THERAPY FOR ALZHEIMER’S DISEASE - FOCUS ON LECANEMAB
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.5795Keywords:
Alzheimer’s Disease; Lecanemab; Amyloid-Beta; Disease-Modifying TherapyAbstract
Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder and the leading cause of dementia worldwide, with prevalence increasing due to population aging. It is characterized by cognitive decline, functional impairment, and significant public health burden. Pathophysiology involves a complex interplay of amyloid-β (Aβ) accumulation, tau pathology and neuroinflammation. Despite extensive research, current pharmacological management of Alzheimer’s disease relies primarily on symptomatic therapies and does not alter the underlying neurodegenerative process. The aim of this review is to summarize the current state of knowledge on therapeutic strategies for AD, with particular emphasis on lecanemab, a recombinant humanized antibody characterized by their selectivity for soluble Aβ oligomers. We discuss its mechanism of action, clinical evidence from recent randomized controlled trials assessing its efficacy and safety. In this review, lecanemab is not only addressed in the context of established and widely used therapies but also alongside novel treatments currently being tested. Lecanemab represents a significant step towards disease-modifying therapy for AD as it reduces brain amyloid. Although the available results are promising, current evidence suggests that monotherapeutic interventions targeting a single pathological mechanism may be insufficient to completely stop or reverse disease progression underscoring the need for further research to optimize therapeutic outcomes.
References
Rowland, L. P. (Ed.). (2008). Merritt’s neurology (11th ed.; K. Kwieciński & A. Kamińska, Eds., 2nd Polish ed., pp. 789–794). Elsevier Urban & Partner.
Safiri, S., Ghaffari Jolfayi, A., Fazlollahi, A., Morsali, S., Sarkesh, A., Daei Sorkhabi, A., Golabi, B., Aletaha, R., Motlagh Asghari, K., Hamidi, S., Mousavi, S. E., Jamalkhani, S., Karamzad, N., Shamekh, A., Mohammadinasab, R., Sullman, M. J. M., Şahin, F., & Kolahi, A. A. (2024). Alzheimer’s disease: A comprehensive review of epidemiology, risk factors, symptoms diagnosis, management, caregiving, advanced treatments and associated challenges. Frontiers in Medicine, 11, 1474043. https://doi.org/10.3389/fmed.2024.1474043
World Health Organization. (n.d.). Dementia. Retrieved February 14, 2026, from https://www.who.int/news-room/fact-sheets/detail/dementia
Atri, A. (2019). The Alzheimer’s disease clinical spectrum: Diagnosis and management. Medical Clinics of North America, 103(2), 263–293. https://doi.org/10.1016/j.mcna.2018.10.009
Zhang, X. X., Tian, Y., Wang, Z. T., Ma, Y. H., Tan, L., & Yu, J. T. (2021). The epidemiology of Alzheimer’s disease modifiable risk factors and prevention. Journal of Prevention of Alzheimer’s Disease, 8(3), 313–321. https://doi.org/10.14283/jpad.2021.15
Alzheimer Europe. (2020). Dementia in Europe yearbook 2019: Estimating the prevalence of dementia in Europe (pp. 9–16). Alzheimer Europe.
Alzheimer’s Association. (2021). 2021 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 17(3), 327–406.
Jack, C. R., Jr., Knopman, D. S., Jagust, W. J., Petersen, R. C., Weiner, M. W., Aisen, P. S., Shaw, L. M., Vemuri, P., Wiste, H. J., Weigand, S. D., Lesnick, T. G., Pankratz, V. S., Donohue, M. C., & Trojanowski, J. Q. (2013). Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. The Lancet Neurology, 12(2), 207–216. https://doi.org/10.1016/S1474-4422(12)70291-0
Tahami Monfared, A. A., Byrnes, M. J., White, L. A., & Zhang, Q. (2022). Alzheimer’s disease: Epidemiology and clinical progression. Neurology and Therapy, 11, 553–569. https://doi.org/10.1007/s40120-022-00338-8
Li, Q., Wu, Y., Chen, J., Xuan, A., & Wang, X. (2022). Microglia and immunotherapy in Alzheimer’s disease. Acta Neurologica Scandinavica, 145(3), 273–278. https://doi.org/10.1111/ane.13551
Hampel, H., Mesulam, M. M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, G. T., Khachaturian, A. S., Vergallo, A., Cavedo, E., Snyder, P. J., & Khachaturian, Z. S. (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 141(7), 1917–1933. https://doi.org/10.1093/brain/awy132
Paroni, G., Bisceglia, P., & Seripa, D. (2019). Understanding the amyloid hypothesis in Alzheimer’s disease. Journal of Alzheimer’s Disease, 68(2), 493–510. https://doi.org/10.3233/JAD-180802
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Jr., Kaye, J., Montine, T. J., Park, D. C., Reiman, E. M., Rowe, C. C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M. C., Thies, B., Morrison-Bogorad, M., ... Phelps, C. H. (2011). Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia, 7(3), 280–292. https://doi.org/10.1016/j.jalz.2011.03.003
Mendez, M. F. (2017). Early-onset Alzheimer disease. Neurologic Clinics, 35(2), 263–281. https://doi.org/10.1016/j.ncl.2017.01.005
Jia, X., Wang, Z., Huang, F., Su, C., Du, W., Jiang, H., Wang, H., Wang, J., Wang, F., Su, W., Xiao, H., Wang, Y., & Zhang, B. (2021). A comparison of the Mini-Mental State Examination (MMSE) with the Montreal Cognitive Assessment (MoCA) for mild cognitive impairment screening in Chinese middle-aged and older population: A cross-sectional study. BMC Psychiatry, 21(1), 485. https://doi.org/10.1186/s12888-021-03495-6
Ciesielska, N., Sokołowski, R., Mazur, E., Podhorecka, M., Polak-Szabela, A., & Kędziora-Kornatowska, K. (2016). Is the Montreal Cognitive Assessment (MoCA) test better suited than the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) detection among people aged over 60? Meta-analysis. Psychiatria Polska, 50(5), 1039–1052. https://doi.org/10.12740/PP/45368
Jack, C. R., Andrews, J. S., Beach, T. G., et al. (2024). Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimer’s & Dementia, 20, 5143–5169. https://doi.org/10.1002/alz.13859
Santacruz, K. S., & Swagerty, D. (2001). Early diagnosis of dementia. American Family Physician, 63(4), 703–713, 717–718.
Haapasalo, A., & Hiltunen, M. (2018). A report from the 8th Kuopio Alzheimer Symposium. Neurodegenerative Disease Management, 8(5), 289–299. https://doi.org/10.2217/nmt-2018-0029
Bottino, C. M., Castro, C. C., Gomes, R. L., Buchpiguel, C. A., Marchetti, R. L., & Neto, M. R. (2002). Volumetric MRI measurements can differentiate Alzheimer’s disease, mild cognitive impairment, and normal aging. International Psychogeriatrics, 14(1), 59–72. https://doi.org/10.1017/S1041610202008281
Harada, C. N., Natelson Love, M. C., & Triebel, K. L. (2013). Normal cognitive aging. Clinics in Geriatric Medicine, 29(4), 737–752. https://doi.org/10.1016/j.cger.2013.07.002
Tahami Monfared, A. A., Byrnes, M. J., White, L. A., & Zhang, Q. (2022). Alzheimer’s disease: Epidemiology and clinical progression. Neurology and Therapy, 11(2), 553–569. https://doi.org/10.1007/s40120-022-00338-8
Frisoni, G. B., Boccardi, M., Barkhof, F., Blennow, K., Cappa, S., Chiotis, K., Démonet, J. F., Garibotto, V., Giannakopoulos, P., Gietl, A., Hansson, O., Herholz, K., Jack, C. R., Jr., Nobili, F., Nordberg, A., Snyder, H. M., Ten Kate, M., Varrone, A., Albanese, E., ... Winblad, B. (2017). Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. The Lancet Neurology, 16(8), 661–676. https://doi.org/10.1016/S1474-4422(17)30159-X
Johnson, K. A., Fox, N. C., Sperling, R. A., & Klunk, W. E. (2012). Brain imaging in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine, 2(4), a006213. https://doi.org/10.1101/cshperspect.a006213
Blennow, K., & Zetterberg, H. (2018). Biomarkers for Alzheimer’s disease: Current status and prospects for the future. Journal of Internal Medicine, 284(6), 643–663. https://doi.org/10.1111/joim.12816
Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate, C., Yen, F. T., & Arab-Tehrany, E. (2022). Alzheimer’s disease: Treatment strategies and their limitations. International Journal of Molecular Sciences, 23(22), 13954. https://doi.org/10.3390/ijms232213954
Zhang, J., Kong, G., Yang, J., Pang, L., & Li, X. (2025). Pathological mechanisms and treatment progression of Alzheimer’s disease. European Journal of Medical Research, 30(1), 625. https://doi.org/10.1186/s40001-025-02886-9
Hansen, R. A., Gartlehner, G., Webb, A. P., Morgan, L. C., Moore, C. G., & Jonas, D. E. (2008). Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: A systematic review and meta-analysis. Clinical Interventions in Aging, 3(2), 211–225.
