AccScience Publishing / IMO / Online First / DOI: 10.36922/IMO025050007
Submit to IMO
Cite this article
11
Download
751
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
REVIEW ARTICLE

Neuroinflammation and progress in clinical trials for the treatment of Alzheimer’s disease and related dementias: An update

Asem Surindro Singh1* ,  Afsar Raza Naqvi2 ,  Machathoibi Takhellambam Chanu3*
Show Less
1 Department of Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
2 Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, Illinois, United States of America
3 Department of Biotechnology, School of Life Sciences, Manipur University, Imphal, Manipur, India
IMO, 025050007 https://doi.org/10.36922/IMO025050007
Submitted: 27 January 2025 | Revised: 24 February 2025 | Accepted: 10 March 2025 | Published: 28 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
Cite
XML
Abstract

According to the latest report in 2024 by the World Health Organization, based on global data from 2021, Alzheimer’s disease (AD) and other forms of dementia rank seventh among the leading causes of death worldwide, with an estimated 1.8 million deaths. This alarming number underscores the urgent requirement for effective treatments. AD and other dementias also severely affect the global economy. Unfortunately, no cure has been found, and effective treatments remain limited. Over the past two decades, thousands of disease-modifying drugs have been developed for AD treatment. However, most have failed to progress beyond phase I clinical trials, with only a few reaching phase III. To date, lecanemab (sold under the brand name Leqembi) is the only drug to receive full approval from the United States Food and Drug Administration for slowing AD progression. This drug is specifically designed to target and clear amyloid-beta (Aβ) plaques. Apart from targeting Aβ aggregation and tau tangles, neuroinflammatory regulatory pathways have emerged as promising therapeutic targets. With advancing research, neuroinflammation has been considered one of the core characteristics of AD and the third major pathological hallmark of the disease after Aβ plaques and neurofibrillary tau tangles. In this review, we summarize key research findings in neuroinflammatory regulation of AD and related dementias that are promising for treatments. We also provide an overview of clinical trials targeting the immune system or neuroinflammatory regulatory pathways, analyzing their challenges and potential successes.

Keywords
Alzheimer’s disease and related dementias
Immune system dysregulation
Neuroinflammation
Amyloid-beta plaques
Tau tangles
Clinical trials
Funding
None.
Conflict of interest
Asem Surindro Singh and Machathoibi Takhellambam Chanu are the guest editors of this special issue but were not in any way involved in the editorial and peer-review processes conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
References
  1. 2024 Alzheimer’s disease facts and figures. Alzheimers Dement. 2024;20:3708-3821. doi: 10.1002/alz.13809

 

  1. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19:1598-1695. doi: 10.1002/alz.13016

 

  1. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol. 2009;66:200-208. doi: 10.1002/ana.21706

 

  1. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69:2197-2204. doi: 10.1212/01.wnl.0000271090.28148.24

 

  1. Kawas CH, Kim RC, Sonnen JA, Bullain SS, Trieu T, Corrada MM. Multiple pathologies are common and related to dementia in the oldest-old: The 90+ study. Neurology. 2015;85:535-542. doi: 10.1212/WNL.0000000000001831

 

  1. Singh AS, Chanu MT. Alzheimer’s disease and Aβ pathways. World J Adv Res Rev. 2021;12:542-544. doi: 10.30574/wjarr.2021.12.3.0740

 

  1. Li X, Feng X, Sun X, Hou N, Han F, Liu Y. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2019. Front Aging Neurosci. 2022;14:937486. doi: 10.3389/fnagi.2022.937486

 

  1. Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement. 2021;17:1966-1975. doi: 10.1002/alz.12362

 

  1. Singh AS, Chanu MT. Alzheimer’s disease and related dementia drug trials, failures and progress: Data update 2024. Preprint. 2024. doi: 10.20944/preprints202412.2518.v1

 

