Prerpints.org logo
Preprint
Review

This version is not peer-reviewed.

Alzheimer’s Disease and Related Dementia Drug Trials, Failures and Progress: Data Update 2024

A peer-reviewed article of this preprint also exists.

Submitted:

29 December 2024

Posted:

30 December 2024

You are already at the latest version

Abstract
According to latest report of 2024 by World Health Organization (WHO) based on global data of 2021, Alzheimer’s disease (AD) and other forms of dementia is placed at seventh position among the leading cause of death, that accounts for killing of 1.8 million lives by the disease; and stroke causes highest number of deaths in the world ("World Health Organisation (WHO) The top 10 causes of death https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death ", 2024) Similarly, Centers for Disease Control and Prevention (CDC) National Center for Health Statistics in 2024 also reported AD to be seventh leading cause of death in the United States, based on data from 2021 to 2022 accounting 1.2 millions of deaths.("CDC’s National Center for Health Statistics, Leading Causes of Death https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm," 2024). This alarming number of deaths due to AD is the call for the urgent need to find proper treatment or cure of the disease. AD also severely affects the global economy. However, there is no appropriate treatment or cure available. In the past two decades thousands of disease modifying drugs have been developed to treat dementia of AD, however most of the drugs could not pass phase I clinical trial and only a few could reach phase II and phase III stage. This review is determined to provide the status of various clinical trials, failures and progress of success of various drugs that have been designed to tread dementia of AD.
Keywords: 
Alzheimer’s disease and related dementias
;  
clinical trial progress
;  
failure and success
Subject: 
Biology and Life Sciences  -   Aging

Introduction

Alzheimer disease (AD) is a neurodegenerative disease, and it is the most common cause of dementia with 60% to 80% cases occurred among the elderly people; dementia is manifested by decline in memory, language, problem-solving, confusion with time/place and poor judgment etc. (ʺ2023 Alzheimerʹs disease facts and figures,ʺ 2023; Kawas et al., 2015; Schneider et al., 2007; Schneider et al., 2009; Singh & Chanu, 2021). AD and other related dementias (ADRD) are the 7th most leading cause of death globally. Over the past three decades, number of deaths due to these diseases have increased from 0.56 million (1990) to 1.62 million (2019) (X. Li et al., 2022). Recent report revealed that 6.7 million Americans i.e., 1 out of 9 Americans with age 65 and older are affected by AD dementia (Rajan et al., 2021). AD and ADRD have direct impact on both health and economy. The 83% of caregivers are comprised of unpaid family members, friends or others (Friedman et al., 2015) that could cost about 339.5 billion USD if paid as of the year 2022. Because lifetime care cost of an individual with dementia is estimated to be 392874 USD as of 2022, of which 70% is covered by the unpaid family caregivers including food and medications (ʺ2023 Alzheimerʹs disease facts and figures,ʺ 2023; Jutkowitz et al., 2017). Over the years, with the increased understanding of the regulatory mechanisms underlying pathophysiology of AD dementia, several drugs have been developed and clinical trials were carried out; however challenges remain in finding a cure or proper treatment due to complex pathogenesis of the disease (Dokholyan et al., 2022; Frozza et al., 2018; Tatulian, 2022). Currently available validated drugs for AD treatments modestly slow down progression of disease, but none can reverse it. Growing evidence on immunological mechanisms are revealed potential role of inflammatory pathway underlying the pathogenesis of AD/ADRD (Ahmad et al., 2022; Bettcher et al., 2021; Heneka et al., 2015; Katsel & Haroutunian, 2019; Lecca et al., 2022; Leng & Edison, 2021; Lopez-Rodriguez et al., 2021; Sobue et al., 2023). This review provides the summary of up-to-date available information on several drugs for treating dementia of AD patients, that have been used in clinical trial phase 1, phase II and phase III. As of now, only three drugs have reached the final stage of clinal trials, of which Lecanemab (Leqembi) has been aproved by the Food and Drug Administration (FDA), Aducanumab (Aduhelm) is on the process of aproval while for Donanemab the appllication for aproval by FDA is on the procress (Huang et al., 2023).

Pathophysiological Findings Linked to Dementia of AD/ADRD

The hallmark findings of AD pathphysiology are the accumulation of amyloid-β (Aβ) plaques that are mainly composed of the Aβ42 variant, and neurofibrillary tangles (NFTs) made up of hyperphosphorylated aggregates of the microtubule-associated protein tau, that associates with the loss of neurons and neurodegeneration in the brain of AD patients (Masters et al., 2015; Medeiros et al., 2011; Selkoe & Hardy, 2016; Singh & Chanu, 2021). Other pathological pathways that have been found to have significant role in the AD disease progression include apolipoprotein E (APOE) mediated cholesterol transportation and metabolism, neuroinflammatory responses, mitochondrial dysfunction and alteration in glucose metabolism etc. (Calsolaro & Edison, 2016; Cenini & Voos, 2019; Kinney et al., 2018; R, 2019; Tzioras et al., 2019; Wang et al., 2019).
Over the last several years, vast number of researses have evidenced presence of a prolonged immune response in the brain of AD patients and immune response have apperaed as a third core pathology in AD (Kinney et al., 2018). The prolong activation of resident macrophages (microglia) and other immune cells in brain aggravate both amyloid and tau pathology indicating its profound impact in the AD disease pathophysiology (Kinney et al., 2018). It may be noted that neuroinflammation has been well documented as a key player in most nervous system dysregulation diseases and continuously identified as a potential mediator of cognitive deficits. Neuroinflammation levels are increased with advancing of age and neurodegeneration, and the influence of age on neuroinflammation may contribute to accelerating cognitive impairment through glial activation, increased production of proinflammatory cytokines, abnormal neuronal signaling, magnifying deterioration of the central nervous system microenvironment etc.(Kumar, 2018; Y. W. Wang et al., 2020). Not only the AD, dementia is one of the clinical symptoms in several other neurological diseases that associates with neuroinflammation such as Vascular Dementia, Dementia Lewy Bodies, Parkinson´s Disease, Frontotemporal Dementia, Huntington´s Disease, Wernicke-Korsakoff Syndrome, Amyotrophic lateral sclerosis etc. (Amin et al., 2023; Bir et al., 2021; Chen et al., 2019; Cheng et al., 2015; Hosoki et al., 2023; Litke et al., 2021). Both the innate and adaptive immune system disregulation have been indidicated to have potential role in AD pathogenesis (Dani et al., 2019; Femminella et al., 2019; Hamelin et al., 2016; Kreisl et al., 2018; Kreisl et al., 2016; Tamburini et al., 2023; Wu et al., 2021). Microglia, astrocyes and oligodendrocytes have been accounted for innate immune system dysregulateion in AD. Whereas, the adaptive immune system dysregulation has been proposed from the detection of B and T lymphocytes in the post-mortem AD brain, cerebrospinal fluid (CSF) of mild cognitive impairment (MCI) individuals as well as AD patients (Lawson et al., 1990; Liu et al., 2018; Lueg et al., 2015; Rogers et al., 1988; Stowe et al., 2017; Tamburini et al., 2023), and the presence of higer frequency of T helper subsets (Saresella et al., 2011). These findings have directed to develelope several drugs that target these regulatory sites to reverse the demenia of AD and ADRD.