Zou, D., Liu, R., Lv, Y., Guo, J., Zhang, C., & Xie, Y. (2023). Latest advances in dual inhibitors of acetylcholinesterase and monoamine oxidase B against Alzheimer’s disease. Journal of Enzyme Inhibition and Medicinal Chemistry, 38(1), 2270781. https://doi.org/10.1080/14756366.2023.2270781
Zuin, M., Cherubini, A., Volpato, S., Ferrucci, L., & Zuliani, G. (2022). Acetylcholinesterase inhibitors slow cognitive decline and decrease overall mortality in older patients with dementia. Scientific Reports, 12(1), 12214. https://doi.org/10.1038/s41598-022-16476-w
Scheltens, P., Blennow, K., Breteler, M. M., De Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016). Alzheimer’s disease. The Lancet, 388(10043), 505–517. https://doi.org/10.1016/S0140-6736(15)01124-1
Fish, P. V., Steadman, D., Bayle, E. D., & Whiting, P. (2019). New approaches for the treatment of Alzheimer’s disease. Bioorganic & Medicinal Chemistry Letters, 29, 125–133. https://doi.org/10.1016/j.bmcl.2018.11.034
Cummings, J. L., Tong, G., & Ballard, C. (2019). Treatment combinations for Alzheimer’s disease: Current and future pharmacotherapy options. Journal of Alzheimer’s Disease, 67(3), 779–794. https://doi.org/10.3233/JAD-180766
Cummings, J., Ritter, A., & Zhong, K. (2018). Clinical trials for disease-modifying therapies in Alzheimer’s disease: A primer, lessons learned, and a blueprint for the future. Journal of Alzheimer’s Disease, 64(s1), S3–S22. https://doi.org/10.3233/JAD-179901
Yu, A., & Lau, A. Y. (2018). Glutamate and glycine binding to the NMDA receptor. Structure, 26(7), 1035–1043.e2. https://doi.org/10.1016/j.str.2018.05.004
Parsons, C. G., Danysz, W., & Quack, G. (1999). Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—A review of preclinical data. Neuropharmacology, 38(6), 735–767. https://doi.org/10.1016/S0028-3908(99)00019-2
Kassa, J., & Zdarova Karasova, J. (2023). Combination of acetylcholinesterase inhibitors and NMDA receptor antagonists increases survival rate in soman-poisoned mice. Toxicology Mechanisms and Methods, 33(7), 590–595. https://doi.org/10.1080/15376516.2023.2202730
Fox, N. C., Belder, C., Ballard, C., Kales, H. C., Mummery, C., Caramelli, P., Ciccarelli, O., Frederiksen, K. S., Gomez-Isla, T., Ismail, Z., Paquet, C., Petersen, R. C., Perneczky, R., Robinson, L., Sayin, O., & Frisoni, G. B. (2025). Treatment for Alzheimer’s disease. The Lancet, 406(10510), 1408–1423. https://doi.org/10.1016/S0140-6736(25)01329-7
Imbimbo, B. P. (2001). Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer’s disease. CNS Drugs, 15(5), 375–390. https://doi.org/10.2165/00023210-200115050-00004
Winblad, B., Cummings, J., Andreasen, N., Grossberg, G., Onofrj, M., Sadowsky, C., Zechner, S., Nagel, J., & Lane, R. (2007). A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease—Rivastigmine patch versus capsule. International Journal of Geriatric Psychiatry, 22(5), 456–467. https://doi.org/10.1002/gps.1788
Masurkar, P. P., Chatterjee, S., Sherer, J. T., Chen, H., Johnson, M. L., & Aparasu, R. R. (2022). Risk of overactive bladder associated with cholinesterase inhibitors in dementia. Journal of the American Geriatrics Society, 70(3), 820–830. https://doi.org/10.1111/jgs.17579
Xu, H., Garcia-Ptacek, S., Jönsson, L., Wimo, A., Nordström, P., & Eriksdotter, M. (2021). Long-term effects of cholinesterase inhibitors on cognitive decline and mortality. Neurology, 96(17), e2220–e2230. https://doi.org/10.1212/WNL.0000000000011832
Truong, C., Recto, C., Lafont, C., Canoui-Poitrine, F., Belmin, J. B., & Lafuente-Lafuente, C. (2022). Effect of cholinesterase inhibitors on mortality in patients with dementia: A systematic review of randomized and nonrandomized trials. Neurology, 99(20), e2313–e2325. https://doi.org/10.1212/WNL.0000000000201161
Tan, E. C. K., Johnell, K., Bell, J. S., Garcia-Ptacek, S., Fastbom, J., Nordström, P., & Eriksdotter, M. (2020). Do acetylcholinesterase inhibitors prevent or delay psychotropic prescribing in people with dementia? Analyses of the Swedish Dementia Registry. American Journal of Geriatric Psychiatry, 28(1), 108–117. https://doi.org/10.1016/j.jagp.2019.06.008
Nørgaard, A., Jensen-Dahm, C., Wimberley, T., Svendsen, J. H., Ishtiak-Ahmed, K., Laursen, T. M., Waldemar, G., & Gasse, C. (2022). Effect of antipsychotics on mortality risk in patients with dementia with and without comorbidities. Journal of the American Geriatrics Society, 70(4), 1169–1179. https://doi.org/10.1111/jgs.17623
Schwertner, E., Secnik, J., Garcia-Ptacek, S., Johansson, B., Nagga, K., Eriksdotter, M., Winblad, B., & Religa, D. (2019). Antipsychotic treatment associated with increased mortality risk in patients with dementia: A registry-based observational cohort study. Journal of the American Medical Directors Association, 20(3), 323–329.e2. https://doi.org/10.1016/j.jamda.2018.12.019
Livingston, G., & Katona, C. (2004). The place of memantine in the treatment of Alzheimer’s disease: A number needed to treat analysis. International Journal of Geriatric Psychiatry, 19(10), 919–925. https://doi.org/10.1002/gps.1166
Peters, K. R. (2013). Utility of an effect size analysis for communicating treatment effectiveness: A case study of cholinesterase inhibitors for Alzheimer’s disease. Journal of the American Geriatrics Society, 61(7), 1170–1174. https://doi.org/10.1111/jgs.12308
Guo, J., Wang, Z., Liu, R., Huang, Y., Zhang, N., & Zhang, R. (2020). Memantine, donepezil, or combination therapy—What is the best therapy for Alzheimer’s disease? A network meta-analysis. Brain and Behavior, 10(11), e01831. https://doi.org/10.1002/brb3.1831
Lopez, O. L., Becker, J. T., Wahed, A. S., Saxton, J., Sweet, R. A., Wolk, D. A., Klunk, W., & DeKosky, S. T. (2009). Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. Journal of Neurology, Neurosurgery & Psychiatry, 80(6), 600–607. https://doi.org/10.1136/jnnp.2008.158964
Matsunaga, S., Kishi, T., & Iwata, N. (2015). Memantine monotherapy for Alzheimer’s disease: A systematic review and meta-analysis. PLoS ONE, 10(4), e0123289. https://doi.org/10.1371/journal.pone.0123289
Doody, R. S., Tariot, P. N., Pfeiffer, E., Olin, J. T., & Graham, S. M. (2007). Meta-analysis of six-month memantine trials in Alzheimer’s disease. Alzheimer’s & Dementia, 3(1), 7–17. https://doi.org/10.1016/j.jalz.2006.10.004
Zenaro, E., Piacentino, G., & Constantin, G. (2017). The blood-brain barrier in Alzheimer’s disease. Neurobiology of Disease, 107, 41–56. https://doi.org/10.1016/j.nbd.2016.07.007
Chakraborty, A., de Wit, N. M., van der Flier, W. M., & de Vries, H. E. (2017). The blood brain barrier in Alzheimer’s disease. Vascular Pharmacology, 89, 12–18. https://doi.org/10.1016/j.vph.2016.11.008
Banks, W. A. (2012). Drug delivery to the brain in Alzheimer’s disease: Consideration of the blood-brain barrier. Advanced Drug Delivery Reviews, 64(7), 629–639. https://doi.org/10.1016/j.addr.2011.12.005
Colin, J., Thomas, M. H., Gregory-Pauron, L., Pinçon, A., Lanhers, M. C., Corbier, C., Claudepierre, T., Yen, F. T., Oster, T., & Malaplate-Armand, C. (2017). Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments. Neurobiology of Aging, 54, 84–93. https://doi.org/10.1016/j.neurobiolaging.2017.02.015
Poon, C. H., Wang, Y., Fung, M. L., Zhang, C., & Lim, L. W. (2020). Rodent models of amyloid-beta feature of Alzheimer’s disease: Development and potential treatment implications. Aging and Disease, 11(5), 1235–1259. https://doi.org/10.14336/AD.2019.1026
Huang, L. K., Chao, S. P., & Hu, C. J. (2020). Clinical trials of new drugs for Alzheimer disease. Journal of Biomedical Science, 27(1), 18. https://doi.org/10.1186/s12929-019-0609-7
Solfrizzi, V., & Imbimbo, B. P. (2026). Comparing clinical effect sizes of Souvenaid™, lecanemab, and donanemab in early Alzheimer’s disease. Journal of Alzheimer’s Disease, 109(3), 1258–1263. https://doi.org/10.1177/13872877251406221
Wu, W., Ji, Y., Wang, Z., Wu, X., Li, J., Gu, F., Chen, Z., & Wang, Z. (2023). The FDA-approved anti-amyloid-β monoclonal antibodies for the treatment of Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. European Journal of Medical Research, 28(1), 544. https://doi.org/10.1186/s40001-023-01512-w
Cummings, J. (2023). Anti-amyloid monoclonal antibodies are transformative treatments that redefine Alzheimer’s disease therapeutics. Drugs, 83(7), 569–576. https://doi.org/10.1007/s40265-023-01858-9
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O’Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M. S., Quintero-Monzon, O., Scannevin, R. H., Arnold, H. M., ... Sandrock, A. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 537(7618), 50–56. https://doi.org/10.1038/nature19323
Chowdhury, S., & Chowdhury, N. S. (2023). Novel anti-amyloid-beta (Aβ) monoclonal antibody lecanemab for Alzheimer’s disease: A systematic review. International Journal of Immunopathology and Pharmacology, 37, 03946320231209839. https://doi.org/10.1177/03946320231209839