  1. Singh AS, Chanu MT. Epigenetic regulation of neuroinflammation leading to dementia of Alzheimer’s disease and other forms of dementias. Preprint. 2024. doi: 10.20944/preprints202412.2476.v1

 

  1. Singh AS, Chanu MT. Microglial, Astrocytic, oligodendrocytic, T-Cell and B-cell inflammatory pathways underlying cognitive impairment in Alzheimer’s disease and related dementias. Preprint. 2024. doi: 10.20944/preprints202412.2427.v1

 

  1. Friedman EM, Shih RA, Langa KM, Hurd MD. US prevalence and predictors of informal caregiving for dementia. Health Aff (Millwood). 2015;34:1637-1641. doi: 10.1377/hlthaff.2015.0510

 

  1. Jutkowitz E, Kane RL, Gaugler JE, MacLehose RF, Dowd B, Kuntz KM. Societal and family lifetime cost of dementia: Implications for policy. J Am Geriatr Soc. 2017;65:2169-2175. doi: 10.1111/jgs.15043

 

  1. Tatulian SA. Challenges and hopes for Alzheimer’s disease. Drug Discov Today. 2022;27:1027-1043. doi: 10.1016/j.drudis.2022.01.016

 

  1. Dokholyan NV, Mohs RC, Bateman RJ. Challenges and progress in research, diagnostics, and therapeutics in Alzheimer’s disease and related dementias. Alzheimers Dement (N Y). 2022;8:e12330. doi: 10.1002/trc2.12330

 

  1. Frozza RL, Lourenco MV, De Felice FG. Challenges for Alzheimer’s disease therapy: Insights from Novel mechanisms beyond memory defects. Front Neurosci. 2018;12:37. doi: 10.3389/fnins.2018.00037

 

  1. Huang LK, Kuan YC, Lin HW, Hu CJ. Clinical trials of new drugs for Alzheimer disease: A 2020-2023 update. J Biomed Sci. 2023;30:83. doi: 10.1186/s12929-023-00976-6

 

  1. Ahmad MA, Kareem O, Khushtar M, et al. Neuroinflammation: A potential risk for dementia. Int J Mol Sci. 2022;23:616. doi: 10.3390/ijms23020616

 

  1. Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388-405. doi: 10.1016/S1474-4422(15)70016-5

 

  1. Lecca D, Jung YJ, Scerba MT, et al. Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis. Alzheimers Dement. 2022;18:2327-2340. doi: 10.1002/alz.12610

 

  1. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here? Nat Rev Neurol. 2021;17:157-172. doi: 10.1038/s41582-020-00435-y

 

  1. Lopez-Rodriguez AB, Hennessy E, Murray CL, et al. Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement. 2021;17:1735-1755. doi: 10.1002/alz.12341

 

  1. Sobue A, Komine O, Yamanaka K. Neuroinflammation in Alzheimer’s disease: Microglial signature and their relevance to disease. Inflamm Regen. 2023;43:26. doi: 10.1186/s41232-023-00277-3

 

  1. Bettcher BM, Tansey MG, Dorothee G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus. Nat Rev Neurol. 2021;17:689-701. doi: 10.1038/s41582-021-00549-x

 

  1. Katsel P, Haroutunian V. Is Alzheimer disease a failure of mobilizing immune defense? Lessons from cognitively fit oldest-old. Dialogues Clin Neurosci. 2019;21:7-19. doi: 10.31887/DCNS.2019.21.1/vharoutunian

 

  1. Xiao D, Zhang C. Current therapeutics for Alzheimer’s disease and clinical trials. Explor Neurosci. 2024;3:255-271. doi: 10.37349/en.2024.00048

 

  1. Adamu A, Li S, Gao F, Xue G. The role of neuroinflammation in neurodegenerative diseases: Current understanding and future therapeutic targets. Front Aging Neurosci. 2024;16:1347987. doi: 10.3389/fnagi.2024.1347987

 

  1. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:575-590. doi: 10.1016/j.trci.2018.06.014

 