Drug Trials and Failures

Over the past two decades, several diseases modifying drugs have been designed for treating dementia of AD and about 2700 clinical trials have been conducted so far since 2004; however only a few showed promising indications of success rate at phase II and III trials (Kim et al., 2022). The rate of failure is estimated to be at the rate of 99% (Cummings et al., 2014; Kim et al., 2022) which means only 1% is the success rate. The promising compounds are immunotherapy drugs, Aducanumab (brand name: Aduhelm), a monoclonal antibody designed to bind and eliminate aggregated Aβ plaques; Lecanemab (brand name: Leqembi) which functions in reduction of brain and CSF Aβ protofibril; Donanemab, a humanized monoclonal antibody developed from mouse mE8-IgG2a that recognizes Aβ (3–42) plaques; Oligomannate (GV-971), a seaweed-derived oligosaccharide that reduce bacterial metabolite–driven peripheral infiltration of immune cells into the brain, inhibit Aβ and Tau formation in animal studies (Huang et al., 2023; Kim et al., 2023; Lu et al., 2022; Murphy & LeVine, 2010). However, their effectiveness is yet to be available. So far and just recently only Lecanemab has been fully approved by Food and Drug Administration (FDA, United States) for AD treatment on July 6, 2023 (https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval) (Huang et al., 2023). There are several potential factors that contributed to the failures in clinical trials whether by the faulty drug development processes or the lack of clear understanding on the complex regulatory mechanisms underlying AD pathophysiology. The main reasons for failure are due to not having sufficient evidence to initiate the pivotal trials, shortcomings of the pivotal trial designs, lack of fulfilment of rational drug development principles for AD therapeutics development and less degree effectiveness (Kim et al., 2022). Even though the data from Phase II studies for compounds were not sufficient enough to convinced, there trials have been pushed into Phase III trials and ultimately failed (Gold, 2017). For example, publicly available data for bapineuzumab and solanezumab compound in the Phase II studies did not provide promising evidence that would justify for these drugs to take into the next decisive trials, but the sponsors ignoring the limitations had taken into Phase III trials, and ultimately failed to cross (Gold, 2017; Henley et al., 2019; Lilly, 2020). Subsequently, failure to acknowledge and apply the critical issues from the past clinical trials have also been a major source of recurrent challenges to the success and thereby resulting to negative outcomes (Cummings, 2018). Additionally, failing of timely treatment of symptomatic dementia, inappropriate therapeutic targets, imprecise or misinformation of clinical methodologies, can lead to the failure of clinical trials of AD (Mehta et al., 2017).
So far, most drugs have been designed to deal with Aβ, that would result in reducing Aβ production, inhibition of Aβ plaque formation, clearance of Aβ plaques and Aβ vaccine etc. (Kim et al., 2023; Masters et al., 2015; Selkoe & Hardy, 2016; Singh & Chanu, 2021). Several more drugs have also been designed attempting different target points that include mitigation of tau pathology (Kametani & Hasegawa, 2018), decrease inflammation (Kinney et al., 2018), reduction of cholesterol accumulation (Tzioras et al., 2019; Xue-Shan et al., 2016), improvement of brain energy utilization (Arvanitakis et al., 2020; Calsolaro & Edison, 2016; Ninomiya, 2019; Shieh et al., 2020), lower vascular burden (Gabin et al., 2017), neuroprotectant/antioxidant etc. (Nunomura & Perry, 2020; Palmer, 2011; Tonnies & Trushina, 2017), to increase neural growth/regeneration (Choi & Tanzi, 2019; Sampaio et al., 2017) and hormone balance(Pike, 2017). Among the 2695 clinical trials for AD (data available at ClinicalTrials.gov), after segmented by disease-modifying versus symptomatic, 41% failed in phase III, and 59% failed in phase II; of which 64% were disease-modifying and 36% were symptomatic agents respectively (Kim et al., 2022). This clearly shows drugs for proper treatment for dementia of AD/ADRD is yet to be available while hopes are still alive though. Extensive further research is required to overcome the challenges to find appropriate drugs for the treatment of AD/ADRD with better approaches. Several clinical trials that have been carried out have used included drugs for BACE1 inhibition, γ-Secretase inhibition, γ-Secretase modulation, Anti-ApoE, Aβ production inhibition, Aβ aggregation inhibition, Aβ dissociation, synaptic modulation, Aβ toxicity modulation, filament modulation, glutaminyl cyclase inhibition, active immunization, passive immunization, RAGE inhibition, mGluR5 modulation etc. for reversing or inhibiting amyloid pathology and cognitive deficit or dementia etc. Summary of the failed compounds/drugs which have been stop further clinical trials, promising the ones which are undergoing clinical as well as FDA approved drugs are briefly provided in the Table 1 and Table 2.

Drug Trial Progress and Hope

While most of the drugs have failed to demonstrate positive result, only three drugs demonstrated promising signs. The three FDA approved drugs Aducanumab, Lecanemab and Donanemab which target Aβ plaques/protofibrils, are still undergoing phase III clinical trial to further examine preventive effects and moreover comparing the therapeutic effects and data among these trials are believed to help in directing the next steps of AD drug development. Aducanumab is a human monoclonal antibody immunoglobulin gamma 1 (IgG1) from aged donors resistant to AD, which binds to N-terminus of Aβ fibrils and blocks amyloid aggregation, but not to Aβ monomers (Arndt et al., 2018; Sevigny et al., 2016). Earlier further clinical trials with Aducanumab were terminated because of not meeting the primary endpoint in CDR-SB scores (Clinical Dementia Rating scale Sum of Boxes) (Kim et al., 2023). In the recent subsequent two, phase III clinical trials conducted, namely ENGAGE and EMERGE studies, a significant slowing of cognitive decline at the highest dose was observed. However, only EMERGE trial reached statistical significance, whereas ENGAGE trial would not reach the primary endpoint(Huang et al., 2023). With this finding FDA approved Aducanumab through ‘accelerated approval pathway’ for MCI and mild dementia stage AD patients’ treatment in June 2021 and is sold as Aduhelm by Biogen (Tampi et al., 2021). In both the trials an intermediate effect of the drug on biomarkers was evidence, showing amyloid removal, that may result to clinical benefit of aducanumab, and the phase IIIb/4 ENVISION trial (Govt identifier: NCT05310071) is currently on progress(Huang et al., 2023; Kim et al., 2023). Donanemab is also humanized IgG1 monoclonal antibody developed from mouse mE8-IgG2a and it recognizes Aβ (3–42), a pyroglutamate form of Aβ which is richly present in the brain of AD patients (Bayer, 2022; Irizarry MC et al., 2016). Interestingly, Donanemab can bind about one-third of Aβ plaques in postmortem brains AD or Down syndrome patients and moreover strongly reacted with the plaque core (Bouter et al., 2022). In the phase 2 TRAILBLAZER-ALZ study, combination therapy using Donanemab and Beta-Secretase 1 (BACE1) inhibitor LY3202626 was carried to target pyroglutamate form Aβ and examined the safety, tolerability, and effectiveness of the treatment. The outcome met primary endpoint of delaying cognitive decline as determined by Integrated Alzheimer’s Disease Rating Scale (iADRS) (Huang et al., 2023; Kim et al., 2023). The reduction of Aβ burden was correlated with improvement in iADRS scores but only in APOE4 carriers (Shcherbinin et al., 2022). Donanemab also reduced the tau aggregation in temporal, parietal, and frontal lobes, and plasma pTau217 also significantly decreased (Pontecorvo et al., 2022). It may be noted that phase I trials of Donanemab was found to sustained reduction in cortical amyloid load and the treatment was well tolerated (Mintun et al., 2021). While phase II trials of Donanemab replicated phase I results in reduction of Aβ plaque levels with no adverse effects, patients received the treatment were more likely to exhibit amyloid-related imaging abnormalities ARIA-E and ARIA-H (Doggrell, 2021). On the other hand, LY3202626 as well as most BACE1 inhibiting candidates was excluded from the further trials due to a lack of evidence regarding the safety and effectiveness except Lenalidomide (Kim et al., 2023). Phase III clinical trials for Donanemab currently on progress. United States FDA granted traditional approval for Lecanemab with the brand name Leqembi in July 2023, for the treatment of AD patients ("FDA Converts Novel Alzheimer’s Disease Treatment to Traditional
Approval-Action Follows Confrmatory Trial to Verify Clinical Benefit," 2023). Lecanemab a humanized IgG1 antibody which is derived from mAb158 and selectively binds to soluble Aβ protofbril (Swanson et al., 2021; Tucker et al., 2015). In the phase II clinical trial with AD patients having MCI or mild dementia had verifed amyloid pathology through amyloid PET or CSF Aβ1-42 and the results showed significant and dose-dependent reduction of Aβ plaque(Swanson et al., 2021). The outcomes were positively judged in all primary and secondary measures, that include Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog14), AD Composite Score (ADCOMS), and AD Cooperative Study–MCI-Activities of Daily Living Inventory ADCS-MCI-ADL scores (van Dyck et al., 2023). The phase III clinical trial for Lecanemab is currently on progress.