Vukmir, R. B. (2024). Amyloid-related imaging abnormalities (ARIA): Diagnosis, management, and care in the setting of amyloid-modifying therapy. Annals of Clinical and Translational Neurology, 11(7), 1669–1680. https://doi.org/10.1002/acn3.52042
Singh, N., Das, B., Zhou, J., Hu, X., & Yan, R. (2022). Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Science Advances, 8(29), eabo3610. https://doi.org/10.1126/sciadv.abo3610
Moussa-Pacha, N. M., Abdin, S. M., Omar, H. A., Alniss, H., & Al-Tel, T. H. (2020). BACE1 inhibitors: Current status and future directions in treating Alzheimer’s disease. Medicinal Research Reviews, 40(1), 339–384. https://doi.org/10.1002/med.21622
Briggs, R., Kennelly, S. P., & O’Neill, D. (2016). Drug treatments in Alzheimer’s disease. Clinical Medicine, 16(3), 247–253. https://doi.org/10.7861/clinmedicine.16-3-247
Klimova, B., & Kuca, K. (2015). Alzheimer’s disease: Potential preventive, non-invasive, intervention strategies in lowering the risk of cognitive decline—A review study. Journal of Applied Biomedicine, 13(4), 257–261. https://doi.org/10.1016/j.jab.2015.07.004
Angeloni, C., Businaro, R., & Vauzour, D. (2020). The role of diet in preventing and reducing cognitive decline. Current Opinion in Psychiatry, 33(4), 432–438. https://doi.org/10.1097/YCO.0000000000000605
Vinciguerra, F., Graziano, M., Hagnäs, M., Frittitta, L., & Tumminia, A. (2020). Influence of the Mediterranean and ketogenic diets on cognitive status and decline: A narrative review. Nutrients, 12(4), 1019. https://doi.org/10.3390/nu12041019
Santangelo, A., Corsello, A., Spolidoro, G. C. I., Trovato, C. M., Agostoni, C., Orsini, A., Milani, G. P., & Peroni, D. G. (2023). The influence of ketogenic diet on gut microbiota: Potential benefits, risks and indications. Nutrients, 15(17), 3680. https://doi.org/10.3390/nu15173680
Dighriri, I. M., Alsubaie, A. M., Hakami, F. M., Hamithi, D. M., Alshekh, M. M., Khobrani, F. A., Dalak, F. E., Hakami, A. A., Alsueaadi, E. H., Alsaawi, L. S., Alshammari, S. F., Alqahtani, A. S., Alawi, I. A., Aljuaid, A. A., & Tawhari, M. Q. (2022). Effects of omega-3 polyunsaturated fatty acids on brain functions: A systematic review. Cureus, 14(10), e30091. https://doi.org/10.7759/cureus.30091
Welty, F. K. (2023). Omega-3 fatty acids and cognitive function. Current Opinion in Lipidology, 34(1), 12–21. https://doi.org/10.1097/MOL.0000000000000862
Moore, K. M., Girens, R. E., Larson, S. K., Jones, M. R., Restivo, J. L., Holtzman, D. M., Cirrito, J. R., Yuede, C. M., Zimmerman, S. D., & Timson, B. F. (2016). A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer’s disease. Neurobiology of Disease, 85, 218–224. https://doi.org/10.1016/j.nbd.2015.11.004
Meng, Q., & Su, C. H. (2024). The impact of physical exercise on oxidative and nitrosative stress: Balancing the benefits and risks. Antioxidants, 13(5), 573. https://doi.org/10.3390/antiox13050573
Martin, B., Mattson, M. P., & Maudsley, S. (2006). Caloric restriction and intermittent fasting: Two potential diets for successful brain aging. Ageing Research Reviews, 5(3), 332–353. https://doi.org/10.1016/j.arr.2006.04.002
Muscat, S. M., & Barrientos, R. M. (2020). Lifestyle modifications with anti-neuroinflammatory benefits in the aging population. Experimental Gerontology, 142, 111144. https://doi.org/10.1016/j.exger.2020.111144
Xu Lou, I., Ali, K., & Chen, Q. (2023). Effect of nutrition in Alzheimer’s disease: A systematic review. Frontiers in Neuroscience, 17, 1147177. https://doi.org/10.3389/fnins.2023.1147177
Tucker, S., Möller, C., Tegerstedt, K., Lord, A., Laudon, H., Sjödahl, J., Söderberg, L., Spens, E., Sahlin, C., Waara, E. R., 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. Journal of Alzheimer’s Disease, 43(2), 575–588. https://doi.org/10.3233/JAD-140741
Tolar, M., Abushakra, S., Hey, J. A., Porsteinsson, A., & Sabbagh, M. (2020). Aducanumab, gantenerumab, BAN2401, and ALZ-801—The first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimer’s Research & Therapy, 12(1), 95. https://doi.org/10.1186/s13195-020-00663-w
Söderberg, L., Johannesson, M., Nygren, P., Laudon, H., Eriksson, F., Osswald, G., Möller, C., & Lannfelt, L. (2023). Lecanemab, aducanumab, and gantenerumab—Binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease. Neurotherapeutics, 20(1), 195–206. https://doi.org/10.1007/s13311-022-01308-6
Lord, A., Gumucio, A., Englund, H., Sehlin, D., Sundquist, V. S., Söderberg, L., Möller, C., Gellerfors, P., Lannfelt, L., Pettersson, F. E., & Nilsson, L. N. (2009). An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer’s disease. Neurobiology of Disease, 36(3), 425–434. https://doi.org/10.1016/j.nbd.2009.08.007
Chowdhury, S. (2023). Monoclonal antibody treatments for Alzheimer’s disease: Aducanumab and lecanemab. Discoveries, 11(3), e173. https://doi.org/10.15190/d.2023.12
Söllvander, S., Ekholm-Pettersson, F., Brundin, R. M., Westman, G., Kilander, L., Paulie, S., Lannfelt, L., & Sehlin, D. (2015). Increased number of plasma B cells producing autoantibodies against Aβ42 protofibrils in Alzheimer’s disease. Journal of Alzheimer’s Disease, 48(1), 63–72. https://doi.org/10.3233/JAD-150236
Nilsberth, C., Westlind-Danielsson, A., Eckman, C. B., Condron, M. M., Axelman, K., Forsell, C., Stenh, C., Luthman, J., Teplow, D. B., Younkin, S. G., Näslund, J., & Lannfelt, L. (2001). The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. Nature Neuroscience, 4(9), 887–893. https://doi.org/10.1038/nn0901-887
Logovinsky, V., Satlin, A., Lai, R., Swanson, C., Kaplow, J., Osswald, G., Basun, H., & Lannfelt, L. (2016). Safety and tolerability of BAN2401—A clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimer’s Research & Therapy, 8(1), 14. https://doi.org/10.1186/s13195-016-0181-2
Cummings, J., Apostolova, L., Rabinovici, G. D., Atri, A., Aisen, P., Greenberg, S., Hendrix, S., Selkoe, D., Weiner, M., Petersen, R. C., & Salloway, S. (2023). Lecanemab: Appropriate use recommendations. Journal of Prevention of Alzheimer’s Disease, 10(3), 362–377. https://doi.org/10.14283/jpad.2023.30
Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., Gamst, A., Holtzman, D. M., Jagust, W. J., Petersen, R. C., Snyder, P. J., Carrillo, M. C., Thies, B., & Phelps, C. H. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia, 7(3), 270–279. https://doi.org/10.1016/j.jalz.2011.03.008
McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Jr., Kawas, C. H., Klunk, W. E., Koroshetz, W. J., Manly, J. J., Mayeux, R., Mohs, R. C., Morris, J. C., Rossor, M. N., Scheltens, P., Carrillo, M. C., Thies, B., Weintraub, S., & Phelps, C. H. (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. Alzheimer’s & Dementia, 7(3), 263–269. https://doi.org/10.1016/j.jalz.2011.03.005
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M., Kramer, L. D., & Iwatsubo, T. (2023). Lecanemab in early Alzheimer’s disease. The New England Journal of Medicine, 388(1), 9–21. https://doi.org/10.1056/NEJMoa2212948
Cohen, S., van Dyck, C. H., Gee, M., Doherty, T., Kanekiyo, M., Dhadda, S., Li, D., Hersch, S., Irizarry, M., & Kramer, L. D. (2023). Lecanemab Clarity AD: Quality-of-life results from a randomized, double-blind phase 3 trial in early Alzheimer’s disease. Journal of Prevention of Alzheimer’s Disease, 10(4), 771–777. https://doi.org/10.14283/jpad.2023.123
Kovacik, A., Vandergriff, K., Jarrett, B., & Clevenger, C. (2025). An update of the treatment landscape for Alzheimer’s disease: From symptomatic treatments to the emergence of amyloid-targeting therapies. SAGE Open Aging, 11, 30495334251376614. https://doi.org/10.1177/30495334251376614
Doessegger, L., & Banholzer, M. L. (2015). Clinical development methodology for infusion-related reactions with monoclonal antibodies. Clinical & Translational Immunology, 4(7), e39. https://doi.org/10.1038/cti.2015.14
Swanson, C. J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R. Y. K., Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., Reyderman, L., Berry, D. A., Berry, S., Gordon, R., Kramer, L. D., & Cummings, J. L. (2021). A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer’s Research & Therapy, 13(1), 80. https://doi.org/10.1186/s13195-021-00813-8
Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., Shcherbinin, S., Sparks, J., Sims, J. R., Brys, M., Apostolova, L. G., Salloway, S. P., & Skovronsky, D. M. (2021). Donanemab in early Alzheimer’s disease. The New England Journal of Medicine, 384(18), 1691–1704. https://doi.org/10.1056/NEJMoa2100708
Budd Haeberlein, S., O’Gorman, J., Chiao, P., Bussière, T., von Rosenstiel, P., Tian, Y., Zhu, Y., von Hehn, C., Gheuens, S., Skordos, L., Chen, T., & Sandrock, A. (2017). Clinical development of aducanumab, an anti-Aβ human monoclonal antibody being investigated for the treatment of early Alzheimer’s disease. Journal of Prevention of Alzheimer’s Disease, 4(4), 255–263. https://doi.org/10.14283/jpad.2017.39