  1. McGeer PL, Rogers J. Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology. 1992;42:447-449. doi: 10.1212/wnl.42.2.447

 

  1. Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer’s disease: Relevance to pathogenesis and therapy. Alzheimers Res Ther. 2010;2:1. doi: 10.1186/alzrt24

 

  1. Gassowska-Dobrowolska M, Chlubek M, Kolasa A, et al. Microglia and astroglia-the potential role in neuroinflammation induced by pre- and neonatal exposure to lead (Pb). Int J Mol Sci. 2023;24:9903. doi: 10.3390/ijms24129903

 

  1. Liddelow SA, Barres BA. Reactive astrocytes: Production, function, and therapeutic potential. Immunity. 2017;46:957-967. doi: 10.1016/j.immuni.2017.06.006

 

  1. Wang YW, Zhou Q, Zhang X, et al. Correction to: Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization. J Neuroinflammation. 2020;17:353. doi: 10.1186/s12974-020-01990-3

 

  1. Kumar A. Editorial: Neuroinflammation and cognition. Front Aging Neurosci. 2018;10:413. doi: 10.3389/fnagi.2018.00413

 

  1. Amin J, Gee C, Stowell K, Coulthard D, Boche D. T Lymphocytes and their potential role in dementia with lewy bodies. Cells. 2023;12:2253. doi: 10.3390/cells12182283

 

  1. Chen N, Caruso C, Alonso A, et al. Association of sickle cell trait with measures of cognitive function and dementia in African Americans. eNeurologicalSci. 2019;16:100201. doi: 10.1016/j.ensci.2019.100201

 

  1. Cheng S, Hou J, Zhang C, et al. Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. Sci Rep. 2015;5:10535. doi: 10.1038/srep10535

 

  1. Hosoki S, Hansra GK, Jayasena T, et al. Molecular biomarkers for vascular cognitive impairment and dementia. Nat Rev Neurol. 2023;19:737-753. doi: 10.1038/s41582-023-00884-1

 

  1. Bir SC, Khan MW, Javalkar V, Toledo EG, Kelley RE. Emerging concepts in vascular dementia: A review. J Stroke Cerebrovasc Dis. 2021;30:105864. doi: 10.1016/j.jstrokecerebrovasdis.2021.105864

 

  1. Litke R, Garcharna LC, Jiwani S, Neugroschl J. Modifiable risk factors in Alzheimer disease and related dementias: A review. Clin Ther. 2021;43:953-965. doi: 10.1016/j.clinthera.2021.05.006

 

  1. Wu KM, Zhang YR, Huang YY, Dong Q, Tan L, Yu JT. The role of the immune system in Alzheimer’s disease. Ageing Res Rev. 2021;70:101409. doi: 10.1016/j.arr.2021.101409

 

  1. Tamburini B, Badami GD, La Manna MP, Shekarkar Azgomi M, Caccamo N, Dieli F. Emerging roles of cells and molecules of innate immunity in Alzheimer’s disease. Int J Mol Sci. 2023;24:11922. doi: 10.3390/ijms241511922

 

  1. Femminella GD, Dani M, Wood M, et al. Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume. Neurology. 2019;92:e1331-e1343. doi: 10.1212/WNL.0000000000007133

 

  1. Dani M, Wood M, Mizoguchi R, et al. Tau aggregation correlates with amyloid deposition in both mild cognitive impairment and Alzheimer’s disease subjects. J Alzheimers Dis. 2019;70:455-465. doi: 10.3233/JAD-181168

 

  1. Hamelin L, Lagarde J, Dorothee G, et al. Early and protective microglial activation in Alzheimer’s disease: A prospective study using 18F-DPA-714 PET imaging. Brain. 2016;139:1252-1264. doi: 10.1093/brain/aww017

 

  1. Kreisl WC, Henter ID, Innis RB. Imaging translocator protein as a biomarker of neuroinflammation in dementia. Adv Pharmacol. 2018;82:163-185. doi: 10.1016/bs.apha.2017.08.004