Discussion and Conclusion

The regulatory mechanisms underlying the pathology of dementia in AD or ADRD is highly complex, and it needs to be examined from several angles to uncover different regulatory pathways that would enable to design appropriate medicine for treatment or cure the cognitive deficit symptoms of the diseases. Enormous efforts with thoughtfully designed vast studies have been carried out and as a result dysregulation of several molecular and cellular signaling pathways have been identified that play potential roles in causing mild/moderate cognitive deficits and dementia of AD/ADRD. Discovering of these pathways has directed to designing and producing drugs for treatment to reduce or recover memory lost occurred to the affected individuals. However, several clinical trials using different probable drugs that have been conducted over the past two decades have not been able to provide an appropriate drug for cognitive deficit or dementia of AD/ADRD. This reveals insufficiency of the available data and the need to take up greater challenges in finding suitable medicine for the treatment. While most of the drugs have failed to demonstrate positive result, immunotherapy looks to be hopeful. The three FDA approved drugs Aducanumab, Lecanemab and Donanemab which target Aβ plaques/protofibrils, are still undergoing phase III clinical trial to further examine preventive effects and moreover comparing the therapeutic effects and data among these trials are believed to help in directing the next steps of AD drug development. The ongoing clinical trials are mainly based on pathophysiology, disease-modifying therapies, and the recruitment of participants in earlier stages of the disease which underline the importance of conducting fundamental research on pathophysiology, prevention, and intervention prior to occurrence of brain damage caused by AD. So far, most drugs that have been designed centralized to the inhibition of formation of toxic Aβ and pTau aggregates. However, recent vast studies have expended the previous knowledge with new findings that include the promising outcomes of clinical trials of Aducanumab, Lecanemab and Donanemab which are monoclonal antibodies resulting in successful clearance Aβ and thereby promising approach in passive immunotherapy linking to neuroinflammatory response. These positive outcomes provide new hopes for AD treatments if the disease is detected at early stages. Other two monoclonal antibodydrugs that are currently undergoing phase III trials are Remternetug (ClinicalTrials,gov.identifer: NCT05463731) and Solanezumab (ClinicalTrials, gov.identifer: NCT01760005). Besides, Sodium Oligoman-nate Capsule (GV-971) is and anti-inflammatory drug that inhibits Aβ fibril formation (ClinicalTrials, gov.identifer: NCT05181475). Moreover, medical research has revealed existence of common disease pathways among neurodegenerative diseases (Bogar et al., 2022) suggesting that the findings in AD/ADRD will also be applicable to other neurological diseases with cognitive deficit or dementia. A vast number of studies have similarly evidenced the improvements in Aβ clearance occurred in the brain through the modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination etc. Currently there are many anti-neuroinflammatory drugs which are currently undergoing phase III trials that include Hydralazine hydrochloride (ClinicalTrials,gov.identifer: NCT04842552), KarXT(xanomeline-trospium) (ClinicalTrials, gov.identifer: NCT05511363), Masitinib (ClinicalTrials, gov.identifer: NCT05564169), NE3107 (ClinicalTrials, gov.identifer: NCT04669028), and Spironolactone (ClinicalTrials, gov.identifer: NCT04522739). Inflammatory pathways related to inflammasomes that associates with potential biomarkers of neuroinflammation associated with AD such as NF-κB, NLRP3 and TREM2, Micorglia have shown to be potential drug targets for AD (T. Li et al., 2022) and further suggests inflammatory pathways connection to Aducanumab, Lecanemab and Donanemab. As there are multiple pathways in neurodegeneration leading to cognitive deficits in AD or ADRD, drugs targeting single target site so far is not working, it is important to find multiple drugs to target multiple sites that could be treated simultaneously. The above several lines of enormous studies and several more that have not been covered in this review, has strongly indicated that, to bring better understanding of AD and ADRD pathophysiology and for treatment or cure requires understanding of histopathologic changes in neurodegenerative diseases as it could highlight key aspects of the degenerative process leading to dementia. Essentially, the questions that arises in the massive failures in clinical trials needs to be thoroughly addressed in moving forward to drug designing and greater success in clinical trials for treating dementia of AD or ADRD.

Funding

None.

Conflict of Interest

Authors declare no conflict of interest.