McDade, E., Cummings, J. L., Dhadda, S., Swanson, C. J., Reyderman, L., Kanekiyo, M., Koyama, A., Irizarry, M., Kramer, L. D., & Bateman, R. J. (2022). Lecanemab in patients with early Alzheimer’s disease: Detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimer’s Research & Therapy, 14(1), 191. https://doi.org/10.1186/s13195-022-01124-2
Honig, L. S., Sabbagh, M. N., van Dyck, C. H., Sperling, R. A., Hersch, S., Matta, A., Giorgi, L., Gee, M., Kanekiyo, M., Li, D., Purcell, D., Dhadda, S., Irizarry, M., & Kramer, L. (2024). Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease. Alzheimer’s Research & Therapy, 16(1), 105. https://doi.org/10.1186/s13195-024-01441-8
Chen, C., Katayama, S., Lee, J. H., Lee, J. Y., Nakagawa, M., Torii, K., Ogawa, T., Dash, A., Irizarry, M., Dhadda, S., Kanekiyo, M., Hersch, S., & Iwatsubo, T. (2025). Clarity AD: Asian regional analysis of a phase III trial of lecanemab in early Alzheimer’s disease. Journal of Prevention of Alzheimer’s Disease, 12(5), 100160. https://doi.org/10.1016/j.tjpad.2025.100160
Rafii, M. S., Sperling, R. A., Donohue, M. C., Zhou, J., Roberts, C., Irizarry, M. C., Dhadda, S., Sethuraman, G., Kramer, L. D., Swanson, C. J., Li, D., Krause, S., Rissman, R. A., Walter, S., Raman, R., Johnson, K. A., & Aisen, P. S. (2023). The AHEAD 3-45 study: Design of a prevention trial for Alzheimer’s disease. Alzheimer’s & Dementia, 19(4), 1227–1233. https://doi.org/10.1002/alz.12748
Eisai Inc. (2026). AHEAD 3-45 study: A study to evaluate efficacy and safety of treatment with lecanemab in participants with preclinical Alzheimer’s disease and elevated amyloid and also in participants with early preclinical Alzheimer’s disease and intermediate amyloid (NCT04468659). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04468659
McShane, R., Westby, M. J., Roberts, E., Minakaran, N., Schneider, L., Farrimond, L. E., Maayan, N., Ware, J., & Debarros, J. (2019). Memantine for dementia. Cochrane Database of Systematic Reviews, 2019(3), CD003154. https://doi.org/10.1002/14651858.CD003154.pub6
Vaci, N., Koychev, I., Kim, C. H., Kormilitzin, A., Liu, Q., Lucas, C., Dehghan, A., Nenadic, G., & Nevado-Holgado, A. (2021). Real-world effectiveness, its predictors and onset of action of cholinesterase inhibitors and memantine in dementia: Retrospective health record study. British Journal of Psychiatry, 218(5), 261–267. https://doi.org/10.1192/bjp.2020.136
Andrews, D., Ducharme, S., Chertkow, H., Sormani, M. P., Collins, D. L., & Alzheimer’s Disease Neuroimaging Initiative. (2025). The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect. Alzheimer’s & Dementia, 21(1), e14467. https://doi.org/10.1002/alz.14467
Arvanitakis, Z., Shah, R. C., & Bennett, D. A. (2019). Diagnosis and management of dementia: Review. JAMA, 322(16), 1589–1599. https://doi.org/10.1001/jama.2019.4782
O’Donnell, A. J., Zhao, X., Parr, A., Aspinall, S., & Anderson, T. S. (2025). Early outcomes of lecanemab for Alzheimer’s disease in the Veterans Health Administration. Journal of Clinical Medicine, 14(23), 8277. https://doi.org/10.3390/jcm14238277
Birks, J. S., & Harvey, R. J. (2018). Donepezil for dementia due to Alzheimer’s disease. Cochrane Database of Systematic Reviews, 2018(6), CD001190. https://doi.org/10.1002/14651858.CD001190.pub3
Lanctôt, K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., & Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: A meta-analysis. CMAJ, 169(6), 557–564.
Wu, C. K., & Fuh, J. L. (2025). A 2025 update on treatment strategies for the Alzheimer’s disease spectrum. Journal of the Chinese Medical Association, 88(7), 495–502. https://doi.org/10.1097/JCMA.0000000000001252
Qi, L., Zheng, F., Tu, M., Abdullah, R., Zhao, Y., Su, X., Zhou, D., & Peng, G. (2026). Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence. Journal of Prevention of Alzheimer’s Disease, 100473. https://doi.org/10.1016/j.tjpad.2025.100473
Kang, W., Gao, C., Li, X., Wang, X., Zhong, H., Wei, Q., Tang, Y., Huang, P., Shen, R., Chen, L., Zhang, J., Fang, R., Wei, W., Zhang, F., Zhou, G., Yuan, W., Chen, X., Yang, Z., Wu, Y., ... Liu, J. (2025). Safety and effectiveness of lecanemab in Chinese patients with early Alzheimer’s disease: Evidence from a multidimensional real-world study. Chinese Medical Journal, 138(22), 2907–2916. https://doi.org/10.1097/CM9.0000000000003888
Rogers, S. L., Farlow, M. R., Doody, R. S., Mohs, R., & Friedhoff, L. T. (1998). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology, 50(1), 136–145. https://doi.org/10.1212/WNL.50.1.136
Abdelazim, K., Allam, A. A., Afifi, B., Abdulazeem, H., & Elbehiry, A. I. (2024). The efficacy and safety of lecanemab 10 mg/kg biweekly compared to a placebo in patients with Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. Neurological Sciences, 45(8), 3583–3597. https://doi.org/10.1007/s10072-024-07477-w
Fox, N. C., Belder, C., Ballard, C., Kales, H. C., Mummery, C., Caramelli, P., Ciccarelli, O., Frederiksen, K. S., Gomez-Isla, T., Ismail, Z., Paquet, C., Petersen, R. C., Perneczky, R., Robinson, L., Sayin, O., & Frisoni, G. B. (2025). Treatment for Alzheimer’s disease. The Lancet, 406(10510), 1408–1423. https://doi.org/10.1016/S0140-6736(25)01329-7
Sims, J. R., Zimmer, J. A., Evans, C. D., Lu, M., Ardayfio, P., Sparks, J., Wessels, A. M., Shcherbinin, S., Wang, H., Monkul Nery, E. S., Collins, E. C., Solomon, P., Salloway, S., Apostolova, L. G., Hansson, O., Ritchie, C., Brooks, D. A., Mintun, M., Skovronsky, D. M., & TRAILBLAZER-ALZ 2 Investigators. (2023). Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA, 330(6), 512–527. https://doi.org/10.1001/jama.2023.13239
Liu, K. Y., Walsh, S., Brayne, C., Merrick, R., Richard, E., & Howard, R. (2023). Evaluation of clinical benefits of treatments for Alzheimer’s disease. The Lancet Healthy Longevity, 4(11), e645–e651. https://doi.org/10.1016/S2666-7568(23)00193-9
Petersen, R. C., Aisen, P. S., Andrews, J. S., Atri, A., Matthews, B. R., Rentz, D. M., Siemers, E. R., Weber, C. J., & Carrillo, M. C. (2023). Expectations and clinical meaningfulness of randomized controlled trials. Alzheimer’s & Dementia, 19(6), 2730–2736. https://doi.org/10.1002/alz.12959
Goldberg, T. E., Lee, S., Devanand, D. P., & Schneider, L. S. (2024). Comparison of relative change with effect size metrics in Alzheimer’s disease clinical trials. Journal of Neurology, Neurosurgery & Psychiatry, 95(1), 2–7. https://doi.org/10.1136/jnnp-2023-331941
U.S. Food and Drug Administration. (n.d.). Prescribing information for Leqembi (lecanemab-irmb) injection, for intravenous use (Reference ID 5203190). Retrieved October 21, 2024.
Wang, H., Serap Monkul Nery, E., Ardayfio, P., Khanna, R., Otero Svaldi, D., Gueorguieva, I., Shcherbinin, S., Andersen, S. W., Hauck, P. M., Engle, S. E., Brooks, D. A., Collins, E. C., Fox, N. C., Greenberg, S. M., Salloway, S., Mintun, M. A., & Sims, J. R. (2025). Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimer’s & Dementia, 21(4), e70062. https://doi.org/10.1002/alz.70062
Zimmer, J. A., Ardayfio, P., Wang, H., Khanna, R., Evans, C. D., Lu, M., Sparks, J., Andersen, S., Lauzon, S., Nery, E. S. M., Battioui, C., Engle, S. E., Biffi, A., Svaldi, D., Salloway, S., Greenberg, S. M., Sperling, R. A., Mintun, M., Brooks, D. A., & Sims, J. R. (2025). Amyloid-related imaging abnormalities with donanemab in early symptomatic Alzheimer disease: Secondary analysis of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials. JAMA Neurology, 82(5), 461–469. https://doi.org/10.1001/jamaneurol.2025.0065
Fox, N. C., Black, R. S., Gilman, S., Rossor, M. N., Griffith, S. G., Jenkins, L., Koller, M., & AN1792(QS-21)-201 Study. (2005). Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology, 64(9), 1563–1572. https://doi.org/10.1212/01.WNL.0000159743.08996.99
Belder, C. R. S., Boche, D., Nicoll, J. A. R., Jaunmuktane, Z., Zetterberg, H., Schott, J. M., Barkhof, F., & Fox, N. C. (2024). Brain volume change following anti-amyloid β immunotherapy for Alzheimer’s disease: Amyloid-removal-related pseudo-atrophy. The Lancet Neurology, 23(10), 1025–1034. https://doi.org/10.1016/S1474-4422(24)00335-1
Alves, F., Kalinowski, P., & Ayton, S. (2023). Accelerated brain volume loss caused by anti-β-amyloid drugs: A systematic review and meta-analysis. Neurology, 100(20), e2114–e2124. https://doi.org/10.1212/WNL.0000000000207156
Hardy, J. (2025). Alzheimer’s disease: Treatment challenges for the future. Journal of Neurochemistry, 169(8), e70176. https://doi.org/10.1111/jnc.70176
Lannfelt, L., Söderberg, L., Laudon, H., Sahlin, C., Johannesson, M., Nygren, P., & Möller, C. (2019). P4-704: BAN2401 shows stronger binding to soluble aggregated amyloid-beta species than aducanumab. Alzheimer’s & Dementia, 15.