 

  1. Kreisl WC, Lyoo CH, Liow JS, et al. (11)C-PBR28 binding to translocator protein increases with progression of Alzheimer’s disease. Neurobiol Aging. 2016;44:53-61. doi: 10.1016/j.neurobiolaging.2016.04.01

 

  1. Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer’s disease. Neurobiol Aging. 1988;9:339-349. doi: 10.1016/s0197-4580(88)80079-4

 

  1. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151-170. doi: 10.1016/0306-4522(90)90229-w

 

  1. Stowe AM, Ireland SJ, Ortega SB, et al. Adaptive lymphocyte profiles correlate to brain Aβ burden in patients with mild cognitive impairment. J Neuroinflammation. 2017;14:149. doi: 10.1186/s12974-017-0910-x

 

  1. Liu Y, He X, Li Y, Wang T. Cerebrospinal fluid CD4+ T lymphocyte-derived miRNA-let-7b can enhances the diagnostic performance of Alzheimer’s disease biomarkers. Biochem Biophys Res Commun. 2018;495:1144-1150. doi: 10.1016/j.bbrc.2017.11.122

 

  1. Lueg G, Gross CC, Lohmann H, et al. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer’s disease. Neurobiol Aging. 2015;36:81-89. doi: 10.1016/j.neurobiolaging.2014.08.008

 

  1. Saresella M, Calabrese E, Marventano I, et al. Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer’s disease. Brain Behav Immun. 2011;25:539-547. doi: 10.1016/j.bbi.2010.12.004

 

  1. Kim CK, Lee YR, Ong L, Gold M, Kalali A, Sarkar J. Alzheimer’s disease: Key insights from two decades of clinical trial failures. J Alzheimers Dis. 2022;87:83-100. doi: 10.3233/JAD-215699

 

  1. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37. doi: 10.1186/alzrt269

 

  1. Murphy MP, LeVine H 3rd. Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis. 2010;19:311-323. doi: 10.3233/JAD-2010-1221

 

  1. Kim J, Jeon H, Yun Kim H, Kim Y. Failure, success, and future direction of alzheimer drugs targeting amyloid-β cascade: Pros and cons of chemical and biological modalities. Chembiochem. 2023;24:e202300328. doi: 10.1002/cbic.202300328

 

  1. Lu J, Pan Q, Zhou J, Weng Y, et al. Pharmacokinetics, distribution, and excretion of sodium oligomannate, a recently approved anti-Alzheimer’s disease drug in China. J Pharm Anal. 2022;12:145-155. doi: 10.1016/j.jpha.2021.06.001

 

  1. Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers. 2015;1:15056. doi: 10.1038/nrdp.2015.56

 

  1. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595-608. doi: 10.15252/emmm.201606210

 

  1. Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front Neurosci. 2018;12:25. doi: 10.3389/fnins.2018.00025

 

  1. Tzioras M, Davies C, Newman A, Jackson R, Spires-Jones T. Invited review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer’s disease. Neuropathol Appl Neurobiol. 2019;45:327-346. doi: 10.1111/nan.12529

 

  1. Xue-Shan Z, Juan P, Qi W, et al. Imbalanced cholesterol metabolism in Alzheimer’s disease. Clin Chim Acta. 2016;456:107-114. doi: 10.1016/j.cca.2016.02.024

 

  1. Calsolaro V, Edison P. Alterations in glucose metabolism in Alzheimer’s disease. Recent Pat Endocr Metab Immune Drug Discov. 2016;10:31-39. doi: 10.2174/1872214810666160615102809

 

  1. Ninomiya T. Epidemiological evidence of the relationship between diabetes and dementia. Adv Exp Med Biol. 2019;1128:13-25. doi: 10.1007/978-981-13-3540-2_2

 

  1. Shieh JC, Huang PT, Lin YF. Alzheimer’s disease and diabetes: Insulin signaling as the bridge linking two pathologies. Mol Neurobiol. 2020;57:1966-1977. doi: 10.1007/s12035-019-01858-5