References

  1. 2023 Alzheimer's disease facts and figures. Alzheimers Dement 2023, 19(4), 1598–1695. [CrossRef]
  2. 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. 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(4), 219–228. [Google Scholar] [CrossRef] [PubMed]
  3. Ahmad, M. A.; Kareem, O.; Khushtar, M.; Akbar, M.; Haque, M. R.; Iqubal, A.; Haider, M. F.; Pottoo, F. H.; Abdulla, F. S.; Al-Haidar, M. B.; Alhajri, N. Neuroinflammation: A Potential Risk for Dementia. Int J Mol Sci 2022, 23(2). [Google Scholar] [CrossRef]
  4. Ahn, J. E.; Carrieri, C.; Dela Cruz, F.; Fullerton, T.; Hajos-Korcsok, E.; He, P.; Kantaridis, C.; Leurent, C.; Liu, R.; Mancuso, J.; Mendes da Costa, L.; Qiu, R. Pharmacokinetic and Pharmacodynamic Effects of a gamma-Secretase Modulator, PF-06648671, on CSF Amyloid-beta Peptides in Randomized Phase I Studies. Clin Pharmacol Ther 2020, 107(1), 211–220. [Google Scholar] [CrossRef] [PubMed]
  5. Amin, J.; Gee, C.; Stowell, K.; Coulthard, D.; Boche, D. T Lymphocytes and Their Potential Role in Dementia with Lewy Bodies. Cells 2023, 12(18). [Google Scholar] [CrossRef] [PubMed]
  6. Arndt, J. W.; Qian, F.; Smith, B. A.; Quan, C.; Kilambi, K. P.; Bush, M. W.; Walz, T.; Pepinsky, R. B.; Bussiere, T.; Hamann, S.; Cameron, T. O.; Weinreb, P. H. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-beta. Sci Rep 2018, 8(1), 6412. [Google Scholar] [CrossRef] [PubMed]
  7. Arvanitakis, Z.; Tatavarthy, M.; Bennett, D. A. The Relation of Diabetes to Memory Function. Curr Neurol Neurosci Rep 2020, 20(12), 64. [Google Scholar] [CrossRef]
  8. Bareggi, S. R.; Cornelli, U. Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 2012, 18(1), 41–46. [Google Scholar] [CrossRef] [PubMed]
  9. Bayer, T. A. Pyroglutamate Abeta cascade as drug target in Alzheimer's disease. Mol Psychiatry 2022, 27(4), 1880–1885. [Google Scholar] [CrossRef] [PubMed]
  10. Bettcher, B. M.; Tansey, M. G.; Dorothee, G.; Heneka, M. T. Peripheral and central immune system crosstalk in Alzheimer disease-a research prospectus. Nat Rev Neurol 2021, 17(11), 689–701. [Google Scholar] [CrossRef] [PubMed]
  11. Bir, S. C.; Khan, M. W.; Javalkar, V.; Toledo, E. G.; Kelley, R. E. Emerging Concepts in Vascular Dementia: A Review. J Stroke Cerebrovasc Dis 2021, 30(8), 105864. [Google Scholar] [CrossRef] [PubMed]
  12. Bogar, F.; Fulop, L.; Penke, B. Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands. Biomolecules 2022, 12(3). [Google Scholar] [CrossRef] [PubMed]
  13. Bouter, Y.; Liekefeld, H.; Pichlo, S.; Westhoff, A. C.; Fenn, L.; Bakrania, P.; Bayer, T. A. Donanemab detects a minor fraction of amyloid-beta plaques in post-mortem brain tissue of patients with Alzheimer's disease and Down syndrome. Acta Neuropathol 2022, 143(5), 601–603. [Google Scholar] [CrossRef] [PubMed]
  14. Bullich, S.; Mueller, A.; De Santi, S.; Koglin, N.; Krause, S.; Kaplow, J.; Kanekiyo, M.; Roe-Vellve, N.; Perrotin, A.; Jovalekic, A.; Scott, D.; Gee, M.; Stephens, A.; Irizarry, M. Evaluation of tau deposition using (18)F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study. Alzheimers Res Ther 2022, 14(1), 105. [Google Scholar] [CrossRef] [PubMed]
  15. Burstein, A. H.; 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(2), 149–154. [Google Scholar] [CrossRef]
  16. Calsolaro, V.; Edison, P. Alterations in Glucose Metabolism in Alzheimer's Disease. Recent Pat Endocr Metab Immune Drug Discov 2016, 10(1), 31–39. [Google Scholar] [CrossRef]
  17. CDC’s National Center for Health Statistics, Leading Causes of Death. 2024. Available online: https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm.
  18. Cenini, G.; Voos, W. Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update. Front Pharmacol 2019, 10, 902. [Google Scholar] [CrossRef] [PubMed]
  19. Chapman, C. D.; Schioth, H. B.; Grillo, C. A.; Benedict, C. Intranasal insulin in Alzheimer's disease: Food for thought. Neuropharmacology 2018, 136 Pt B, 196–201. [Google Scholar] [CrossRef]
  20. Chen, N.; Caruso, C.; Alonso, A.; Derebail, V. K.; Kshirsagar, A. V.; Sharrett, A. R.; Key, N. S.; Gottesman, R. F.; Grove, M. L.; Bressler, J.; Boerwinkle, E.; Windham, B. G.; Mosley, T. H., Jr.; Hyacinth, H. I. Association of sickle cell trait with measures of cognitive function and dementia in African Americans. eNeurologicalSci 2019, 16, 100201. [Google Scholar] [CrossRef]
  21. Cheng, S.; Hou, J.; Zhang, C.; Xu, C.; Wang, L.; Zou, X.; Yu, H.; Shi, Y.; Yin, Z.; Chen, G. Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. Sci Rep 2015, 5, 10535. [Google Scholar] [CrossRef] [PubMed]
  22. 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. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001, 30(3), 665–676. [Google Scholar] [CrossRef]
  23. Choi, S. H.; Tanzi, R. E. Is Alzheimer's Disease a Neurogenesis Disorder? Cell Stem Cell 2019, 25(1), 7–8. [Google Scholar] [CrossRef] [PubMed]
  24. Coric, V.; Salloway, S.; van Dyck, C. H.; Dubois, B.; Andreasen, N.; Brody, M.; Curtis, C.; Soininen, H.; Thein, S.; Shiovitz, T.; Pilcher, G.; Ferris, S.; Colby, S.; Kerselaers, W.; Dockens, R.; Soares, H.; Kaplita, S.; Luo, F.; Pachai, C.; Berman, R. M. Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial. JAMA Neurol 2015, 72(11), 1324–1333. [Google Scholar] [CrossRef] [PubMed]
  25. Coric, V.; van Dyck, C. H.; Salloway, S.; Andreasen, N.; Brody, M.; Richter, R. W.; Soininen, H.; Thein, S.; Shiovitz, T.; Pilcher, G.; Colby, S.; Rollin, L.; Dockens, R.; Pachai, C.; Portelius, E.; Andreasson, U.; Blennow, K.; Soares, H.; Albright, C.; Berman, R. M. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012, 69(11), 1430–1440. [Google Scholar] [CrossRef] [PubMed]
  26. Craft, S.; Baker, L. D.; Montine, T. J.; Minoshima, S.; Watson, G. S.; Claxton, A.; Arbuckle, M.; Callaghan, M.; Tsai, E.; Plymate, S. R.; Green, P. S.; Leverenz, J.; Cross, D.; Gerton, B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012, 69(1), 29–38. [Google Scholar] [CrossRef] [PubMed]
  27. Cumbo, E.; Ligori, L. D. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. Epilepsy Behav 2010, 17(4), 461–466. [Google Scholar] [CrossRef]
  28. Cummings, J. Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes. Clin Transl Sci 2018, 11(2), 147–152. [Google Scholar] [CrossRef] [PubMed]
  29. Cummings, J. L.; Morstorf, T.; Zhong, K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014, 6(4), 37. [Google Scholar] [CrossRef] [PubMed]
  30. Dani, M.; Wood, M.; Mizoguchi, R.; Fan, Z.; Edginton, T.; Hinz, R.; Win, Z.; Brooks, D. J.; Edison, P. Tau Aggregation Correlates with Amyloid Deposition in Both Mild Cognitive Impairment and Alzheimer's Disease Subjects. J Alzheimers Dis 2019, 70(2), 455–465. [Google Scholar] [CrossRef] [PubMed]
  31. Decourt, B.; Drumm-Gurnee, D.; Wilson, J.; Jacobson, S.; Belden, C.; Sirrel, S.; Ahmadi, M.; Shill, H.; Powell, J.; Walker, A.; Gonzales, A.; Macias, M.; Sabbagh, M. N. 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(4), 403–411. [Google Scholar] [CrossRef]
  32. Doggrell, S. A. Still grasping at straws: donanemab in Alzheimer's disease. Expert Opin Investig Drugs 2021, 30(8), 797–801. [Google Scholar] [CrossRef] [PubMed]
  33. Dokholyan, N. V.; Mohs, R. C.; Bateman, R. J. Challenges and progress in research, diagnostics, and therapeutics in Alzheimer's disease and related dementias. Alzheimers Dement (N Y) 2022, 8(1), e12330. [Google Scholar] [CrossRef]
  34. Doody, R. S.; Raman, R.; Farlow, M.; Iwatsubo, T.; Vellas, B.; Joffe, S.; Kieburtz, K.; He, F.; Sun, X.; Thomas, R. G.; Aisen, P. S.; Alzheimer's Disease Cooperative Study Steering, C.; Siemers, E.; Sethuraman, G.; Mohs, R.; Semagacestat Study, G. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013, 369(4), 341–350. [Google Scholar] [CrossRef]