Vaz, M., Silva, V., Monteiro, C., & Silvestre, S. (2022). Role of aducanumab in the treatment of Alzheimer’s disease: Challenges and opportunities. Clinical Interventions in Aging, 17, 797–810. https://doi.org/10.2147/CIA.S325026
Esparza, T. J., Zhao, H., Cirrito, J. R., Cairns, N. J., Bateman, R. J., Holtzman, D. M., & Brody, D. L. (2013). Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Annals of Neurology, 73(1), 104–119. https://doi.org/10.1002/ana.23748
Kocis, P., Tolar, M., Yu, J., Sinko, W., Ray, S., Blennow, K., Fillit, H., & Hey, J. A. (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(6), 495–509. https://doi.org/10.1007/s40263-017-0434-z
Erwin, M. (2023). A dab of MAB: Lecanemab, aducanumab vs standard of care treatment for Alzheimer disease. Pharmacy Times.
Biogen. (2021). 221AD302 phase 3 study of aducanumab (BIIB037) in early Alzheimer’s disease (EMERGE) (NCT02484547). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02484547
Biogen. (2021). 221AD301 phase 3 study of aducanumab (BIIB037) in early Alzheimer’s disease (ENGAGE) (NCT02477800). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02477800
Budd Haeberlein, S., Aisen, P. S., Barkhof, F., Chalkias, S., Chen, T., Cohen, S., Dent, G., Hansson, O., Harrison, K., von Hehn, C., Iwatsubo, T., Mallinckrodt, C., Mummery, C. J., Muralidharan, K. K., Nestorov, I., Nisenbaum, L., Rajagovindan, R., Skordos, L., Tian, Y., ... Sandrock, A. (2022). Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. Journal of Prevention of Alzheimer’s Disease, 9(2), 197–210. https://doi.org/10.14283/jpad.2022.30
Eisai Inc. (2025). A study to confirm safety and efficacy of lecanemab in participants with early Alzheimer’s disease (Clarity AD) (NCT03887455). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT03887455
Villain, N. (2022). Therapeutic news in Alzheimer’s disease: Soon a disease-modifying therapy? Revue Neurologique, 178(5), 437–440. https://doi.org/10.1016/j.neurol.2022.02.456
Winslow, B. T., Onysko, M. K., Stob, C. M., & Hazlewood, K. A. (2011). Treatment of Alzheimer disease. American Family Physician, 83(12), 1403–1412. https://www.aafp.org/pubs/afp/issues/2011/0615/p1403.html
Hogervorst, E., Yaffe, K., Richards, M., & Huppert, F. A. (2009). Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database of Systematic Reviews, 2009(1), CD003799.
Rigaud, A. S., André, G., Vellas, B., Touchon, J., Pere, J. J., & French Study Group. (2003). No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology, 60(1), 148–149.
Isaac, M. G., Quinn, R., & Tabet, N. (2008). Vitamin E for Alzheimer’s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews, 2008(3), CD002854.
Feldman, H. H., Doody, R. S., Kivipelto, M., et al., & LEADe Investigators. (2010). Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology, 74(12), 956–964.
Sato, T., Hanyu, H., Hirao, K., Kanetaka, H., Sakurai, H., & Iwamoto, T. (2009). Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiology of Aging. http://www.sciencedirect.com/science/article/pii/S019745800900339X
Tan, R. S., & Pu, S. J. (2003). A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. The Aging Male, 6(1), 13–17.
Cherrier, M. M., Matsumoto, A. M., Amory, J. K., et al. (2005). Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology, 64(12), 2063–2068.
Lu, P. H., Masterman, D. A., Mulnard, R., Cotman, C., Miller, B., Yaffe, K., Reback, E., Porter, V., Swerdloff, R., & Cummings, J. L. (2006). Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Archives of Neurology, 63(2), 177–185. https://doi.org/10.1001/archneur.63.2.nct50002
Basaria, S., Coviello, A. D., Travison, T. G., et al. (2010). Adverse events associated with testosterone administration. The New England Journal of Medicine, 363(2), 109–122.
Birks, J., & Grimley Evans, J. (2009). Ginkgo biloba for cognitive impairment and dementia. Cochrane Database of Systematic Reviews, 2009(1), CD003120.
Akhondzadeh, S., & Abbasi, S. H. (2006). Herbal medicine in the treatment of Alzheimer’s disease. American Journal of Alzheimer’s Disease & Other Dementias, 21(2), 113–118. https://doi.org/10.1177/153331750602100211
Perry, E. K., Pickering, A. T., Wang, W. W., et al. (1998). Medicinal plants and Alzheimer’s disease: Integrating ethnobotanical and contemporary scientific evidence. Journal of Alternative and Complementary Medicine, 4, 419–428.
Perry, E. K., Pickering, A. T., Wang, W. W., et al. (1999). Medicinal plants and Alzheimer’s disease: From ethnobotany to phytotherapy. Journal of Pharmacy and Pharmacology, 51, 527–534.
Kennedy, D. O., Scholey, A. B., Tildesley, N. T. J., et al. (2002). Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm). Pharmacology Biochemistry and Behavior, 72, 953–964.
Akhondzadeh, S., Noroozian, M., Mohammadi, M., et al. (2003). Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: A double-blind, randomised, placebo-controlled trial. Journal of Neurology, Neurosurgery & Psychiatry, 74, 863–866.
Akhondzadeh, S., Noroozian, M., Mohammadi, M., et al. (2003). Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: A double-blind, randomized and placebo-controlled trial. Journal of Clinical Pharmacy and Therapeutics, 28, 53–59.
Wake, G., Court, J., Pickering, A., et al. (2000). CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory. Journal of Ethnopharmacology, 69, 105–114.
Folch, J., Petrov, D., Ettcheto, M., Abad, S., Sánchez-López, E., García, M. L., Olloquequi, J., Beas-Zarate, C., Auladell, C., & Camins, A. (2016). Current research therapeutic strategies for Alzheimer’s disease treatment. Neural Plasticity, 2016, 8501693. https://doi.org/10.1155/2016/8501693
Gauthier, S., Aisen, P. S., Ferris, S. H., Saumier, D., Duong, A., Haine, D., Garceau, D., Suhy, J., Oh, J., Lau, W., & Sampalis, J. (2009). Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: Exploratory analyses of the MRI sub-group of the Alphase study. Journal of Nutrition, Health & Aging, 13(6), 550–557. https://doi.org/10.1007/s12603-009-0106-x
Aisen, P. S., Gauthier, S., Ferris, S. H., Saumier, D., Haine, D., Garceau, D., Duong, A., Suhy, J., Oh, J., Lau, W. C., & Sampalis, J. (2011). Tramiprosate in mild-to-moderate Alzheimer’s disease—A randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Archives of Medical Science, 7(1), 102–111. https://doi.org/10.5114/aoms.2011.20612
Gupta-Bansal, R., Frederickson, R. C., & Brunden, K. R. (1995). Proteoglycan-mediated inhibition of A beta proteolysis: A potential cause of senile plaque accumulation. Journal of Biological Chemistry, 270(31), 18666–18671. https://doi.org/10.1074/jbc.270.31.18666
Bilikiewicz, A., & Gaus, W. (2004). Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer’s disease. Journal of Alzheimer’s Disease, 6(1), 17–26. https://doi.org/10.3233/JAD-2004-6103
Salloway, S., Sperling, R., Keren, R., Porsteinsson, A. P., van Dyck, C. H., Tariot, P. N., Gilman, S., Arnold, D., Abushakra, S., Hernandez, C., Crans, G., Liang, E., Quinn, G., Bairu, M., Pastrak, A., Cedarbaum, J. M., & ELND005-AD201 Investigators. (2011). A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology, 77(13), 1253–1262. https://doi.org/10.1212/WNL.0b013e3182309fa5
Deane, R. J. (2012). Is RAGE still a therapeutic target for Alzheimer’s disease? Future Medicinal Chemistry, 4(7), 915–925. https://doi.org/10.4155/fmc.12.51
Galasko, D., Bell, J., Mancuso, J. Y., Kupiec, J. W., Sabbagh, M. N., van Dyck, C., Thomas, R. G., Aisen, P. S., & Alzheimer’s Disease Cooperative Study. (2014). Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology, 82(17), 1536–1542. https://doi.org/10.1212/WNL.0000000000000364
Deane, R., Sagare, A., & Zlokovic, B. V. (2008). The role of the cell surface LRP and soluble LRP in blood-brain barrier Aβ clearance in Alzheimer’s disease. Current Pharmaceutical Design, 14(16), 1601–1605. https://doi.org/10.2174/138161208784705487
vTv Therapeutics. (2015). A safety study of TTP4000 in subjects with Alzheimer’s disease (NCT01548430). ClinicalTrials.gov.