 

  1. Arvanitakis Z, Tatavarthy M, Bennett DA. The relation of diabetes to memory function. Curr Neurol Neurosci Rep. 2020;20:64. doi: 10.1007/s11910-020-01085-9

 

  1. Gabin JM, Tambs K, Saltvedt I, Sund E, Holmen J. Association between blood pressure and Alzheimer disease measured up to 27 years prior to diagnosis: The HUNT Study. Alzheimers Res Ther. 2017;9:37. doi: 10.1186/s13195-017-0262-x

 

  1. Nunomura A, Perry G. RNA and oxidative stress in Alzheimer’s disease: Focus on microRNAs. Oxid Med Cell Longev. 2020;2020:2638130. doi: 10.1155/2020/2638130

 

  1. Palmer AM. Neuroprotective therapeutics for Alzheimer’s disease: Progress and prospects. Trends Pharmacol Sci. 2011;32:141-147. doi: 10.1016/j.tips.2010.12.007

 

  1. Tonnies E, Trushina E. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis. 2017;57:1105-1121. doi: 10.3233/JAD-161088

 

  1. Choi SH, Tanzi RE. Is Alzheimer’s disease a neurogenesis disorder? Cell Stem Cell. 2019;25:7-8. doi: 10.1016/j.stem.2019.06.001

 

  1. Sampaio TB, Savall AS, Gutierrez MEZ, Pinton S. Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: Implications for pathogenesis and therapy. Neural Regen Res. 2017;12:549-557. doi: 10.4103/1673-5374.205084

 

  1. Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res. 2017;95:671-680. doi: 10.1002/jnr.23827

 

  1. Gold M. Phase II clinical trials of anti-amyloid β antibodies: When is enough, enough? Alzheimers Dement (N Y). 2017;3:402-409. doi: 10.1016/j.trci.2017.04.005

 

  1. Henley D, Raghavan N, Sperling R, Aisen P, Raman R, Romano G. Preliminary results of a trial of atabecestat in preclinical Alzheimer’s disease. N Engl J Med. 2019;380:1483-1485. doi: 10.1056/NEJMc1813435

 

  1. Lilly E. Lilly Announces Topline Results for Solanezumab from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Study. 2020.

 

  1. Cummings J. Lessons learned from Alzheimer disease: Clinical trials with negative outcomes. Clin Transl Sci. 2018;11:147-152. doi: 10.1111/cts.12491

 

  1. Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs. 2017;26:735-739. doi: 10.1080/13543784.2017.1323868

 

  1. Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8:6412. doi: 10.1038/s41598-018-24501-0

 

  1. Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50-56. doi: 10.1038/nature19323

 

  1. Tampi RR, Forester BP, Agronin M. Aducanumab: Evidence from clinical trial data and controversies. Drugs Context. 2021;10. doi: 10.7573/dic.2021-7-3

 

  1. Bayer TA. Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease. Mol Psychiatry. 2022;27:1880-1885. doi: 10.1038/s41380-021-01409-2

 

  1. Irizarry MC, Sims JR, Lowe SL, et al. Safety, Pharmacokinetics (PK), and Florbetapir F-18 Positron Emission Tomography (PET) after multiple dose administration of LY3002813, A β-amyloid plaque-specific antibody, in Alzheimer’s Disease (AD). Alzheimers Dement. 2016;12:P352-P353. doi: 10.1016/j.jalz.2016.06.665

 

  1. Bouter Y, Liekefeld H, Pichlo S, et al. Donanemab detects a minor fraction of amyloid-β plaques in post-mortem brain tissue of patients with Alzheimer’s disease and Down syndrome. Acta Neuropathol. 2022;143:601-603. doi: 10.1007/s00401-022-02418-3

 

  1. Shcherbinin S, Evans CD, Lu M, et al. Association of amyloid reduction after donanemab treatment with tau pathology and clinical outcomes: The TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. 2022;79:1015-1024. doi: 10.1001/jamaneurol.2022.2793

