of baseline data from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial. Alzheimers Dement. 2023;19:1938–46. [DOI] [PubMed] [PMC]

45.

Tariot PN, Lopera F, Langbaum JB, Thomas RG, Hendrix S, Schneider LS, et al. The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimers Dement (N Y). 2018;4:150–60. [DOI] [PubMed] [PMC]

46.

Robinson SR, Bishop GM, Lee HG, Münch G. Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging. 2004;25:609–15. [DOI] [PubMed]

47.

Wang CY, Wang P, Chiu M, Finstad CL, Lin F, Lynn S, et al. UB-311, a novel UBITh^® amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement (N Y). 2017;3:262–72. [DOI] [PubMed] [PMC]

48.

Cullen NC, Novak P, Tosun D, Kovacech B, Hanes J, Kontsekova E, et al. Efficacy assessment of an active tau immunotherapy in Alzheimer’s disease patients with amyloid and tau pathology: a post hoc analysis of the “ADAMANT” randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial. EBioMedicine. 2024;99:104923. [DOI] [PubMed] [PMC]

49.

Krishnadas N, Doré V, Robertson JS, Ward L, Fowler C, Masters CL, et al. Rates of regional tau accumulation in ageing and across the Alzheimer’s disease continuum: an AIBL ¹⁸F-MK6240 PET study. EBioMedicine. 2023;88:104450. [DOI] [PubMed] [PMC]

50.

Ossenkoppele R, van der Kant R, Hansson O. Tau biomarkers in Alzheimer’s disease: towards implementation in clinical practice and trials. Lancet Neurol. 2022;21:726–34. [DOI] [PubMed]

51.

Sandusky-Beltran LA, Sigurdsson EM. Tau immunotherapies: Lessons learned, current status and future considerations. Neuropharmacology. 2020;175:108104. [DOI] [PubMed] [PMC]

52.

Teng E, Manser PT, Pickthorn K, Brunstein F, Blendstrup M, Bohorquez SS, et al.; Tauriel Investigators. Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2022;79:758–67. [DOI] [PubMed] [PMC]

53.

Colom-Cadena M, Davies C, Sirisi S, Lee J-E, Simzer EM, Tzioras M, et al. Synaptic oligomeric tau in Alzheimer’s disease - A potential culprit in the spread of tau pathology through the brain. Neuron. 2023;11:2170–83.e6. [DOI]

54.

Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, et al. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease. Brain. 2021;144:3742–55. [DOI] [PubMed] [PMC]

55.

Matthews DC, Ritter A, Thomas RG, Andrews RD, Lukic AS, Revta C, et al. Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer’s dementia. Alzheimers Dement (N Y). 2021;7:e12106. [DOI] [PubMed] [PMC]

56.

Ruthirakuhan MT, Herrmann N, Gallagher D, Andreazza AC, Kiss A, Verhoeff NPLG, et al. Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer’s disease: Study protocol for a cross-over randomized controlled trial. Contemp Clin Trials Commun. 2019;15:100385. [DOI] [PubMed] [PMC]

57.

Ruthirakuhan M, Herrmann N, Andreazza AC, Verhoeff NPLG, Gallagher D, Black SE, et al. Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation. J Geriatr Psychiatry Neurol. 2020;33:175–84. [DOI] [PubMed]

58.

Nirogi R, Goyal VK, Benade V, Subramanian R, Ravula J, Jetta S, et al. Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase 2 Randomized Placebo-Controlled Study. Neurol Ther. 2022;11:1583–94. [DOI] [PubMed] [PMC]

59.

Nirogi R, Ieni J, Goyal VK, Ravula J, Jetta S, Shinde A, et al. Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer’s disease: A randomized, double-blind, phase 2, proof-of-concept study. Alzheimers Dement (N Y). 2022;8:e12307. [DOI] [PubMed] [PMC]

60.

Hori Y, Takeda S, Cho H, Wegmann S, Shoup TM, Takahashi K, et al. 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. 2015;290:1966–78. [DOI] [PubMed] [PMC]

61.

Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci. 2020:23:1183–1193. [DOI]

62.