Gilman, S., Koller, M., Black, R. S., Jenkins, L., Griffith, S. G., Fox, N. C., Eisner, L., Kirby, L., Rovira, M. B., Forette, F., Orgogozo, J. M., & AN1792(QS-21)-201 Study Team. (2005). Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64(9), 1553–1562. https://doi.org/10.1212/01.WNL.0000159740.16984.3C
Wiessner, C., Wiederhold, K. H., Tissot, A. C., Frey, P., Danner, S., Jacobson, L. H., Jennings, G. T., Lüönd, R., Ortmann, R., Reichwald, J., Zurini, M., Mir, A., Bachmann, M. F., & Staufenbiel, M. (2011). The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. Journal of Neuroscience, 31(25), 9323–9331. https://doi.org/10.1523/JNEUROSCI.0293-11.2011
Janssen Alzheimer Immunotherapy Research & Development, LLC. (2015). Amyloid imaging and safety study of ACC-001 in subjects with mild to moderate Alzheimer’s disease (ACCTION) (NCT01284387). ClinicalTrials.gov.
Pfizer. (2016). Study evaluating safety, tolerability, and immunogenicity of ACC-001 in subjects with mild to moderate Alzheimer’s disease (NCT00479557). ClinicalTrials.gov.
ClinicalTrials.gov. (2016). Amyloid imaging and safety study of ACC-001 in subjects with early Alzheimer’s disease (NCT01227564).
Liu, B., Frost, J. L., Sun, J., Fu, H., Grimes, S., Blackburn, P., & Lemere, C. A. (2013). MER5101, a novel Aβ1-15:DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuates Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice. Journal of Neuroscience, 33(16), 7027–7037. https://doi.org/10.1523/JNEUROSCI.5924-12.2013
Panza, F., Solfrizzi, V., Imbimbo, B. P., & Logroscino, G. (2014). Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: The point of no return? Expert Opinion on Biological Therapy, 14(10), 1465–1476. https://doi.org/10.1517/14712598.2014.935332
Panza, F., Solfrizzi, V., Imbimbo, B. P., Tortelli, R., Santamato, A., & Logroscino, G. (2014). Amyloid-based immunotherapy for Alzheimer’s disease in the time of prevention trials: The way forward. Expert Review of Clinical Immunology, 10(3), 405–419. https://doi.org/10.1586/1744666X.2014.883921
Behl, T., Kaur, D., Sehgal, A., Singla, R. K., Makeen, H. A., Albratty, M., Alhazmi, H. A., Meraya, A. M., & Bungau, S. (2022). Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease. Frontiers in Pharmacology, 13, 976799. https://doi.org/10.3389/fphar.2022.976799
Huang, X., Zhang, H., Zhen, J., Dong, S., Guo, Y., Van Halm-Lutterodt, N., & Yuan, L. (2018). Diminished circulating retinol and elevated α-TOH/retinol ratio predict an increased risk of cognitive decline in aging Chinese adults, especially in subjects with ApoE2 or ApoE4 genotype. Aging, 10(12), 4066–4083. https://doi.org/10.18632/aging.101694
Touyarot, K., Bonhomme, D., Roux, P., Alfos, S., Lafenêtre, P., Richard, E., Higueret, P., & Pallet, V. (2013). A mid-life vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I. PLoS ONE, 8(8), e72101. https://doi.org/10.1371/journal.pone.0072101
Sahin, M., Karauzum, S. B., Perry, G., Smith, M. A., & Aliciguzel, Y. (2005). Retinoic acid isomers protect hippocampal neurons from amyloid-beta induced neurodegeneration. Neurotoxicity Research, 7(3), 243–250. https://doi.org/10.1007/BF03036453
Husson, M., Enderlin, V., Delacourte, A., Ghenimi, N., Alfos, S., Pallet, V., & Higueret, P. (2006). Retinoic acid normalizes nuclear receptor mediated hypo-expression of proteins involved in beta-amyloid deposits in the cerebral cortex of vitamin A deprived rats. Neurobiology of Disease, 23(1), 1–10. https://doi.org/10.1016/j.nbd.2006.01.008
Goncalves, M. B., Clarke, E., Hobbs, C., Malmqvist, T., Deacon, R., Jack, J., & Corcoran, J. P. (2013). Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by a retinoic acid receptor α agonist. European Journal of Neuroscience, 37(7), 1182–1192. https://doi.org/10.1111/ejn.12142
Tippmann, F., Hundt, J., Schneider, A., Endres, K., & Fahrenholz, F. (2009). Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB Journal, 23(6), 1643–1654. https://doi.org/10.1096/fj.08-121392
Endres, K., Fahrenholz, F., Lotz, J., Hiemke, C., Teipel, S., Lieb, K., Tüscher, O., & Fellgiebel, A. (2014). Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology, 83(21), 1930–1935. https://doi.org/10.1212/WNL.0000000000001017
Holthoewer, D., Endres, K., Schuck, F., Hiemke, C., Schmitt, U., & Fahrenholz, F. (2012). Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein. Neurodegenerative Diseases, 10(1–4), 224–228. https://doi.org/10.1159/000334300
Kobayashi, M., Matsuoka, I., & Kurihara, K. (1994). Cholinergic differentiation of cultured sympathetic neurons induced by retinoic acid: Induction of choline acetyltransferase-mRNA and suppression of tyrosine hydroxylase-mRNA levels. FEBS Letters, 337(3), 259–264. https://doi.org/10.1016/0014-5793(94)80204-1
Goodman, A. B. (2006). Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. Journal of Cellular Physiology, 209(3), 598–603. https://doi.org/10.1002/jcp.20784
Treiber, C., et al. (2004). Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer’s disease. Journal of Biological Chemistry, 279(50), 51958–51964.
Bayer, T. A., Schäfer, S., Simons, A., Kemmling, A., Kamer, T., Tepest, R., Eckert, A., Schüssel, K., Eikenberg, O., Sturchler-Pierrat, C., Abramowski, D., Staufenbiel, M., & Multhaup, G. (2003). Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 100(24), 14187–14192. https://doi.org/10.1073/pnas.2332818100
Maynard, C. J., Cappai, R., Volitakis, I., Cherny, R. A., White, A. R., Beyreuther, K., Masters, C. L., Bush, A. I., & Li, Q. X. (2002). Overexpression of Alzheimer’s disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. Journal of Biological Chemistry, 277(47), 44670–44676. https://doi.org/10.1074/jbc.M204379200
Phinney, A. L., Drisaldi, B., Schmidt, S. D., Lugowski, S., Coronado, V., Liang, Y., Horne, P., Yang, J., Sekoulidis, J., Coomaraswamy, J., Chishti, M. A., Cox, D. W., Mathews, P. M., Nixon, R. A., Carlson, G. A., St George-Hyslop, P., & Westaway, D. (2003). In vivo reduction of amyloid-beta by a mutant copper transporter. Proceedings of the National Academy of Sciences of the United States of America, 100(24), 14193–14198. https://doi.org/10.1073/pnas.2332851100
White, A. R., Reyes, R., Mercer, J. F., Camakaris, J., Zheng, H., Bush, A. I., Multhaup, G., Beyreuther, K., Masters, C. L., & Cappai, R. (1999). Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Research, 842(2), 439–444. https://doi.org/10.1016/S0006-8993(99)01861-2
Squitti, R., Lupoi, D., Pasqualetti, P., Dal Forno, G., Vernieri, F., Chiovenda, P., Rossi, L., Cortesi, M., Cassetta, E., & Rossini, P. M. (2002). Elevation of serum copper levels in Alzheimer’s disease. Neurology, 59(8), 1153–1161. https://doi.org/10.1212/WNL.59.8.1153
Samudralwar, D. L., Diprete, C. C., Ni, B. F., Ehmann, W. D., & Markesbery, W. R. (1995). Elemental imbalances in the olfactory pathway in Alzheimer’s disease. Journal of the Neurological Sciences, 130(2), 139–145. https://doi.org/10.1016/0022-510X(95)00018-W
Thompson, C. M., Markesbery, W. R., Ehmann, W. D., Mao, Y. X., & Vance, D. E. (1988). Regional brain trace-element studies in Alzheimer’s disease. Neurotoxicology, 9(1), 1–7.
Borchardt, T., Camakaris, J., Cappai, R., Masters, C. L., Beyreuther, K., & Multhaup, G. (1999). Copper inhibits beta-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion. Biochemical Journal, 344(Pt 2), 461–467.
Cherny, R. A., Atwood, C. S., Xilinas, M. E., Gray, D. N., Jones, W. D., McLean, C. A., Barnham, K. J., Volitakis, I., Fraser, F. W., Kim, Y., Huang, X., Goldstein, L. E., Moir, R. D., Lim, J. T., Beyreuther, K., Zheng, H., Tanzi, R. E., Masters, C. L., & Bush, A. I. (2001). Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron, 30(3), 665–676. https://doi.org/10.1016/S0896-6273(01)00317-8
Ritchie, C. W., Bush, A. I., Mackinnon, A., Macfarlane, S., Mastwyk, M., MacGregor, L., Kiers, L., Cherny, R., Li, Q. X., Tammer, A., Carrington, D., Mavros, C., Volitakis, I., Xilinas, M., Ames, D., Davis, S., Beyreuther, K., Tanzi, R. E., & Masters, C. L. (2003). Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: A pilot phase 2 clinical trial. Archives of Neurology, 60(12), 1685–1691. https://doi.org/10.1001/archneur.60.12.1685
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., Reichert, M., Ketter, N., Nejadnik, B., Guenzler, V., Miloslavsky, M., Wang, D., Lu, Y., Lull, J., Tudor, I. C., ... Brashear, H. R. (2014). Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. The New England Journal of Medicine, 370(4), 322–333. https://doi.org/10.1056/NEJMoa1304839
Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P. S., Siemers, E., Liu-Seifert, H., Mohs, R., Alzheimer’s Disease Cooperative Study Steering Committee, & Solanezumab Study Group. (2014). Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. The New England Journal of Medicine, 370(4), 311–321. https://doi.org/10.1056/NEJMoa1312889
Tayeb, H. O., Murray, E. D., Price, B. H., & Tarazi, F. I. (2013). Bapineuzumab and solanezumab for Alzheimer’s disease: Is the “amyloid cascade hypothesis” still alive? Expert Opinion on Biological Therapy, 13(7), 1075–1084. https://doi.org/10.1517/14712598.2013.789856
Eli Lilly and Company. (2019). Continued safety monitoring of solanezumab (LY2062430) in Alzheimer’s disease (EXPEDITION EXT) (NCT01127633). ClinicalTrials.gov.
Eli Lilly and Company. (2019). Progress of mild Alzheimer’s disease in participants on solanezumab versus placebo (EXPEDITION 3) (NCT01900665). ClinicalTrials.gov.
Eli Lilly and Company. (2023). Clinical trial of solanezumab for older individuals who may be at risk for memory loss (A4) (NCT02008357). ClinicalTrials.gov.
Washington University School of Medicine. (2026). Dominantly Inherited Alzheimer Network trial: An opportunity to prevent dementia: Master protocol DIAN-TU-001 (DIAN-TU) (NCT01760005). ClinicalTrials.gov.
Novakovic, D., Feligioni, M., Scaccianoce, S., Caruso, A., Piccinin, S., Schepisi, C., Errico, F., Mercuri, N. B., Nicoletti, F., & Nisticò, R. (2013). Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Design, Development and Therapy, 7, 1359–1364. https://doi.org/10.2147/DDDT.S53401
Bohrmann, B., Baumann, K., Benz, J., Gerber, F., Huber, W., Knoflach, F., Messer, J., Oroszlan, K., Rauchenberger, R., Richter, W. F., Rothe, C., Urban, M., Bardroff, M., Winter, M., Nordstedt, C., & Loetscher, H. (2012). Gantenerumab: A novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. Journal of Alzheimer’s Disease, 28(1), 49–69. https://doi.org/10.3233/JAD-2011-110977
Jacobsen, H., Ozmen, L., Caruso, A., Narquizian, R., Hilpert, H., Jacobsen, B., Terwel, D., Tanghe, A., & Bohrmann, B. (2014). Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. Journal of Neuroscience, 34(35), 11621–11630. https://doi.org/10.1523/JNEUROSCI.1405-14.2014
Hoffmann-La Roche. (2023). A study of gantenerumab in participants with mild Alzheimer disease (NCT02051608). ClinicalTrials.gov.
Hoffmann-La Roche. (2021). A study of gantenerumab in participants with prodromal Alzheimer’s disease (Scarlet Road) (NCT01224106). ClinicalTrials.gov.
Jindal, H., Bhatt, B., Sk, S., & Singh Malik, J. (2014). Alzheimer disease immunotherapeutics: Then and now. Human Vaccines & Immunotherapeutics, 10(9), 2741–2743. https://doi.org/10.4161/21645515.2014.970959
Genentech, Inc. (2017). A study to evaluate the efficacy and safety of MABT5102A in patients with mild to moderate Alzheimer’s disease (ABBY) (NCT01343966). ClinicalTrials.gov.
Genentech, Inc. (2024). A study of crenezumab versus placebo in preclinical presenilin1 (PSEN1) E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated non-carrier cohort (NCT01998841). ClinicalTrials.gov.
Baxalta. (2021). A phase 3 study evaluating safety and effectiveness of immune globulin intravenous (IGIV 10%) for the treatment of mild-to-moderate Alzheimer’s disease (NCT00818662). ClinicalTrials.gov.
Dodel, R., Rominger, A., Bartenstein, P., Barkhof, F., Blennow, K., Förster, S., Winter, Y., Bach, J. P., Popp, J., Alferink, J., Wiltfang, J., Buerger, K., Otto, M., Antuono, P., Jacoby, M., Richter, R., Stevens, J., Melamed, I., Goldstein, J., ... Jessen, F. (2013). Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. The Lancet Neurology, 12(3), 233–243. https://doi.org/10.1016/S1474-4422(13)70014-0
Relkin, N. R., Szabo, P., Adamiak, B., Burgut, T., Monthe, C., Lent, R. W., Younkin, S., Younkin, L., Schiff, R., & Weksler, M. E. (2009). 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiology of Aging, 30(11), 1728–1736. https://doi.org/10.1016/j.neurobiolaging.2007.12.021
Szabo, P., Mujalli, D. M., Rotondi, M. L., Sharma, R., Weber, A., Schwarz, H. P., Weksler, M. E., & Relkin, N. (2010). Measurement of anti-beta amyloid antibodies in human blood. Journal of Neuroimmunology, 227(1–2), 167–174. https://doi.org/10.1016/j.jneuroim.2010.06.010
Hey, J. A., Kocis, P., Hort, J., Abushakra, S., Power, A., Vyhnálek, M., Yu, J. Y., & Tolar, M. (2018). Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs, 32(9), 849–861. https://doi.org/10.1007/s40263-018-0554-0
Liang, C., Savinov, S. N., Fejzo, J., Eyles, S. J., & Chen, J. (2019). Modulation of amyloid-β42 conformation by small molecules through nonspecific binding. Journal of Chemical Theory and Computation, 15(10), 5169–5174. https://doi.org/10.1021/acs.jctc.9b00599
Gervais, F., Paquette, J., Morissette, C., Krzywkowski, P., Yu, M., Azzi, M., Lacombe, D., Kong, X., Aman, A., Laurin, J., Szarek, W. A., & Tremblay, P. (2007). Targeting soluble Aβ peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiology of Aging, 28(4), 537–547. https://doi.org/10.1016/j.neurobiolaging.2006.02.015
Hey, J. A., Yu, J. Y., Versavel, M., Abushakra, S., Kocis, P., Power, A., Kaplan, P. L., Amedio, J., & Tolar, M. (2018). Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clinical Pharmacokinetics, 57(3), 315–333. https://doi.org/10.1007/s40262-017-0608-3
Abushakra, S., Porsteinsson, A., Vellas, B., Cummings, J., Gauthier, S., Hey, J. A., Power, A., Hendrix, S., Wang, P., Shen, L., Sampalis, J., & Tolar, M. (2016). Clinical benefits of tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 alleles: The “APOE4 gene-dose effect.” Journal of Prevention of Alzheimer’s Disease, 3(4), 219–228. https://doi.org/10.14283/jpad.2016.115
Abushakra, S., Porsteinsson, A., Scheltens, P., Sadowsky, C., Vellas, B., Cummings, J., Gauthier, S., Hey, J. A., 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. Journal of Prevention of Alzheimer’s Disease, 4(3), 149–156. https://doi.org/10.14283/jpad.2017.26
Cowan, C. M., & Mudher, A. (2013). Are tau aggregates toxic or protective in tauopathies? Frontiers in Neurology, 4, 114. https://doi.org/10.3389/fneur.2013.00114
West, S., & Bhugra, P. (2015). Emerging drug targets for Aβ and tau in Alzheimer’s disease: A systematic review. British Journal of Clinical Pharmacology, 80(2), 221–234. https://doi.org/10.1111/bcp.12621
Shefet-Carasso, L., & Benhar, I. (2015). Antibody-targeted drugs and drug resistance—Challenges and solutions. Drug Resistance Updates, 18, 36–46. https://doi.org/10.1016/j.drup.2014.11.001
Mehta, D. C., Short, J. L., Hilmer, S. N., & Nicolazzo, J. A. (2015). Drug access to the central nervous system in Alzheimer’s disease: Preclinical and clinical insights. Pharmaceutical Research, 32(3), 819–839. https://doi.org/10.1007/s11095-014-1522-0
Berk, C., Paul, G., & Sabbagh, M. (2014). Investigational drugs in Alzheimer’s disease: Current progress. Expert Opinion on Investigational Drugs, 23(6), 837–846. https://doi.org/10.1517/13543784.2014.905542
Hochgräfe, K., Sydow, A., Matenia, D., Cadinu, D., Könen, S., Petrova, O., Pickhardt, M., Goll, P., Morellini, F., Mandelkow, E., & Mandelkow, E. M. (2015). Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathologica Communications, 3, 25. https://doi.org/10.1186/s40478-015-0204-4
Grüninger, F. (2015). Invited review: Drug development for tauopathies. Neuropathology and Applied Neurobiology, 41(1), 81–96. https://doi.org/10.1111/nan.12192
Iqbal, K., Gong, C. X., & Liu, F. (2014). Microtubule-associated protein tau as a therapeutic target in Alzheimer’s disease. Expert Opinion on Therapeutic Targets, 18(3), 307–318. https://doi.org/10.1517/14728222.2014.870156
Gourmaud, S., Paquet, C., Dumurgier, J., Pace, C., Bouras, C., Gray, F., Laplanche, J. L., Meurs, E. F., Mouton-Liger, F., & Hugon, J. (2015). Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: Links to cognitive decline. Journal of Psychiatry & Neuroscience, 40(3), 151–161. https://doi.org/10.1503/jpn.140062
Yoon, S. O., Park, D. J., Ryu, J. C., Ozer, H. G., Tep, C., Shin, Y. J., Lim, T. H., Pastorino, L., Kunwar, A. J., Walton, J. C., Nagahara, A. H., Lu, K. P., Nelson, R. J., Tuszynski, M. H., & Huang, K. (2012). JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron, 75(5), 824–837. https://doi.org/10.1016/j.neuron.2012.06.024
Kimura, T., Ishiguro, K., & Hisanaga, S. I. (2014). Physiological and pathological phosphorylation of tau by Cdk5. Frontiers in Molecular Neuroscience, 7, 65. https://doi.org/10.3389/fnmol.2014.00065
Zhou, Q., Wang, M., Du, Y., Zhang, W., Bai, M., Zhang, Z., Li, Z., & Miao, J. (2015). Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice. Annals of Neurology, 77(4), 637–654. https://doi.org/10.1002/ana.24361
Resnick, L., & Fennell, M. (2004). Targeting JNK3 for the treatment of neurodegenerative disorders. Drug Discovery Today, 9(21), 932–939. https://doi.org/10.1016/S1359-6446(04)03251-9
Shukla, V., Skuntz, S., & Pant, H. C. (2012). Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Archives of Medical Research, 43(8), 655–662. https://doi.org/10.1016/j.arcmed.2012.10.015
Camins, A., Verdaguer, E., Folch, J., Canudas, A. M., & Pallàs, M. (2006). The role of CDK5/P25 formation/inhibition in neurodegeneration. Drug News & Perspectives, 19(8), 453–460. https://doi.org/10.1358/dnp.2006.19.8.1043961
de la Torre, A. V., Junyent, F., Folch, J., Pelegrí, C., Vilaplana, J., Auladell, C., Beas-Zarate, C., Pallàs, M., Verdaguer, E., & Camins, A. (2012). GSK3β inhibition is involved in the neuroprotective effects of cyclin-dependent kinase inhibitors in neurons. Pharmacological Research, 65(1), 66–73. https://doi.org/10.1016/j.phrs.2011.08.006
Jorda, E. G., Verdaguer, E., Canudas, A. M., Jiménez, A., Bruna, A., Caelles, C., Bravo, R., Escubedo, E., Pubill, D., Camarasa, J., Pallàs, M., & Camins, A. (2003). Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Neuropharmacology, 45(5), 672–683. https://doi.org/10.1016/S0028-3908(03)00204-1
Noscira SA. (2012). Efficacy, safety and tolerability of tideglusib to treat mild-to-moderate Alzheimer’s disease patients (ARGO) (NCT01350362). ClinicalTrials.gov.
Noscira SA. (2009). Safety study of a glycogen synthase kinase 3 (GSK3) inhibitor in patients with Alzheimer’s disease (NCT00948259). ClinicalTrials.gov.
Velacor Therapeutic. (2011). A phase IIa clinical trial of VEL015 (sodium selenate) in mild to moderate Alzheimer’s disease (ACTRN12611001200976).
Lovestone, S., Boada, M., Dubois, B., Hüll, M., Rinne, J. O., Huppertz, H. J., Calero, M., Andrés, M. V., Gómez-Carrillo, B., León, T., del Ser, T., & ARGO Investigators. (2015). A phase II trial of tideglusib in Alzheimer’s disease. Journal of Alzheimer’s Disease, 45(1), 75–88. https://doi.org/10.3233/JAD-141959
Corcoran, N. M., Martin, D., Hutter-Paier, B., Windisch, M., Nguyen, T., Nheu, L., Sundstrom, L. E., Costello, A. J., & Hovens, C. M. (2010). Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model. Journal of Clinical Neuroscience, 17(8), 1025–1033. https://doi.org/10.1016/j.jocn.2010.04.020
van Eersel, J., Ke, Y. D., Liu, X., Delerue, F., Kril, J. J., Götz, J., & Ittner, L. M. (2010). Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proceedings of the National Academy of Sciences of the United States of America, 107(31), 13888–13893. https://doi.org/10.1073/pnas.1009038107
Baddeley, T. C., McCaffrey, J., Storey, J. M., Cheung, J. K., Melis, V., Horsley, D., Harrington, C. R., & Wischik, C. M. (2015). Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. Journal of Pharmacology and Experimental Therapeutics, 352(1), 110–118. https://doi.org/10.1124/jpet.114.219352
TauRx Therapeutics Ltd. (2014). Study of TRx0237 in patients already taking medications for mild and moderate Alzheimer’s disease (NCT01626391). ClinicalTrials.gov.
TauRx Therapeutics Ltd. (2018). Safety and efficacy study evaluating TRx0237 in subjects with mild Alzheimer’s disease (NCT01689233). ClinicalTrials.gov.
TauRx Therapeutics Ltd. (2018). Safety and efficacy study evaluating TRx0237 in subjects with mild to moderate Alzheimer’s disease (NCT01689246). ClinicalTrials.gov.
TauRx Therapeutics Ltd. (2018). Safety and efficacy study evaluating TRx0237 in subjects with behavioral variant frontotemporal dementia (bvFTD) (NCT01626378). ClinicalTrials.gov.
Wischik, C. M., Staff, R. T., Wischik, D. J., Bentham, P., Murray, A. D., Storey, J. M., Kook, K. A., & Harrington, C. R. (2015). Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer’s disease. Journal of Alzheimer’s Disease, 44(2), 705–720. https://doi.org/10.3233/JAD-142874
Shemesh, O. A., & Spira, M. E. (2011). Rescue of neurons from undergoing hallmark tau-induced Alzheimer’s disease cell pathologies by the antimitotic drug paclitaxel. Neurobiology of Disease, 43(1), 163–175. https://doi.org/10.1016/j.nbd.2011.03.008
University of California, San Francisco. (2020). A safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy study of TPI-287 in Alzheimer’s disease (NCT01966666). ClinicalTrials.gov.
Zhang, B., Carroll, J., Trojanowski, J. Q., Yao, Y., Iba, M., Potuzak, J. S., Hogan, A. M., Xie, S. X., Ballatore, C., Smith, A. B., III, Lee, V. M., & Brunden, K. R. (2012). The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. Journal of Neuroscience, 32(11), 3601–3611. https://doi.org/10.1523/JNEUROSCI.4922-11.2012
Wisniewski, T., & Goñi, F. (2015). Immunotherapeutic approaches for Alzheimer’s disease. Neuron, 85(6), 1162–1176. https://doi.org/10.1016/j.neuron.2014.12.064
Axon Neuroscience SE. (2015). Safety study of AADvac1, a tau peptide-KLH-conjugate active vaccine to treat Alzheimer’s disease (NCT01850238). ClinicalTrials.gov.
Axon Neuroscience SE. (2017). 18-month safety follow-up study of AADvac1, an active tau vaccine for Alzheimer’s disease (FUNDAMANT) (NCT02031198). ClinicalTrials.gov.
Konishi, K., Hori, K., Tani, M., Tomioka, H., Kitajima, Y., Akashi, N., Inamoto, A., Kurosawa, K., Yuda, H., Hanashi, T., Ouchi, H., Hosoi, M., & Hachisu, M. (2015). Hypothesis of endogenous anticholinergic activity in Alzheimer’s disease. Neurodegenerative Diseases, 15(3), 149–156. https://doi.org/10.1159/000381511
Wallace, T. L., & Bertrand, D. (2013). Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. Biochemical Pharmacology, 85(12), 1713–1720. https://doi.org/10.1016/j.bcp.2013.04.001
Weinreb, O., Amit, T., Bar-Am, O., & Youdim, M. B. (2012). Ladostigil: A novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Current Drug Targets, 13(4), 483–494. https://doi.org/10.2174/138945012799499794
Weinreb, O., Amit, T., Bar-Am, O., & Youdim, M. B. (2011). A novel anti-Alzheimer’s disease drug, ladostigil: Neuroprotective, multimodal brain-selective monoamine oxidase and cholinesterase inhibitor. International Review of Neurobiology, 100, 191–215. https://doi.org/10.1016/B978-0-12-386467-3.00010-8
Avraham Pharmaceuticals Ltd. (2017). A 3 year study to evaluate the safety and efficacy of low dose ladostigil in patients with mild cognitive impairment (NCT01429623). ClinicalTrials.gov.
Avraham Pharmaceuticals Ltd. (2020). Safety and efficacy study of ladostigil in mild to moderate probable Alzheimer’s disease (NCT01354691). ClinicalTrials.gov.
Shirazi, S. K., & Wood, J. G. (1993). The protein tyrosine kinase, fyn, in Alzheimer’s disease pathology. NeuroReport, 4(4), 435–437. https://doi.org/10.1097/00001756-199304000-00024
Cochran, J. N., Hall, A. M., & Roberson, E. D. (2014). The dendritic hypothesis for Alzheimer’s disease pathophysiology. Brain Research Bulletin, 103, 18–28. https://doi.org/10.1016/j.brainresbull.2013.12.004
Nygaard, H. B., van Dyck, C. H., & Strittmatter, S. M. (2014). Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimer’s Research & Therapy, 6(1), 8. https://doi.org/10.1186/alzrt238
Strittmatter, S. M. (2021). Safety and tolerability of AZD0530 (saracatinib) in Alzheimer’s disease (NCT01864655). ClinicalTrials.gov.
Yale University. (2019). A phase IIa multi-center study of 18F-FDG PET, safety, and tolerability of AZD0530 in mild Alzheimer’s disease (NCT02167256). ClinicalTrials.gov.
AB Science. (2018). Activity of masitinib (AB1010) in mild to moderate Alzheimer’s disease (NCT00976118). ClinicalTrials.gov.
AB Science. (2023). Masitinib in patients with mild to moderate Alzheimer’s disease (NCT01872598). ClinicalTrials.gov.
Yang, K., Belrose, J., Trepanier, C. H., Lei, G., Jackson, M. F., & MacDonald, J. F. (2011). Fyn, a potential target for Alzheimer’s disease. Journal of Alzheimer’s Disease, 27(2), 243–252. https://doi.org/10.3233/JAD-2011-110353
Folch, J., Petrov, D., Ettcheto, M., Pedrós, I., Abad, S., Beas-Zarate, C., Lazarowski, A., Marin, M., Olloquequi, J., Auladell, C., & Camins, A. (2015). Masitinib for the treatment of mild to moderate Alzheimer’s disease. Expert Review of Neurotherapeutics, 15(6), 587–596. https://doi.org/10.1586/14737175.2015.1045419
Piette, F., Belmin, J., Vincent, H., Schmidt, N., Pariel, S., Verny, M., Marquis, C., Mely, J., Hugonot-Diener, L., Kinet, J.-P., Dubreuil, P., Moussy, A., & Hermine, O. (2011). Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: A randomised, placebo-controlled phase 2 trial. Alzheimer’s Research & Therapy, 3, 16. https://doi.org/10.1186/alzrt75
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