 

  1. Pontecorvo MJ, Lu M, Burnham SC, 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;79:1250-1259. doi: 10.1001/jamaneurol.2022.3392

 

  1. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384:1691-1704. doi: 10.1056/NEJMoa2100708

 

  1. Doggrell SA. Still grasping at straws: Donanemab in Alzheimer’s disease. Expert Opin Investig Drugs. 2021;30:797-801. doi: 10.1080/13543784.2021.1948010

 

  1. US Food and Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval-action Follows Confrmatory Trial to Verify Clinical Benefit. Maryland: US Food and Drug Administration; 2023.

 

  1. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021;13:80. doi: 10.1186/s13195-021-00813-8

 

  1. Tucker S, Moller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43:575-588. doi: 10.3233/JAD-140741

 

  1. Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9-21. doi: 10.1056/NEJMoa2212948

 

  1. Green RC, Schneider LS, Amato DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA. 2009;302:2557-2564. doi: 10.1001/jama.2009.1866

 

  1. Valera E, Spencer B, Fields JA, et al. Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun. 2017;5:2. doi: 10.1186/s40478-016-0409-1

 

  1. Decourt B, Drumm-Gurnee D, Wilson J, et al. Poor safety and tolerability hamper reaching a potentially therapeutic dose in the use of thalidomide for Alzheimer’s disease: Results from a double-blind, placebo-controlled trial. Curr Alzheimer Res. 2017;14:403-411. doi: 10.2174/1567205014666170117141330

 

  1. Rishton GM, Look GC, Ni ZJ, et al. Discovery of investigational drug CT1812, an antagonist of the sigma-2 receptor complex for Alzheimer’s disease. ACS Med Chem Lett. 2021;12:1389-1395. doi: 10.1021/acsmedchemlett.1c00048

 

  1. Grundman M, Morgan R, Lickliter JD, et al. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y). 2019;5:20-26. doi: 10.1016/j.trci.2018.11.001

 

  1. Hamilton A, Vasefi M, Vander Tuin C, McQuaid RJ, Anisman H, Ferguson SS. Chronic pharmacological mGluR5 inhibition prevents cognitive impairment and reduces pathogenesis in an Alzheimer disease mouse model. Cell Rep. 2016;15:1859-1865. doi: 10.1016/j.celrep.2016.04.077

 

  1. Haas LT, Salazar SV, Smith LM, et al. Silent allosteric modulation of mGluR5 maintains glutamate signaling while rescuing Alzheimer’s mouse phenotypes. Cell Rep. 2017;20:76-88. doi: 10.1016/j.celrep.2017.06.023

 

  1. Fang C, Hernandez P, Liow K, et al. Buntanetap, a novel translational inhibitor of multiple neurotoxic proteins, proves to be safe and promising in both Alzheimer’s and Parkinson’s patients. J Prev Alzheimers Dis. 2023;10:25-33. doi: 10.14283/jpad.2022.84

 

  1. Lahiri DK, Chen D, Maloney B, et al. The experimental Alzheimer’s disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther. 2007;320:386-396. doi: 10.1124/jpet.106.112102

 

  1. Vossel K, Ranasinghe KG, Beagle AJ, et al. Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity: A randomized clinical trial. JAMA Neurol. 2021;78:1345-1354. doi: 10.1001/jamaneurol.2021.3310

 

  1. Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 2010;17:461-466. doi: 10.1016/j.yebeh.2010.01.015

 

  1. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70:440-448. doi: 10.1212/01.WNL.0000265401.62434.36

 

  1. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch Neurol. 2012;69:29-38. doi: 10.1001/archneurol.2011.233

 

  1. Chapman CD, Schioth HB, Grillo CA, Benedict C. Intranasal insulin in Alzheimer’s disease: Food for thought. Neuropharmacology. 2018;136:196-201. doi: 10.1016/j.neuropharm.2017.11.037

 