Gaitán JM, Boots EA, Dougherty RJ, Oh JM, Ma Y, Edwards DF, et al. Brain Glucose Metabolism, Cognition, and Cardiorespiratory Fitness Following Exercise Training in Adults at Risk for Alzheimer’s Disease. Brain Plast. 2019;5:83–95. [DOI] [PubMed] [PMC]

63.

Thumuluri D, Lyday R, Babcock P, Ip EH, Kraft RA, Laurienti PJ, et al. Improvisational Movement to Improve Quality of Life in Older Adults With Early-Stage Dementia: A Pilot Study. Front Sports Act Living. 2022;3:796101. [DOI] [PubMed] [PMC]

64.

Thakkar A, Vora A, Kaur G, Akhtar J. Dysbiosis and Alzheimer’s disease: role of probiotics, prebiotics and synbiotics. Naunyn Schmiedebergs Arch Pharmacol. 2023;396:2911–23. [DOI] [PubMed]

65.

Sen D, Rathee S, Pandey V, Jain SK, Patil UK. Comprehensive Insights into Pathophysiology of Alzheimer’s Disease: Herbal Approaches for Mitigating Neurodegeneration. Curr Alzheimer Res. Forthcoming 2024. [DOI] [PubMed]

66.

Jia X, Kohli P, Virani SS. Omega-3 Fatty Acid and Cardiovascular Outcomes: Insights From Recent Clinical Trials. Curr Atheroscler Rep. 2019;10;21:1. [DOI] [PubMed]

67.

Den H, Dong X, Chen M, Zou Z. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer’s disease or mild cognitive impairment — a meta-analysis of randomized controlled trials. Aging (Albany NY). 2020;12:4010–39. [DOI] [PubMed] [PMC]

68.

Beishon L, Evley R, Panerai RB, Subramaniam H, Mukaetova-Ladinska E, Robinson T, et al. Effects of brain training on brain blood flow (The Cognition and Flow Study-CogFlowS): protocol for a feasibility randomised controlled trial of cognitive training in dementia. BMJ Open. 2019;9:e027817. [DOI] [PubMed] [PMC]

69.

Xiao D, Wang K, Theriault L, Charbel E; Alzheimer’s Disease Neuroimaging Initiative. White matter integrity and key structures affected in Alzheimer’s disease characterized by diffusion tensor imaging. Eur J Neurosci. 2022;56:5319–31. [DOI]

70.

Sprugnoli G, Munsch F, Cappon D, Paciorek R, Macone J, Connor A, et al. Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease. Alzheimers Res Ther. 2021;13:203. [DOI] [PubMed] [PMC]

71.

Martorell AJ, Paulson AL, Suk H, Abdurrob F, Drummond GT, Guan W, et al. Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition. Cell. 2019;177:256–271.e22. [DOI] [PubMed] [PMC]

72.

Pini L, Pizzini FB, Boscolo-Galazzo I, Ferrari C, Galluzzi S, Cotelli M, et al. Brain network modulation in Alzheimer’s and frontotemporal dementia with transcranial electrical stimulation. Neurobiol Aging. 2022;111:24–34. [DOI]

73.

Zhao Q, Tan L, Wang H, Jiang T, Tan M, Tan L, et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord. 2016;190:264–71. [DOI] [PubMed]

74.

Ismail Z, Creese B, Aarsland D, Kales HC, Lyketsos CG, Sweet RA, et al. Psychosis in Alzheimer disease - mechanisms, genetics and therapeutic opportunities. Nat Rev Neurol. 2022;18:131–44. [DOI] [PubMed] [PMC]

75.

Tariot PN, Cummings JL, Soto-Martin ME, Ballard C, Erten-Lyons D, Sultzer DL, et al. Trial of Pimavanserin in Dementia-Related Psychosis. N Engl J Med. 2021;385:309–19. [DOI] [PubMed]

76.

Bondi MW, Edmonds EC, Salmon DP. Alzheimer’s Disease: Past, Present, and Future. J Int Neuropsychol Soc. 2017;23:818–31. [DOI] [PubMed] [PMC]