  35. Egan, M. F.; Kost, J.; Tariot, P. N.; Aisen, P. S.; Cummings, J. L.; Vellas, B.; Sur, C.; Mukai, Y.; Voss, T.; Furtek, C.; Mahoney, E.; Harper Mozley, L.; Vandenberghe, R.; Mo, Y.; Michelson, D. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med 2018, 378(18), 1691–1703. [Google Scholar] [CrossRef] [PubMed]
  36. Egan, M. F.; Kost, J.; Voss, T.; Mukai, Y.; Aisen, P. S.; Cummings, J. L.; Tariot, P. N.; Vellas, B.; van Dyck, C. H.; Boada, M.; Zhang, Y.; Li, W.; Furtek, C.; Mahoney, E.; Harper Mozley, L.; Mo, Y.; Sur, C.; Michelson, D. Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. N Engl J Med 2019, 380(15), 1408–1420. [Google Scholar] [CrossRef]
  37. Egan, M. F.; Mukai, Y.; Voss, T.; Kost, J.; Stone, J.; Furtek, C.; Mahoney, E.; Cummings, J. L.; Tariot, P. N.; Aisen, P. S.; Vellas, B.; Lines, C.; Michelson, D. 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(1), 68. [Google Scholar] [CrossRef]
  38. Endres, K.; Fahrenholz, F.; Lotz, J.; Hiemke, C.; Teipel, S.; Lieb, K.; Tuscher, O.; Fellgiebel, A. Increased CSF APPs-alpha levels in patients with Alzheimer disease treated with acitretin. Neurology 2014, 83(21), 1930–1935. [Google Scholar] [CrossRef]
  39. Fang, C.; Hernandez, P.; Liow, K.; Damiano, E.; Zetterberg, H.; Blennow, K.; Feng, D.; Chen, M.; Maccecchini, M. 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(1), 25–33. [Google Scholar] [CrossRef] [PubMed]
  40. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval-Action Follows Confrmatory Trial to Verify Clinical Benefit. 2023.
  41. Femminella, G. D.; Dani, M.; Wood, M.; Fan, Z.; Calsolaro, V.; Atkinson, R.; Edginton, T.; Hinz, R.; Brooks, D. J.; Edison, P. Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume. Neurology 2019, 92(12), e1331–e1343. [Google Scholar] [CrossRef]
  42. Friedman, E. M.; Shih, R. A.; Langa, K. M.; Hurd, M. D. US Prevalence And Predictors Of Informal Caregiving For Dementia. Health Aff (Millwood) 2015, 34(10), 1637–1641. [Google Scholar] [CrossRef]
  43. Frozza, R. L.; Lourenco, M. V.; De Felice, F. G. Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects. Front Neurosci 2018, 12, 37. [Google Scholar] [CrossRef]
  44. Gabin, J. M.; 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(1), 37. [Google Scholar] [CrossRef] [PubMed]
  45. Gold, M. Phase II clinical trials of anti-amyloid beta antibodies: When is enough, enough? Alzheimers Dement (N Y) 2017, 3(3), 402–409. [Google Scholar] [CrossRef]
  46. Green, R. C.; Schneider, L. S.; Amato, D. A.; Beelen, A. P.; Wilcock, G.; Swabb, E. A.; Zavitz, K. H.; Tarenflurbil Phase 3 Study, G. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009, 302(23), 2557–2564. [Google Scholar] [CrossRef] [PubMed]
  47. Grundman, M.; Morgan, R.; Lickliter, J. D.; Schneider, L. S.; DeKosky, S.; Izzo, N. J.; Guttendorf, R.; Higgin, M.; Pribyl, J.; Mozzoni, K.; Safferstein, H.; Catalano, S. M. 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. [Google Scholar] [CrossRef] [PubMed]
  48. Haas, L. T.; Salazar, S. V.; Smith, L. M.; Zhao, H. R.; Cox, T. O.; Herber, C. S.; Degnan, A. P.; Balakrishnan, A.; Macor, J. E.; Albright, C. F.; Strittmatter, S. M. Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes. Cell Rep 2017, 20(1), 76–88. [Google Scholar] [CrossRef] [PubMed]
  49. Hamelin, L.; Lagarde, J.; Dorothee, G.; Leroy, C.; Labit, M.; Comley, R. A.; de Souza, L. C.; Corne, H.; Dauphinot, L.; Bertoux, M.; Dubois, B.; Gervais, P.; Colliot, O.; Potier, M. C.; Bottlaender, M.; Sarazin, M.; Clinical, I. t. Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain 2016, 139 Pt 4, 1252–1264. [Google Scholar] [CrossRef] [PubMed]
  50. Hamilton, A.; Vasefi, M.; Vander Tuin, C.; McQuaid, R. J.; Anisman, H.; Ferguson, S. S. Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model. Cell Rep 2016, 15(9), 1859–1865. [Google Scholar] [CrossRef] [PubMed]
  51. Heneka, M. T.; Carson, M. J.; El Khoury, J.; Landreth, G. E.; Brosseron, F.; Feinstein, D. L.; Jacobs, A. H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R. M.; Herrup, K.; Frautschy, S. A.; Finsen, B.; Brown, G. C.; Verkhratsky, A.; Yamanaka, K.; Koistinaho, J.; Latz, E.; Halle, A.; Kummer, M. P. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015, 14(4), 388–405. [Google Scholar] [CrossRef]
  52. 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(15), 1483–1485. [Google Scholar] [CrossRef] [PubMed]
  53. Hoffmann, T.; Rahfeld, J. U.; Schenk, M.; Ponath, F.; Makioka, K.; Hutter-Paier, B.; Lues, I.; Lemere, C. A.; Schilling, S. Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Abeta Pathology in Transgenic Mice. Int J Mol Sci 2021, 22(21). [Google Scholar] [CrossRef] [PubMed]
  54. 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(1-4), 224–228. [Google Scholar] [CrossRef] [PubMed]
  55. Hosoki, S.; Hansra, G. K.; Jayasena, T.; Poljak, A.; Mather, K. A.; Catts, V. S.; Rust, R.; Sagare, A.; Kovacic, J. C.; Brodtmann, A.; Wallin, A.; Zlokovic, B. V.; Ihara, M.; Sachdev, P. S. Molecular biomarkers for vascular cognitive impairment and dementia. Nat Rev Neurol 2023, 19(12), 737–753. [Google Scholar] [CrossRef]
  56. Huang, L. K.; Kuan, Y. C.; Lin, H. W.; Hu, C. J. Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update. J Biomed Sci 2023, 30(1), 83. [Google Scholar] [CrossRef] [PubMed]
  57. Imbimbo, B. P.; Frigerio, E.; Breda, M.; Fiorentini, F.; Fernandez, M.; Sivilia, S.; Giardino, L.; Calza, L.; Norris, D.; Casula, D.; Shenouda, M. Pharmacokinetics and pharmacodynamics of CHF5074 after short-term administration in healthy subjects. Alzheimer Dis Assoc Disord 2013, 27(3), 278–286. [Google Scholar] [CrossRef] [PubMed]
  58. Irizarry, M. C.; Sims, J. R.; Lowe; et al. O4–08-06: Safety, p. P., and forbetapir F-18 positron, of, e. t. P. a. m. d. a., LY3002813, a. β.-a. p.-s. a., in Alzheimer’s disease., & 2016;12:P352–3. (2016). O4-08-06: 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 & Dementia 12.
  59. Jacobsen, H.; Ozmen, L.; Caruso, A.; Narquizian, R.; Hilpert, H.; Jacobsen, B.; Terwel, D.; Tanghe, A.; Bohrmann, B. Combined treatment with a BACE inhibitor and anti-Abeta antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci 2014, 34(35), 11621–11630. [Google Scholar] [CrossRef] [PubMed]
  60. Jutkowitz, E.; Kane, R. L.; Gaugler, J. E.; MacLehose, R. F.; Dowd, B.; Kuntz, K. M. Societal and Family Lifetime Cost of Dementia: Implications for Policy. J Am Geriatr Soc 2017, 65(10), 2169–2175. [Google Scholar] [CrossRef] [PubMed]
  61. Kametani, F.; Hasegawa, M. Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Front Neurosci 2018, 12, 25. [Google Scholar] [CrossRef] [PubMed]
  62. Katsel, P.; Haroutunian, V. Is Alzheimer disease a failure of mobilizing immune defense? Lessons from cognitively fit oldest-old. Dialogues Clin Neurosci 2019, 21(1), 7–19. [Google Scholar] [CrossRef] [PubMed]
  63. Kawas, C. H.; Kim, R. C.; Sonnen, J. A.; Bullain, S. S.; Trieu, T.; Corrada, M. M. Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study. Neurology 2015, 85(6), 535–542. [Google Scholar] [CrossRef]
  64. Kim, C. K.; Lee, Y. R.; 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(1), 83–100. [Google Scholar] [CrossRef]
  65. Kim, J.; Jeon, H.; Yun Kim, H.; Kim, Y. Failure, Success, and Future Direction of Alzheimer Drugs Targeting Amyloid-beta Cascade: Pros and Cons of Chemical and Biological Modalities. Chembiochem 2023, 24(19), e202300328. [Google Scholar] [CrossRef]
  66. Kinney, J. W.; Bemiller, S. M.; Murtishaw, A. S.; Leisgang, A. M.; Salazar, A. M.; Lamb, B. T. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y) 2018, 4, 575–590. [Google Scholar] [CrossRef] [PubMed]
  67. Kreisl, W. C.; Henter, I. D.; Innis, R. B. Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia. Adv Pharmacol 2018, 82, 163–185. [Google Scholar] [CrossRef] [PubMed]
  68. Kreisl, W. C.; Lyoo, C. H.; Liow, J. S.; Wei, M.; Snow, J.; Page, E.; Jenko, K. J.; Morse, C. L.; Zoghbi, S. S.; Pike, V. W.; Turner, R. S.; Innis, R. B. (11)C-PBR28 binding to translocator protein increases with progression of Alzheimer's disease. Neurobiol Aging 2016, 44, 53–61. [Google Scholar] [CrossRef] [PubMed]
  69. Kumar, A. Editorial: Neuroinflammation and Cognition. Front Aging Neurosci 2018, 10, 413. [Google Scholar] [CrossRef]
  70. Kutzsche, J.; Jurgens, D.; Willuweit, A.; Adermann, K.; Fuchs, C.; Simons, S.; Windisch, M.; Humpel, M.; Rossberg, W.; Wolzt, M.; Willbold, D. 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(1), e12001. [Google Scholar] [CrossRef]
  71. LaClair, K. D.; Manaye, K. F.; Lee, D. L.; Allard, J. S.; Savonenko, A. V.; Troncoso, J. C.; Wong, P. C. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener 2013, 8, 18. [Google Scholar] [CrossRef]
  72. Lahiri, D. K.; Chen, D.; Maloney, B.; Holloway, H. W.; Yu, Q. S.; Utsuki, T.; Giordano, T.; Sambamurti, K.; Greig, N. H. The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther 2007, 320(1), 386–396. [Google Scholar] [CrossRef]
  73. Lawson, L. J.; Perry, V. H.; Dri, P.; Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 1990, 39(1), 151–170. [Google Scholar] [CrossRef] [PubMed]
  74. Lecca, D.; Jung, Y. J.; Scerba, M. T.; Hwang, I.; Kim, Y. K.; Kim, S.; Modrow, S.; Tweedie, D.; Hsueh, S. C.; Liu, D.; Luo, W.; Glotfelty, E.; Li, Y.; Wang, J. Y.; Luo, Y.; Hoffer, B. J.; Kim, D. S.; McDevitt, R. A.; Greig, N. H. Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis. Alzheimers Dement 2022, 18(11), 2327–2340. [Google Scholar] [CrossRef]
  75. Leng, F.; Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 2021, 17(3), 157–172. [Google Scholar] [CrossRef]
  76. 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(12). [Google Scholar] [CrossRef]
  77. 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. [Google Scholar] [CrossRef] [PubMed]
  78. Lilly, E. Lilly Announces Topline Results for Solanezumab from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Study. 2020. Available online: https://investor.lilly.com/news-releases/news-release-details/lilly-announces-topline-results-solanezumab-dominantly-inherited.
  79. Litke, R.; Garcharna, L. C.; Jiwani, S.; Neugroschl, J. Modifiable Risk Factors in Alzheimer Disease and Related Dementias: A Review. Clin Ther 2021, 43(6), 953–965. [Google Scholar] [CrossRef] [PubMed]
  80. 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(1), 1144–1150. [Google Scholar] [CrossRef]
  81. Lopez-Rodriguez, A. B.; Hennessy, E.; Murray, C. L.; Nazmi, A.; Delaney, H. J.; Healy, D.; Fagan, S. G.; Rooney, M.; Stewart, E.; Lewis, A.; de Barra, N.; Scarry, P.; Riggs-Miller, L.; Boche, D.; Cunningham, M. O.; Cunningham, C. Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1beta drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement 2021, 17(10), 1735–1755. [Google Scholar] [CrossRef]
  82. Lu, J.; Pan, Q.; Zhou, J.; Weng, Y.; Chen, K.; Shi, L.; Zhu, G.; Chen, C.; Li, L.; Geng, M.; Zhang, Z. Pharmacokinetics, distribution, and excretion of sodium oligomannate, a recently approved anti-Alzheimer's disease drug in China. J Pharm Anal 2022, 12(1), 145–155. [Google Scholar] [CrossRef] [PubMed]
  83. Lueg, G.; Gross, C. C.; Lohmann, H.; Johnen, A.; Kemmling, A.; Deppe, M.; Groger, J.; Minnerup, J.; Wiendl, H.; Meuth, S. G.; Duning, T. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiol Aging 2015, 36(1), 81–89. [Google Scholar] [CrossRef] [PubMed]
  84. Maia, M. A.; Sousa, E. BACE-1 and gamma-Secretase as Therapeutic Targets for Alzheimer's Disease. Pharmaceuticals (Basel) 2019, 12(1). [Google Scholar] [CrossRef]
  85. 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. [Google Scholar] [CrossRef] [PubMed]
  86. Masters, C. L.; Bateman, R.; Blennow, K.; Rowe, C. C.; Sperling, R. A.; Cummings, J. L. Alzheimer's disease. Nat Rev Dis Primers 2015, 1, 15056. [Google Scholar] [CrossRef] [PubMed]
  87. May, P. C.; Willis, B. A.; Lowe, S. L.; Dean, R. A.; Monk, S. A.; Cocke, P. J.; Audia, J. E.; Boggs, L. N.; Borders, A. R.; Brier, R. A.; Calligaro, D. O.; Day, T. A.; Ereshefsky, L.; Erickson, J. A.; Gevorkyan, H.; Gonzales, C. R.; James, D. E.; Jhee, S. S.; Komjathy, S. F.; Mergott, D. J. The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans. J Neurosci 2015, 35(3), 1199–1210. [Google Scholar] [CrossRef] [PubMed]
  88. Medeiros, R.; Baglietto-Vargas, D.; LaFerla, F. M. The role of tau in Alzheimer's disease and related disorders. CNS Neurosci Ther 2011, 17(5), 514–524. [Google Scholar] [CrossRef] [PubMed]
  89. 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(6), 735–739. [Google Scholar] [CrossRef] [PubMed]
  90. 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. Donanemab in Early Alzheimer's Disease. N Engl J Med 2021, 384(18), 1691–1704. [Google Scholar] [CrossRef] [PubMed]
  91. Murphy, M. P.; LeVine, H., 3rd. Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis 2010, 19(1), 311–323. [Google Scholar] [CrossRef]
  92. Nicoll, J. A.; Wilkinson, D.; Holmes, C.; Steart, P.; Markham, H.; Weller, R. O. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003, 9(4), 448–452. [Google Scholar] [CrossRef] [PubMed]
  93. Ninomiya, T. Epidemiological Evidence of the Relationship Between Diabetes and Dementia. Adv Exp Med Biol 2019, 1128, 13–25. [Google Scholar] [CrossRef] [PubMed]
  94. Nunomura, A.; Perry, G. RNA and Oxidative Stress in Alzheimer's Disease: Focus on microRNAs. Oxid Med Cell Longev 2020, 2020, 2638130. [Google Scholar] [CrossRef]
  95. O'Hare, E.; Jeggo, R.; Kim, E. M.; Barbour, B.; Walczak, J. S.; Palmer, P.; Lyons, T.; Page, D.; Hanna, D.; Meara, J. R.; Spanswick, D.; Guo, J. P.; McGeer, E. G.; McGeer, P. L.; Hobson, P. Lack of support for bexarotene as a treatment for Alzheimer's disease. Neuropharmacology 2016, 100, 124–130. [Google Scholar] [CrossRef] [PubMed]
  96. O'Neill, B. T.; Beck, E. M.; Butler, C. R.; Nolan, C. E.; Gonzales, C.; Zhang, L.; Doran, S. D.; Lapham, K.; Buzon, L. M.; Dutra, J. K.; Barreiro, G.; Hou, X.; Martinez-Alsina, L. A.; Rogers, B. N.; Villalobos, A.; Murray, J. C.; Ogilvie, K.; LaChapelle, E. A.; Chang, C.; Brodney, M. A. Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. J Med Chem 2018, 61(10), 4476–4504. [Google Scholar] [CrossRef]
  97. Palmer, A. M. Neuroprotective therapeutics for Alzheimer's disease: progress and prospects. Trends Pharmacol Sci 2011, 32(3), 141–147. [Google Scholar] [CrossRef] [PubMed]
  98. Pasqualetti, P.; Bonomini, C.; Dal Forno, G.; Paulon, L.; Sinforiani, E.; Marra, C.; Zanetti, O.; Rossini, P. M. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease. Aging Clin Exp Res 2009, 21(2), 102–110. [Google Scholar] [CrossRef] [PubMed]
  99. Pike, C. J. Sex and the development of Alzheimer's disease. J Neurosci Res 2017, 95(1-2), 671–680. [Google Scholar] [CrossRef]
  100. Pontecorvo, M. J.; Lu, M.; Burnham, S. C.; Schade, A. E.; Dage, J. L.; Shcherbinin, S.; Collins, E. C.; Sims, J. R.; Mintun, M. A. 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(12), 1250–1259. [Google Scholar] [CrossRef] [PubMed]
  101. Qiu, R.; Ahn, J. E.; Alexander, R.; Brodney, M. A.; He, P.; Leurent, C.; Mancuso, J.; Margolin, R. A.; Tankisheva, E.; Chen, D. 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(2), 581–595. [Google Scholar] [CrossRef] [PubMed]
  102. R, A. A. Risk factors for Alzheimer's disease. Folia Neuropathol 2019, 57(2), 87–105. [Google Scholar] [CrossRef]
  103. Rajan, K. B.; Weuve, J.; Barnes, L. L.; McAninch, E. A.; Wilson, R. S.; Evans, D. A. Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement 2021, 17(12), 1966–1975. [Google Scholar] [CrossRef]
  104. Reger, M. A.; Watson, G. S.; Green, P. S.; Wilkinson, C. W.; Baker, L. D.; Cholerton, B.; Fishel, M. A.; Plymate, S. R.; Breitner, J. C.; DeGroodt, W.; Mehta, P.; Craft, S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008, 70(6), 440–448. [Google Scholar] [CrossRef] [PubMed]
  105. Rishton, G. M.; Look, G. C.; Ni, Z. J.; Zhang, J.; Wang, Y.; Huang, Y.; Wu, X.; Izzo, N. J.; LaBarbera, K. M.; Limegrover, C. S.; Rehak, C.; Yurko, R.; Catalano, S. M. Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease. ACS Med Chem Lett 2021, 12(9), 1389–1395. [Google Scholar] [CrossRef] [PubMed]
  106. Rogers, J.; Luber-Narod, J.; Styren, S. D.; Civin, W. H. 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(4), 339–349. [Google Scholar] [CrossRef] [PubMed]
  107. Rynearson, K. D.; Ponnusamy, M.; Prikhodko, O.; Xie, Y.; Zhang, C.; Nguyen, P.; Hug, B.; Sawa, M.; Becker, A.; Spencer, B.; Florio, J.; Mante, M.; Salehi, B.; Arias, C.; Galasko, D.; Head, B. P.; Johnson, G.; Lin, J. H.; Duddy, S. K.; Wagner, S. L. Preclinical validation of a potent gamma-secretase modulator for Alzheimer's disease prevention. J Exp Med 2021, 218(4). [Google Scholar] [CrossRef] [PubMed]
  108. 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.; Investigators, E. A. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011, 77(13), 1253–1262. [Google Scholar] [CrossRef] [PubMed]
  109. Sampaio, T. B.; Savall, A. S.; Gutierrez, M. E. Z.; Pinton, S. Neurotrophic factors in Alzheimer's and Parkinson's diseases: implications for pathogenesis and therapy. Neural Regen Res 2017, 12(4), 549–557. [Google Scholar] [CrossRef] [PubMed]
  110. Saresella, M.; Calabrese, E.; Marventano, I.; Piancone, F.; Gatti, A.; Alberoni, M.; Nemni, R.; Clerici, M. 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(3), 539–547. [Google Scholar] [CrossRef] [PubMed]
  111. Schneider, J. A.; Arvanitakis, Z.; Bang, W.; Bennett, D. A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007, 69(24), 2197–2204. [Google Scholar] [CrossRef] [PubMed]
  112. Schneider, J. A.; Arvanitakis, Z.; Leurgans, S. E.; Bennett, D. A. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 2009, 66(2), 200–208. [Google Scholar] [CrossRef] [PubMed]
  113. Selkoe, D. J.; Hardy, J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016, 8(6), 595–608. [Google Scholar] [CrossRef]
  114. Sevigny, J.; Chiao, P.; Bussiere, 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. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 2016, 537(7618), 50–56. [Google Scholar] [CrossRef] [PubMed]
  115. Shcherbinin, S.; Evans, C. D.; Lu, M.; Andersen, S. W.; Pontecorvo, M. J.; Willis, B. A.; Gueorguieva, I.; Hauck, P. M.; Brooks, D. A.; Mintun, M. A.; Sims, J. R. Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurol 2022, 79(10), 1015–1024. [Google Scholar] [CrossRef]
  116. Shieh, J. C.; Huang, P. T.; Lin, Y. F. Alzheimer's Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies. Mol Neurobiol 2020, 57(4), 1966–1977. [Google Scholar] [CrossRef] [PubMed]
  117. Singh, A. S.; Chanu, M. T. Alzheimer’s disease and Aβ pathways. World Journal of Advanced Research and Reviews 2021, 12(3), 542–544. [Google Scholar] [CrossRef]
  118. Sobue, A.; Komine, O.; Yamanaka, K. Neuroinflammation in Alzheimer's disease: microglial signature and their relevance to disease. Inflamm Regen 2023, 43(1), 26. [Google Scholar] [CrossRef] [PubMed]
  119. Stowe, A. M.; Ireland, S. J.; Ortega, S. B.; Chen, D.; Huebinger, R. M.; Tarumi, T.; Harris, T. S.; Cullum, C. M.; Rosenberg, R.; Monson, N. L.; Zhang, R. Adaptive lymphocyte profiles correlate to brain Abeta burden in patients with mild cognitive impairment. J Neuroinflammation 2017, 14(1), 149. [Google Scholar] [CrossRef] [PubMed]
  120. Sudduth, T. L.; Greenstein, A.; Wilcock, D. M. Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Abeta in APP/PS1 mice along a different time course than anti-Abeta antibodies. J Neurosci 2013, 33(23), 9684–9692. [Google Scholar] [CrossRef] [PubMed]
  121. 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. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther 2021, 13(1), 80. [Google Scholar] [CrossRef]
  122. Tamburini, B.; Badami, G. D.; La Manna, M. P.; 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(15). [Google Scholar] [CrossRef] [PubMed]
  123. Tampi, R. R.; Forester, B. P.; Agronin, M. Aducanumab: evidence from clinical trial data and controversies. Drugs Context 2021, 10. [Google Scholar] [CrossRef] [PubMed]
  124. Tatulian, S. A. Challenges and hopes for Alzheimer's disease. Drug Discov Today 2022, 27(4), 1027–1043. [Google Scholar] [CrossRef]
  125. Thakker, D. R.; Sankaranarayanan, S.; Weatherspoon, M. R.; Harrison, J.; Pierdomenico, M.; Heisel, J. M.; Thompson, L. A.; Haskell, R.; Grace, J. E.; Taylor, S. J.; Albright, C. F.; Shafer, L. L. Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice. J Neurosci 2015, 35(17), 6931–6936. [Google Scholar] [CrossRef]
  126. Tonnies, E.; Trushina, E. Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease. J Alzheimers Dis 2017, 57(4), 1105–1121. [Google Scholar] [CrossRef] [PubMed]
  127. Tucker, S.; Moller, C.; Tegerstedt, K.; Lord, A.; Laudon, H.; Sjodahl, J.; Soderberg, L.; Spens, E.; Sahlin, C.; Waara, E. R.; Satlin, A.; Gellerfors, P.; Osswald, G.; Lannfelt, L. 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(2), 575–588. [Google Scholar] [CrossRef]
  128. 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(4), 327–346. [Google Scholar] [CrossRef]
  129. Valera, E.; Spencer, B.; Fields, J. A.; Trinh, I.; Adame, A.; Mante, M.; Rockenstein, E.; Desplats, P.; Masliah, E. Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 2017, 5(1), 2. [Google Scholar] [CrossRef]
  130. 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. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023, 388(1), 9–21. [Google Scholar] [CrossRef] [PubMed]
  131. Vijverberg, E. G. B.; Axelsen, T. M.; Bihlet, A. R.; Henriksen, K.; Weber, F.; Fuchs, K.; Harrison, J. E.; Kuhn-Wache, K.; Alexandersen, P.; Prins, N. D.; Scheltens, P. 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(1), 142. [Google Scholar] [CrossRef] [PubMed]
  132. Villemagne, V. L.; Rowe, C. C.; Barnham, K. J.; Cherny, R.; Woodward, M.; Bozinosvski, S.; Salvado, O.; Bourgeat, P.; Perez, K.; Fowler, C.; Rembach, A.; Maruff, P.; Ritchie, C.; Tanzi, R.; Masters, C. L. A randomized, exploratory molecular imaging study targeting amyloid beta with a novel 8-OH quinoline in Alzheimer's disease: The PBT2-204 IMAGINE study. Alzheimers Dement (N Y) 2017, 3(4), 622–635. [Google Scholar] [CrossRef] [PubMed]
  133. Vossel, K.; Ranasinghe, K. G.; Beagle, A. J.; La, A.; Ah Pook, K.; Castro, M.; Mizuiri, D.; Honma, S. M.; Venkateswaran, N.; Koestler, M.; Zhang, W.; Mucke, L.; Howell, M. J.; Possin, K. L.; Kramer, J. H.; Boxer, A. L.; Miller, B. L.; Nagarajan, S. S.; Kirsch, H. E. Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial. JAMA Neurol 2021, 78(11), 1345–1354. [Google Scholar] [CrossRef]
  134. Wang, C.; Shou, Y.; Pan, J.; Du, Y.; Liu, C.; Wang, H. The relationship between cholesterol level and Alzheimer's disease-associated APP proteolysis/Abeta metabolism. Nutr Neurosci 2019, 22(7), 453–463. [Google Scholar] [CrossRef] [PubMed]
  135. Wang, H. Y.; Lee, K. C.; Pei, Z.; Khan, A.; Bakshi, K.; Burns, L. H. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging 2017, 55, 99–114. [Google Scholar] [CrossRef] [PubMed]
  136. Wang, H. Y.; Pei, Z.; Lee, K. C.; Lopez-Brignoni, E.; Nikolov, B.; Crowley, C. A.; Marsman, M. R.; Barbier, R.; Friedmann, N.; Burns, L. H. PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients. J Prev Alzheimers Dis 2020, 7(4), 256–264. [Google Scholar] [CrossRef]
  137. Wang, Y. W.; Zhou, Q.; Zhang, X.; Qian, Q. Q.; Xu, J. W.; Ni, P. F.; Qian, Y. N. Correction to: Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization. J Neuroinflammation 2020, 17(1), 353. [Google Scholar] [CrossRef]
  138. Wessels, A. M.; Tariot, P. N.; Zimmer, J. A.; Selzler, K. J.; Bragg, S. M.; Andersen, S. W.; Landry, J.; Krull, J. H.; Downing, A. M.; Willis, B. A.; Shcherbinin, S.; Mullen, J.; Barker, P.; Schumi, J.; Shering, C.; Matthews, B. R.; Stern, R. A.; Vellas, B.; Cohen, S.; Sims, J. R. 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(2), 199–209. [Google Scholar] [CrossRef]
  139. World Health Organisation (WHO) The top 10 causes of death. 2024. Available online: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.
  140. Wu, K. M.; Zhang, Y. R.; Huang, Y. Y.; Dong, Q.; Tan, L.; Yu, J. T. The role of the immune system in Alzheimer's disease. Ageing Res Rev 2021, 70, 101409. [Google Scholar] [CrossRef] [PubMed]
  141. Xue-Shan, Z.; Juan, P.; Qi, W.; Zhong, R.; Li-Hong, P.; Zhi-Han, T.; Zhi-Sheng, J.; Gui-Xue, W.; Lu-Shan, L. Imbalanced cholesterol metabolism in Alzheimer's disease. Clin Chim Acta 2016, 456, 107–114. [Google Scholar] [CrossRef] [PubMed]
Table 1. List of drugs with approval status by FDA of the United States of America.
Table 1. List of drugs with approval status by FDA of the United States of America.
Drug name Company Mode of action and effect Approval status
Aducanumab (Aduhelm) Biogen, Neuroimmune Eliminate aggregated Aβ plaques Approval in progress (Green et al., 2009; Huang et al., 2023; Kim et al., 2023)
Lecanemab (Leqembi) BioArctic AB, Biogen, Eisai Reduce soluble Aβ protofibrils Fully approved (Huang et al., 2023; Kim et al., 2023)
Donanemab Eli Lilly & Co Eliminate aggregated Aβ plaques Application for full approval (Huang et al., 2023; Kim et al., 2023)
Table 2. List of drugs with clinical trial status ongoing, completed or discontinued.
Table 2. List of drugs with clinical trial status ongoing, completed or discontinued.
Drug name Mode of action and effect Trial phase status Side effects/outcome
Lenalidomide BACE1 inhibition, inflammation reduction Ongoing phase II Yet to be available (Decourt et al., 2017; Valera et al., 2017)
CT1812 Aβ aggregation inhibition, Aβ oligomer reduction, behavioral improvement Ongoing phase II Yet to be available (Grundman et al., 2019; Rishton et al., 2021)
ALX-001 mGluR5 modulation, Synaptic function, and behavioral enhancement Ongoing phase I Yet to be available (Hamilton et al., 2016) (Haas et al., 2017)
Buntanetap Aβ production inhibition, Aβ generation reduction Ongoing phase III Yet to be available (Fang et al., 2023; Lahiri et al., 2007)
GV-971 Aβ dissociation, Aβ, plaque burden reduction Ongoing phase II Yet to be available (Cumbo & Ligori, 2010; Vossel et al., 2021)
Nasal insulin Aβ toxicity modulation, Memory improvement Ongoing (phase II/III Yet to be available (Chapman et al., 2018; Craft et al., 2012; Reger et al., 2008)
Simufilam Filament modulation, Amyloid, tau deposition, neuroinflammation reduction Ongoing phase III Yet to be available (Wang et al., 2017; H. Y. Wang et al., 2020)
Varoglutamstat Glutaminyl cyclase inhibition, Amyloid pathology and pAβ reduction Ongoing phase II Yet to be available (Hoffmann et al., 2021; Vijverberg et al., 2021)
Aducanumab Passive immunization, plaque clearance Approved and ongoing phase III Application for full approval (Green et al., 2009; Huang et al., 2023)
Lecanemab Passive immunization, brain, and CSF Aβ protofibril reduction Approved and ongoing phase III Approved (Huang et al., 2023; Kim et al., 2023)
Donanemab Passive immunization, plaque clearance Approved and ongoing phase III Approved (Ahn et al., 2020; Huang et al., 2023; Kim et al., 2023)
Thalidomide BACE1 inhibition, Amyloid pathology, and gliosis reduction Completed phase III Adverse consequences (Decourt et al., 2017)
CHF5074 γ-Secretase modulation. Aβ reduction Completed phase II Decision unavailable (Imbimbo et al., 2013)
PBT2 RAGE inhibition, Spine density and synaptic protein level improvement Completed phase II Lack of effectiveness (Villemagne et al., 2017)
Contraloid Aβ aggregation inhibition, Amyloid deposition reduction Completed phase I Yet to be available (Kutzsche et al., 2020)
Acitretin Aβ production inhibition, Aβ reduction Completed phase II Yet to be available (Endres et al., 2014; Holthoewer et al., 2012)
Bexarotene Anti-ApoE, Aβ reduction, cognitive deficit improvement Discontinued phase II Adverse outcomes/ lack of efficiency (LaClair et al., 2013; O'Hare et al., 2016)
AN-1792 Active immunization, Amyloid plaque formation reduction Discontinued phase II Adverse events(Nicoll et al., 2003
ACC-001 Active immunization, Amyloid plaque formation prevention Discontinued phase II Adverse incidents (Maia & Sousa, 2019)
CAD106 Active immunization, Amyloid accumulation in brain reduction Discontinued phase II No results available (May et al., 2015)
Ponezumab Passive immunization, Cerebral blood vessel amyloid deposition reduction Discontinued phase II Lack of efficiency (Wessels et al., 2020)
Gammagard Passive immunization, Aβ reduction Discontinued phase II Lack of efficiency (Bullich et al., 2022; Sudduth et al., 2013)
Bapineuzumab Passive immunization, Plaque burden reduction Discontinued phase II Lack of efficiency (Henley et al., 2019)
Crenezumab Passive immunization, Localized to Aβ oligomers Discontinued phase II Lack of efficiency (Doody et al., 2013)
Gantenerumab Passive immunization, Ongoing phase III Yet to be available (Coric et al., 2015; Coric et al., 2012)
Atabecestat BACE1 inhibition, reverse amyloid pathology and cognitive deficit Discontinued phase II/III Clinical worsening(Henley et al., 2019),(Thakker et al., 2015)
Elenbecestat BACE1 inhibition, Brain, CSF, and plasma Aβ reduction Discontinued phase III Unfavorable risk-benefit ratio (Bullich et al., 2022)
LY2886721 BACE1 inhibition, Dose-dependent Aβ reduction Discontinued phase II Adverse consequence (May et al., 2015)
Lanabecestat BACE1 inhibition, Aβ reduction Discontinued phase III Lack of effectiveness (Wessels et al., 2020)
PF-06751979 BACE1 inhibition, CSF Aβ42 reduction Discontinued phase I Pfizer ended R&D in neurology (O'Neill et al., 2018; Qiu et al., 2019)
RG7129 BACE1 inhibition, Aβ reduction Discontinued phase I Adverse incidents (Jacobsen et al., 2014; Maia & Sousa, 2019)
Verubecestat Dose dependent Aβ40,42 reduction Discontinued phase III Clinical worsening (Egan et al., 2018; Egan, Kost, et al., 2019; Egan, Mukai, et al., 2019)
Avagacestat γ-Secretase inhibition, CSF Aβ reduction Discontinued phase II Clinical worsening/adverse events (Coric et al., 2015; Coric et al., 2012)
PF-06648671 γ-Secretase inhibition, Brain Aβ42 reduction Discontinued phase I Pfizer ended.R&D in neurology(Ahn et al., 2020; Rynearson et al., 2021)
Semagacestat γ-Secretase inhibition, Soluble Aβ and plaque reduction Discontinuedphase II Clinical worsening/adverse events (Doody et al., 2013)
Azeliragon γ-Secretase modulation, Aβ load reduction, behavioral improvement Discontinued phase III Lack of effectiveness (Burstein et al., 2018)
Tarenflurbil γ-Secretase modulation, Aβ reduction Discontinued phase III Lack of effectiveness (Green et al., 2009)
Ibuprofen γ-Secretase modulation, Aβ reduction Discontinued phase II Lack of effectiveness (Pasqualetti et al., 2009)
Clioquinol Aβ aggregation inhibition, Amyloid deposition reduction Discontinued phase III Toxic contaminant in manufacturing process (Bareggi & Cornelli, 2012; Cherny et al., 2001)
ELND005 Aβ aggregation inhibition, Amyloid pathology reduction, learning deficit restored Discontinued phase II Lack of effectiveness (Salloway et al., 2011)
Tramiprosate Aβ aggregation inhibition, Aβ40 reduction Discontinued phase III Lack of effectiveness (Abushakra et al., 2016; Manzano et al., 2020)
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
bsky
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

Privacy Settings

© 2025 MDPI (Basel, Switzerland) unless otherwise stated