  1. Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH. PTI- 125 binds and reverses an altered conformation of filamin A to reduce Alzheimer’s disease pathogenesis. Neurobiol Aging. 2017;55:99-114. doi: 10.1016/j.neurobiolaging.2017.03.016

 

  1. Wang HY, Pei Z, Lee KC, et al. PTI-125 reduces biomarkers of Alzheimer’s disease in patients. J Prev Alzheimers Dis. 2020;7:256-264. doi: 10.14283/jpad.2020.6

 

  1. Hoffmann T, Rahfeld JU, Schenk M, et al. Combination of the glutaminyl cyclase inhibitor PQ912 (Varoglutamstat) and the murine monoclonal antibody PBD-C06 (m6) shows additive effects on brain Aβ pathology in transgenic Mice. Int J Mol Sci. 2021;22:11791. doi: 10.3390/ijms222111791

 

  1. Vijverberg EGB, Axelsen TM, Bihlet AR, et al. Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD. Alzheimers Res Ther. 2021;13:142. doi: 10.1186/s13195-021-00882-9

 

  1. Ahn JE, Carrieri C, Dela Cruz F, et al. Pharmacokinetic and pharmacodynamic effects of a γ-secretase modulator, PF-06648671, on CSF Amyloid-β peptides in randomized phase I studies. Clin Pharmacol Ther. 2020;107:211-220. doi: 10.1002/cpt.1570

 

  1. Imbimbo BP, Frigerio E, Breda M, et al. Pharmacokinetics and pharmacodynamics of CHF5074 after short-term administration in healthy subjects. Alzheimer Dis Assoc Disord. 2013;27:278-286. doi: 10.1097/WAD.0b013e3182622ace

 

  1. Villemagne VL, Rowe CC, Barnham KJ, et al. A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer’s disease: The PBT2-204 IMAGINE study. Alzheimers Dement (N Y). 2017;3:622-635. doi: 10.1016/j.trci.2017.10.001

 

  1. Kutzsche J, Jurgens D, Willuweit A, et al. Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020;6:e12001. doi: 10.1002/trc2.12001

 

  1. Holthoewer D, Endres K, Schuck F, Hiemke C, Schmitt U, Fahrenholz F. Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein. Neurodegener Dis. 2012;10:224-228. doi: 10.1159/000334300

 

  1. Endres K, Fahrenholz F, Lotz J, et al. Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology. 2014;83:1930-1935. doi: 10.1212/WNL.0000000000001017

 

  1. O’Hare E, Jeggo R, Kim EM, et al. Lack of support for bexarotene as a treatment for Alzheimer’s disease. Neuropharmacology. 2016;100:124-130. doi: 10.1016/j.neuropharm.2015.04.020

 

  1. LaClair KD, Manaye KF, Lee DL, et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener. 2013;8:18. doi: 10.1186/1750-1326-8-18

 

  1. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: A case report. Nat Med. 2003;9:448-452. doi: 10.1038/nm840

 

  1. Maia MA, Sousa E. BACE-1 and γ-secretase as therapeutic targets for Alzheimer’s disease. Pharmaceuticals (Basel). 2019;12:41. doi: 10.3390/ph12010041

 

  1. May PC, Willis BA, Lowe SL, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015;35:1199-1210. doi: 10.1523/JNEUROSCI.4129-14.2015

 

  1. Wessels AM, Tariot PN, Zimmer JA, et al. Efficacy and safety of lanabecestat for treatment of early and mild alzheimer disease: The AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol. 2020;77:199-209. doi: 10.1001/jamaneurol.2019.3988

 

  1. Bullich S, Mueller A, De Santi S, et al. Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study. Alzheimers Res Ther. 2022;14:105. doi: 10.1186/s13195-022-01048-x

 

  1. Sudduth TL, Greenstein A, Wilcock DM. Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Aβ in APP/PS1 mice along a different time course than anti-Aβ antibodies. J Neurosci. 2013;33:9684-9692. doi: 10.1523/JNEUROSCI.1220-13.2013

 

  1. Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341-350. doi: 10.1056/NEJMoa1210951

 

  1. Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69:1430-1440. doi: 10.1001/archneurol.2012.2194

 

  1. Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial. JAMA Neurol. 2015;72:1324-1333. doi: 10.1001/jamaneurol.2015.0607

 

  1. Thakker DR, Sankaranarayanan S, Weatherspoon MR, et al. Centrally delivered BACE1 inhibitor activates microglia, and reverses amyloid pathology and cognitive deficit in aged Tg2576 mice. J Neurosci. 2015;35:6931-6936. doi: 10.1523/JNEUROSCI.2262-14.2015

 

  1. Qiu R, Ahn JE, Alexander R, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of PF-06751979, a potent and selective oral BACE1 inhibitor: Results from phase I studies in healthy adults and healthy older subjects. J Alzheimers Dis. 2019;71:581-595. doi: 10.3233/JAD-190228

 

  1. O’Neill BT, Beck EM, Butler CR, et al. Design and synthesis of clinical candidate PF-06751979: A potent, brain penetrant, β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor lacking hypopigmentation. J Med Chem. 2018;61:4476-4504. doi: 10.1021/acs.jmedchem.8b00246

 

  1. Jacobsen H, Ozmen L, Caruso A, et al. Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci. 2014;34:11621-11630. doi: 10.1523/JNEUROSCI.1405-14.2014

 

  1. Egan MF, Mukai Y, Voss T, et al. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2019;11:68. doi: 10.1186/s13195-019-0520-1

 

  1. Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2018;378:1691-1703. doi: 10.1056/NEJMoa1706441

 

  1. Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380:1408-1420. doi: 10.1056/NEJMoa1812840

 

  1. Rynearson KD, Ponnusamy M, Prikhodko O, et al. Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J Exp Med. 2021;218:e20202560. doi: 10.1084/jem.20202560

 

  1. Burstein AH, Sabbagh M, Andrews R, Valcarce C, Dunn I, Altstiel L. Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s disease. J Prev Alzheimers Dis. 2018;5:149-154. doi: 10.14283/jpad.2018.18

 

  1. Pasqualetti P, Bonomini C, Dal Forno G, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease. Aging Clin Exp Res. 2009;21:102-110. doi: 10.1007/BF03325217

 

  1. Bareggi SR, Cornelli U. Clioquinol: Review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther. 2012;18:41-46. doi: 10.1111/j.1755-5949.2010.00231.x

 

  1. Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron. 2001;30:665-676. doi: 10.1016/s0896-6273(01)00317-8

 

  1. Salloway S, Sperling R, Keren R, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77:1253-1262. doi: 10.1212/WNL.0b013e3182309fa5

 

  1. Abushakra S, Porsteinsson A, Vellas B, et al. Clinical benefits of tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 alleles: The “APOE4 gene-dose effect”. J Prev Alzheimers Dis. 2016;3:219-228. doi: 10.14283/jpad.2016.115

 

  1. Manzano S, Aguera L, Aguilar M, Olazaran J. A review on tramiprosate (Homotaurine) in Alzheimer’s disease and other neurocognitive disorders. Front Neurol. 2020;11:614. doi: 10.3389/fneur.2020.00614

 

  1. Li T, Lu L, Pember E, Li X, Zhang B, Zhu Z. New insights into neuroinflammation involved in pathogenic mechanism of Alzheimer’s disease and its potential for therapeutic intervention. Cells. 2022;11:1925. doi: 10.3390/cells11121925

 

  1. Bogar F, Fulop L, Penke B. Novel therapeutic target for prevention of neurodegenerative diseases: Modulation of neuroinflammation with Sig-1R ligands. Biomolecules. 2022;12:363. doi: 10.3390/biom12030363
Share
Back to top
Innovative Medicines & Omics, Electronic ISSN: 3060-8740 Print ISSN: 3060-8910, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept