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Cited by 56Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease

Open access
Thawabteh, Amin Mahmood, Ghanem, Aseel Wasel, AbuMadi, Sara, Thaher, Dania, Jaghama, Weam, Karaman, Donia, Karaman, Rafik·2024·Molecules
DOI 10.3390/molecules29215131PMC PMC11547905
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Abstract

The most prevalent chronic neurodegenerative illness in the world is Alzheimer’s disease (AD). It results in mental symptoms including behavioral abnormalities and cognitive impairment, which have a substantial financial and psychological impact on the relatives of the patients. The review discusses various pathophysiological mechanisms contributing to AD, including amyloid beta, tau protein, inflammation, and other factors, while emphasizing the need for effective disease-modifying therapeutics that alter disease progression rather than merely alleviating symptoms. This review mainly covers medications that are now being studied in clinical trials or recently approved by the FDA that fall under the disease-modifying treatment (DMT) category, which alters the progression of the disease by targeting underlying biological mechanisms rather than merely alleviating symptoms. DMTs focus on improving patient outcomes by slowing cognitive decline, enhancing neuroprotection, and supporting neurogenesis. Additionally, the review covers amyloid-targeting therapies, tau-targeting therapies, neuroprotective therapies, and others. This evaluation specifically looked at studies on FDA-approved novel DMTs in Phase II or III development that were carried out between 2021 and 2024. A thorough review of the US government database identified clinical trials of biologics and small molecule drugs for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028.

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TL;DR

This review summarizes Alzheimer’s disease pathophysiology and disease-modifying therapies, focusing on amyloid-, tau-, and neuroprotective strategies and recent FDA-approved or clinical-stage agents. It reports the 2024 AD drug development pipeline and highlights challenges including disease heterogeneity, blood–brain barrier penetration, biomarkers, and regulation.

Key findings

  • The 2024 AD drug development pipeline included 164 trials, of which 127 were testing possible treatments or medicines; 41% targeted disease-modifying small molecules and 34% targeted disease-modifying biological agents, with the remaining trials focused on cognitive or neuropsychiatric symptoms.
  • A review of the US government clinical trials database identified disease-modifying biologic and small-molecule trials for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028. Section 3.2 separately reports Phase I: 26 trials assessing 25 agents; Phase II: 90 studies of 81 medicines; Phase III: 48 trials testing 32 medications.
  • Lecanemab reduced total brain amyloid plaque burden versus placebo at 79 weeks, with a mean difference of −73.5 centiloids and −0.31 standardized uptake value ratio (SUVR) units; the treatment effect was dose- and exposure-dependent, and the study suggested a 20%–40% risk reduction in clinical symptom progression.
  • Aducanumab showed inconsistent results in the Phase III EMERGE and ENGAGE trials; FDA expedited approval was based on the EMERGE trial’s amyloid reduction. Both aducanumab and lecanemab slowed cognitive decline and reduced amyloid plaques but were more likely to cause amyloid-related imaging abnormalities (ARIAs), especially ARIA-E with aducanumab.

Methods

  • Narrative review of AD pathophysiology, disease-modifying therapeutic mechanisms, current treatments, clinical trials, and emerging therapies; no formal systematic review or meta-analysis is described.
  • The evaluation focused on studies of FDA-approved novel DMTs in Phase II or III development conducted between 2021 and 2024, and a thorough review of the US government clinical trials database identified disease-modifying biologic and small-molecule agents across phases.
  • Findings are presented in narrative text and in Tables 2 and 3, which summarize clinical trials of disease-modifying biological agents and disease-modifying small-molecule drugs, respectively.

Limitations

  • Stated challenges include disease heterogeneity complicating diagnosis, treatment, and trial design; blood–brain barrier penetration limits drug delivery, with the text noting impermeability to 98% of small molecules and around 100% of large molecules in relevant quantities; lack of validated diagnostic biomarkers and low clinical diagnostic specificity can require larger trials and inclusion of “slow/no progressors”; regulatory obstacles include inconsistent review levels and restrictions on biobanking and repository research.
  • The conclusion states that only a small percentage of AD patients benefit from the two currently approved DMTs, that more research comparing DMTs with diverse therapeutic targets and across patient groups is needed, and that natural compounds require clinical trials to verify safety and efficacy.
  • Evident from the text: this is a narrative review without a described systematic search strategy, inclusion/exclusion criteria, or risk-of-bias assessment; trial-count figures in the abstract and Section 3.2 differ, which may reflect different database snapshots or definitions.

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Crossref · 10.3390/molecules29215131

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  • Findingown data

    A thorough review of the US government database identified clinical trials of biologics and small molecule drugs for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028.

    “A thorough review of the US government database identified clinical trials of biologics and small molecule drugs for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028.”
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    The hydrophobic C-terminus of Aβ42 facilitates its aggregation and formation of senile plaques.

    “The hydrophobic C-terminus of Aβ42 facilitates its aggregation and the formation of senile plaques.”
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    • cites [11] Ma, C., Hong, F., and Yang, S. (2022). Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions. Molecules, 27. source

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    • cites [12] Hampel, 2021, The Amyloid-β Pathway in Alzheimer’s Disease, Mol. Psychiatry source

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    Mutations in PS1 can promote Aβ accumulation through increased production and impaired autophagy functions.

    “Mutations in presenilin-1 (PS1) can promote Aβ accumulation through increased production and impaired autophagy functions.”
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    • cites [11] Ma, C., Hong, F., and Yang, S. (2022). Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions. Molecules, 27. source

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    • cites [12] Hampel, 2021, The Amyloid-β Pathway in Alzheimer’s Disease, Mol. Psychiatry source

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    A reduction in synthesis and release of ACh impairs its physiological functions, which are critical for learning, memory, and other cognitive processes.

    “This hypothesis suggests that a reduction in the synthesis and release of ACh impairs its physiological functions, which are critical for learning, memory, and other cognitive processes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Chen, Z.-R., Huang, J.-B., Yang, S.-L., and Hong, F.-F. (2022). Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules, 27. source

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    • cites [9] Giacobini, 2022, Reimagining cholinergic therapy for Alzheimer’s disease, Brain source

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    Various pathological factors, such as Aβ plaques, pro-inflammatory cytokines, and oxidative stress, activate microglia, leading to release of pro-inflammatory mediators that exacerbate neurotoxicity.

    “This hypothesis posits that various pathological factors, such as Aβ plaques, pro-inflammatory cytokines, and oxidative stress, activate microglia, the central nervous system’s innate immune cells. Upon activation, microglia undergo morphological changes and initiate a variety of inflammatory responses, which can lead to the release of pro-inflammatory mediators that exacerbate neurotoxicity.”
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    • cites [15] Sinyor, 2020, Alzheimer’s Disease, Inflammation, and the Role of Antioxidants, J. Alzheimer’s Dis. Rep. source

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    • cites [16] Qian, 2021, Inflammatory pathways in Alzheimer’s disease mediated by gut microbiota, Ageing Res. Rev. source

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    Premisecitation

    AD is a progressive neurodegenerative disorder and the leading cause of dementia among older adults, characterized by a gradual decline in cognitive function, memory loss, and behavioral changes, ultimately leading to complete dependence on caregivers.

    “AD is a progressive neurodegenerative disorder and the leading cause of dementia among older adults, characterized by a gradual decline in cognitive function, memory loss, and behavioral changes, ultimately leading to complete dependence on caregivers [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Chen, Z.-R., Huang, J.-B., Yang, S.-L., and Hong, F.-F. (2022). Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules, 27. source

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    The tau protein hypothesis focuses on hyperphosphorylation of tau leading to detachment from microtubules and formation of NFTs, a hallmark of AD.

    “The tau protein hypothesis focuses on the hyperphosphorylation of tau protein leading to its detachment from microtubules, resulting in the formation of neurofibrillary tangles (NFTs) which are a hallmark of AD.”
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    • cites [13] Muralidar, 2020, Role of tau protein in Alzheimer’s disease: The prime pathological player, Int. J. Biol. Macromol. source

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    • cites [14] Arnsten, 2020, Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer’s disease, Alzheimer’s Dement. source

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    The glutamatergic hypothesis posits that dysregulation of glutamate plays a critical role in the pathogenesis of AD.

    “The glutamatergic hypothesis posits that dysregulation of glutamate, the main excitatory neurotransmitter in the central nervous system, plays a critical role in the pathogenesis of AD.”
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    • cites [10] Conway, 2020, Alzheimer’s disease: Targeting the glutamatergic system, Biogerontology source

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    The relationship between FAD mutations and Aβ levels is complex, and plaque formation in sporadic AD is influenced by a dynamic imbalance between Aβ production and clearance mechanisms.

    “However, the relationship between FAD mutations and Aβ levels is complex, and the plaque formation in sporadic AD is influenced by a dynamic imbalance between Aβ production and clearance mechanisms [11,12].”
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    • cites [11] Ma, C., Hong, F., and Yang, S. (2022). Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions. Molecules, 27. source

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    • cites [12] Hampel, 2021, The Amyloid-β Pathway in Alzheimer’s Disease, Mol. Psychiatry source

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    AChE inhibitors donepezil, rivastigmine, and galantamine have limited efficacy and do not halt disease progression.

    “AChE inhibitors, such as donepezil, rivastigmine, and galantamine, have been developed as treatments based on this hypothesis, although their efficacy is limited and they do not halt disease progression [7,9].”
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    • cites [7] Chen, Z.-R., Huang, J.-B., Yang, S.-L., and Hong, F.-F. (2022). Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules, 27. source

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    • cites [9] Giacobini, 2022, Reimagining cholinergic therapy for Alzheimer’s disease, Brain source

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    The inflammatory hypothesis suggests that chronic neuroinflammation plays a significant role in the pathogenesis of AD.

    “The inflammatory hypothesis suggests that chronic neuroinflammation plays a significant role in the pathogenesis of AD.”
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    • cites [15] Sinyor, 2020, Alzheimer’s Disease, Inflammation, and the Role of Antioxidants, J. Alzheimer’s Dis. Rep. source

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    • cites [16] Qian, 2021, Inflammatory pathways in Alzheimer’s disease mediated by gut microbiota, Ageing Res. Rev. source

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    The microbiota-gut-brain axis hypothesis suggests a bidirectional communication system between the gut and the brain, involving metabolic, endocrine, neural, and immune pathways.

    “The microbiota–gut–brain axis hypothesis suggests a bidirectional communication system between the gut and the brain, involving metabolic, endocrine, neural, and immune pathways.”
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    • cites [17] Wiatrak, B., Balon, K., Jawień, P., Bednarz, D., Jęśkowiak, I., and Szeląg, A. (2022). The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer’s Disease. Int. J. Mol. Sci., 23. source

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    • cites [18] Doifode, 2020, The impact of the microbiota-gut-brain axis on Alzheimer’s disease pathophysiology, Pharmacol. Res. source

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    The cholinergic hypothesis posits that degeneration of cholinergic neurons, particularly in the basal forebrain, is a central feature of AD and is closely linked to cognitive decline.

    “The cholinergic hypothesis posits that the degeneration of cholinergic neurons, particularly in the basal forebrain, is a central feature of AD and is closely linked to cognitive decline.”
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    • cites [7] Chen, Z.-R., Huang, J.-B., Yang, S.-L., and Hong, F.-F. (2022). Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules, 27. source

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    • cites [9] Giacobini, 2022, Reimagining cholinergic therapy for Alzheimer’s disease, Brain source

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    The pathophysiological process of AD is multifaceted, involving cholinergic, glutamatergic, amyloid, tau protein, inflammatory, microbiota-gut-brain axis, oxidative stress, metal ion, and abnormal autophagy hypotheses.

    “The pathophysiological process of AD is multifaceted, involving several key hypotheses: the cholinergic, glutamatergic, amyloid, tau protein, inflammatory, microbiota–gut–brain axis, oxidative stress, metal ion, and abnormal autophagy hypotheses, as shown in the summary of AD pathophysiology in Figure 1 [8].”
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    • cites [8] Zhang, 2024, Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies, Signal Transduct. Target. Ther. source

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    Hyperphosphorylation promotes tau aggregation into paired helical filaments and NFTs, which correlate strongly with clinical symptoms of AD.

    “This hyperphosphorylation promotes tau aggregation into paired helical filaments and NFTs, which correlate strongly with clinical symptoms of AD.”
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    • cites [13] Muralidar, 2020, Role of tau protein in Alzheimer’s disease: The prime pathological player, Int. J. Biol. Macromol. source

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    • cites [14] Arnsten, 2020, Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer’s disease, Alzheimer’s Dement. source

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    Dysbiosis can lead to a compromised intestinal epithelial barrier, allowing harmful substances and microorganisms to enter the bloodstream and trigger systemic inflammation, which may affect microglia and exacerbate neuroinflammation.

    “Dysbiosis, or disruption of the microbiota’s composition and functionality, can occur due to factors such as dietary changes, antibiotic use, psychosocial stress, or immune irregularities, leading to a compromised intestinal epithelial barrier.”
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    • cites [17] Wiatrak, B., Balon, K., Jawień, P., Bednarz, D., Jęśkowiak, I., and Szeląg, A. (2022). The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer’s Disease. Int. J. Mol. Sci., 23. source

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    • cites [18] Doifode, 2020, The impact of the microbiota-gut-brain axis on Alzheimer’s disease pathophysiology, Pharmacol. Res. source

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    Aβ originates from processing of APP through sequential cleavage by β-secretase and γ-secretase, resulting in various lengths of Aβ fragments, with Aβ40 and Aβ42 predominant.

    “Aβ originates from the processing of the amyloid precursor protein (APP) through sequential cleavage by β-secretase and γ-secretase, resulting in various lengths of Aβ fragments, with Aβ40 and Aβ42 being predominant.”
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    • cites [11] Ma, C., Hong, F., and Yang, S. (2022). Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions. Molecules, 27. source

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    • cites [12] Hampel, 2021, The Amyloid-β Pathway in Alzheimer’s Disease, Mol. Psychiatry source

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    The amyloid hypothesis emphasizes that accumulation of Aβ plaques in the brain is a central event in the pathogenesis of AD, leading to neurodegeneration and cognitive decline.

    “The amyloid hypothesis emphasizes that the accumulation of Aβ plaques in the brain is a central event in the pathogenesis of AD, leading to neurodegeneration and cognitive decline.”
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    • cites [11] Ma, C., Hong, F., and Yang, S. (2022). Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions. Molecules, 27. source

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    • cites [12] Hampel, 2021, The Amyloid-β Pathway in Alzheimer’s Disease, Mol. Psychiatry source

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    Decline in ChAT activity combined with detrimental effects of Aβ on cholinergic signaling leads to decreased ACh levels, contributing to cognitive deficits in AD patients.

    “The decline in choline acetyltransferase (ChAT) activity, combined with the detrimental effects of amyloid beta (Aβ) on cholinergic signaling, leads to decreased ACh levels. Consequently, this reduction contributes to the cognitive deficits observed in AD patients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Chen, Z.-R., Huang, J.-B., Yang, S.-L., and Hong, F.-F. (2022). Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules, 27. source

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    • cites [9] Giacobini, 2022, Reimagining cholinergic therapy for Alzheimer’s disease, Brain source

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    Tau pathology is associated with neuroinflammation, as pro-inflammatory cytokines can increase tau transcription and activate inflammatory pathways that exacerbate tau-related neurodegeneration.

    “Additionally, tau pathology is associated with neuroinflammation, as pro-inflammatory cytokines can increase tau transcription and activate inflammatory pathways that further exacerbate tau-related neurodegeneration [13,14].”
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    • cites [13] Muralidar, 2020, Role of tau protein in Alzheimer’s disease: The prime pathological player, Int. J. Biol. Macromol. source

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    • cites [14] Arnsten, 2020, Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer’s disease, Alzheimer’s Dement. source

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    Mitochondrial dysfunction reduces activities of essential enzymes and disrupts mitochondrial dynamics, contributing to oxidative stress in AD.

    “Key contributors to oxidative stress in AD include mitochondrial dysfunction, which reduces the activities of essential enzymes and disrupts mitochondrial dynamics.”
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    • cites [19] Jurcau, 2020, Oxidative Stress in the Pathogenesis of Alzheimer’s Disease and Cerebrovascular Disease with Therapeutic Implications, CNS Neurol. Disord.—Drug Targets

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    • cites [20] Bai, 2022, Oxidative stress: The core pathogenesis and mechanism of Alzheimer’s disease, Ageing Res. Rev. source

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    Exposure to air pollution may worsen neuroinflammation and cognitive decline.

    “Moreover, exposure to air pollution may worsen neuroinflammation and cognitive decline [49,50].”
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    • cites [49] Attademo, 2020, Air Pollution as Risk Factor for Mental Disorders: In Search for a Possible Link with Alzheimer’s Disease and Schizophrenia, J. Alzheimer’s Dis. source

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    • cites [50] He, 2022, Impact of air pollution exposure on the risk of Alzheimer’s disease in China: A community-based cohort study, Environ. Res. source

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    Sedentary lifestyles and bad dietary habits, such as consuming large amounts of carbs and saturated fats, are connected to increased AD risk.

    “Furthermore, sedentary lifestyles and bad dietary habits, such as consuming large amounts of carbs and saturated fats, have been connected to an increased risk [54,55,56,57].”
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    • cites [54] Gentreau, 2020, Refined carbohydrate-rich diet is associated with long-term risk of dementia and Alzheimer’s disease in apolipoprotein E ε4 allele carriers, Alzheimer’s Dement. source

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    • cites [57] Khemka, 2023, Role of diet and exercise in aging, Alzheimer’s disease, and other chronic diseases, Ageing Res. Rev. source

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    AD is categorized into three stages: mild, moderate, and severe.

    “AD is categorized into three stages: mild, moderate, and severe [24,25,26,27,28].”
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    • cites [24] Liew, 2021, Neuropsychiatric symptoms in early stage of Alzheimer’s and non-Alzheimer’s dementia, and the risk of progression to severe dementia, Age Ageing source

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    • cites [25] Cummings, 2021, The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases, Am. J. Geriatr. Psychiatry source

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    • cites [26] Wiels, W.A., Wittens, M.M.J., Zeeuws, D., Baeken, C., and Engelborghs, S. (2021). Neuropsychiatric Symptoms in Mild Cognitive Impairment and Dementia Due to AD: Relation with Disease Stage and Cognitive Deficits. Front. Psychiatry, 12. source

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    • cites [27] Devanand, 2022, Associations Between Neuropsychiatric Symptoms and Neuropathological Diagnoses of Alzheimer Disease and Related Dementias, JAMA Psychiatry source

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    • cites [28] Abbate, 2019, Signs and symptoms method in neuropsychology: A preliminary investigation of a standardized clinical interview for assessment of cognitive decline in dementia, Appl. Neuropsychol. Adult source

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    Dementia risk rises with toxic exposure to heavy metals such as lead, mercury, and aluminum.

    “Dementia risk has been shown to rise with toxic exposure to heavy metals as lead, mercury, and aluminum [45,46,47,48].”
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    • cites [45] Antoniadou, 2020, Toxic Environmental Factors and their Association with the Development of Dementia: A Mini Review on Heavy Metals and Ambient Particulate Matter, Mater. Socio Medica source

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    • cites [47] Islam, F., Shohag, S., Akhter, S., Islam, M.R., Sultana, S., Mitra, S., Chandran, D., Khandaker, M.U., Ashraf, G.M., and Idris, A.M. (2022). Exposure of metal toxicity in Alzheimer’s disease: An extensive review. Front. Pharmacol., 13. source

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    The abnormal autophagy hypothesis suggests that disruptions in autophagy are closely linked to the pathogenesis of AD.

    “The abnormal autophagy hypothesis suggests that disruptions in the autophagy process are closely linked to the pathogenesis of AD.”
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    • cites [22] Curtis, 2019, Autophagy Dysfunction in Alzheimer’s Disease: Mechanistic Insights and New Therapeutic Opportunities, Biol. Psychiatry

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    • cites [23] Hamano, 2018, The Implications of Autophagy in Alzheimer’s Disease, Curr. Alzheimer Res. source

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    Mutations in PSEN1, PSEN2, and APP can cause early-onset familial AD, which often manifests before age 65.

    “The most well-known genes are those for presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP). Mutations in these genes can cause early-onset familial AD, which often manifests before the age of 65 [38].”
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    The two main gene categories associated with AD are deterministic and risk-factor genes.

    “The two main gene categories associated with AD are deterministic and risk-factor genes [29,37].”
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    • cites [29] Scheltens, 2021, Alzheimer’s disease, Lancet source

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    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

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    Genetics is one of the main variables that causes AD, with certain inherited genes connected to the condition as risk factors.

    “One of the main variables that causes AD is genetics. Certain genes that are inherited have been connected to the condition as risk factors.”
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    • cites [29] Scheltens, 2021, Alzheimer’s disease, Lancet source

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    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

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    AD risk factors include obesity, diabetes, high blood pressure, and high cholesterol.

    “AD risk factors include obesity, diabetes, high blood pressure, and high cholesterol [51,52,53].”
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    • cites [51] Yang, 2022, Association of Healthy Lifestyles with Risk of Alzheimer Disease and Related Dementias in Low-Income Black and White Americans, Neurology source

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    • cites [52] Heneghan, 2023, Modifiable Lifestyle Activities Affect Cognition in Cognitively Healthy Middle-Aged Individuals at Risk for Late-Life Alzheimer’s Disease, J. Alzheimer’s Dis. source

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    • cites [53] Shafighi, K., Villeneuve, S., Neto, P.R., Badhwar, A., Poirier, J., Sharma, V., Medina, Y.I., Silveira, P.P., Dube, L., and Glahn, D. (2023). Social isolation is linked to classical risk factors of Alzheimer’s disease-related dementias. PLoS ONE, 18. source

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    The most common symptoms of AD are short-term memory loss, followed by progressive impairment in implicit and explicit memory, and neuropsychiatric symptoms with eventual loss of ability to perform basic daily duties.

    “The most common symptoms of AD are short-term memory loss, which is followed by a progressive impairment in both implicit and explicit memory. Those who have the condition also exhibit neuropsychiatric symptoms, and with time, they lose their ability to perform basic daily duties [24,25,26,27,28].”
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    • cites [24] Liew, 2021, Neuropsychiatric symptoms in early stage of Alzheimer’s and non-Alzheimer’s dementia, and the risk of progression to severe dementia, Age Ageing source

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    • cites [25] Cummings, 2021, The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases, Am. J. Geriatr. Psychiatry source

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    • cites [26] Wiels, W.A., Wittens, M.M.J., Zeeuws, D., Baeken, C., and Engelborghs, S. (2021). Neuropsychiatric Symptoms in Mild Cognitive Impairment and Dementia Due to AD: Relation with Disease Stage and Cognitive Deficits. Front. Psychiatry, 12. source

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    • cites [27] Devanand, 2022, Associations Between Neuropsychiatric Symptoms and Neuropathological Diagnoses of Alzheimer Disease and Related Dementias, JAMA Psychiatry source

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    • cites [28] Abbate, 2019, Signs and symptoms method in neuropsychology: A preliminary investigation of a standardized clinical interview for assessment of cognitive decline in dementia, Appl. Neuropsychol. Adult source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The emotional toll of AD is high, causing worry, despair, and exhaustion in caregivers.

    “The emotional toll is high, causing worry, despair, and exhaustion in those who provide care [35,36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Vu, 2022, Impact of Alzheimer’s Disease on Caregivers in the United States, Health Psychol. Res. source

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    • cites [36] Kerwin, 2022, Alzheimer’s disease diagnosis and management: Perspectives from around the world, Alzheimer’s Dement. Diagn. Assess. Dis. Monit.

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    Premisecitation

    Metal dyshomeostasis can lead to oxidative stress, which is linked to amyloidosis and tauopathy.

    “This hypothesis suggests that metal dyshomeostasis can lead to oxidative stress, which is linked to various pathological events in AD, such as amyloidosis and tauopathy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Chen, L.-L., Fan, Y.-G., Zhao, L.-X., Zhang, Q., and Wang, Z.-Y. (2022). The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators. Bioorganic Chem., 131. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients with AD and their families, as well as the healthcare system, bear a heavy burden, with families dealing with social, economic, and emotional difficulties as the illness worsens.

    “Patients with AD and their families, as well as the healthcare system, bear a heavy burden. Families must deal with social, economic, and emotional difficulties as the illness worsens.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Vu, 2022, Impact of Alzheimer’s Disease on Caregivers in the United States, Health Psychol. Res. source

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    • cites [36] Kerwin, 2022, Alzheimer’s disease diagnosis and management: Perspectives from around the world, Alzheimer’s Dement. Diagn. Assess. Dis. Monit.

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Maintaining cardiovascular health, eating a balanced diet rich in antioxidants, and exercising frequently can lower the incidence of AD.

    “Conversely, maintaining cardiovascular health, eating a balanced diet rich in antioxidants, and exercising frequently can all lower the incidence of AD [55,58].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Frausto, D.M., Forsyth, C.B., Keshavarzian, A., and Voigt, R.M. (2021). Dietary Regulation of Gut-Brain Axis in Alzheimer’s Disease: Importance of Microbiota Metabolites. Front. Neurosci., 15. source

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    • cites [58] Zhu, 2021, Dietary fatty acids and risk for Alzheimer’s disease, dementia, and mild cognitive impairment: A prospective cohort meta-analysis, Nutrition source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Amyloidogenic proteins (Aβ) and tau are examples of heat-shock proteins (HSPs) that can both promote and inhibit the aggregation of misfolded proteins.

    “Amyloidogenic proteins (Aβ) and tau are two examples of heat-shock proteins (HSPs) that can both promote and inhibit the aggregation of misfolded proteins [37,101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

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    • cites [101] Yang, 2019, Heat Shock Protein Inspired Nanochaperones Restore Amyloid-β Homeostasis for Preventative Therapy of Alzheimer’s Disease, Adv. Sci. source

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    Premisecitation

    According to the amyloid cascade hypothesis, tau protein tangles and neuroinflammation are brought on by Aβ aggregation, which in turn leads to neuronal death and cognitive decline.

    “According to the amyloid cascade hypothesis, tau protein tangles and neuroinflammation are brought on by Aβ aggregation, which in turn leads to neuronal death and cognitive decline [90,91,92].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] Rabinovici, 2023, Amyloid-Targeting Monoclonal Antibodies for Alzheimer Disease, JAMA source

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    • cites [91] Fedele, E. (2023). Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis. Int. J. Mol. Sci., 24. source

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    • cites [92] Qiao, 2024, Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer’s Disease: A Systematic Review and Network Meta-Analysis, CNS Drugs source

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    Premisecitation

    Tau pathology has a stronger correlation with cognitive deficits than Aβ plaques, indicating treatment benefits from targeting tau may outweigh those from concentrating only on amyloid clearance.

    “Research has indicated that tau pathology has a stronger correlation with cognitive deficits than Aβ plaques, indicating that treatment benefits from targeting tau may outweigh those from concentrating only on amyloid clearance [94,95].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Congdon, 2023, Tau-targeting therapies for Alzheimer disease: Current status and future directions, Nat. Rev. Neurol. source

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    • cites [95] Congdon, 2018, Tau-targeting therapies for Alzheimer disease, Nat. Rev. Neurol. source

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    Premisecitation

    Inadequate operation of HSP systems can lead to oxidative stress, mitochondrial dysfunction, and other pathological conditions that damage the body, cause neuronal death, and exacerbate dementia.

    “Inadequate operation of these systems can lead to oxidative stress, mitochondrial dysfunction, and various other pathological conditions that damage the body, cause neuronal death, and exacerbate dementia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

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    • cites [101] Yang, 2019, Heat Shock Protein Inspired Nanochaperones Restore Amyloid-β Homeostasis for Preventative Therapy of Alzheimer’s Disease, Adv. Sci. source

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    Premisecitation

    Donepezil is authorized for treatment of AD in all phases and reversibly binds to acetylcholinesterase, slowing hydrolysis of acetylcholine and increasing ACh concentration at synapses.

    “The second generation of AChEIs, donepezil (labeled as 1, Figure 5), is an indanonebenzylpiperidine derivative that is authorized for the treatment of AD in all phases. By reversibly binding to acetylcholinesterase, it slows the hydrolysis of acetylcholine, increasing the concentration of ACh at synapses [106,107].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Cummings, 2021, New approaches to symptomatic treatments for Alzheimer’s disease, Mol. Neurodegener.

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    • cites [107] Eissa, 2022, Development of new Alzheimer’s disease drug candidates using donepezil as a key model, Arch. Der Pharm. source

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    Premisecitation

    Several clinical investigations focusing on Aβ have produced contradictory findings, casting doubt on the veracity of the amyloid theory in general.

    “Several clinical investigations focusing on Aβ have produced contradictory findings, casting doubt on the veracity of the amyloid theory in general.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] Zhang, 2023, Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future, Signal Transduct. Target. Ther. source

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    • cites [93] Wu, 2024, Targeting aging and age-related diseases with vaccines, Nat. Aging source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    DMTs are treatments that postpone, moderate, or even reverse the evolution of an illness by addressing its underlying cause.

    “DMTs are treatments that postpone, moderate, or even reverse the evolution of an illness by addressing its underlying cause.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Sperling, 2022, Meaningful benefits: A framework to assess disease-modifying therapies in preclinical and early Alzheimer’s disease, Alzheimer’s Res. Ther. source

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    • cites [59] Forester, 2020, Setbacks and Opportunities in Disease-Modifying Therapies in Alzheimer Disease, JAMA Psychiatry source

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    • cites [60] Morató, X., Pytel, V., Jofresa, S., Ruiz, A., and Boada, M. (2022). Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach. Int. J. Mol. Sci., 23. source

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    Premisecitation

    Galantamine is a first-line medication for mild-to-severe AD with good efficacy and tolerability in improving behavioral symptoms, activities of daily living, and cognitive performance.

    “It is a first-line medication for mild-to-severe AD that has a good efficacy and tolerability in improving behavioral symptoms, activities of daily living, and cognitive performance [110,112,113].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [110] Manickam, 2022, Galantamine tethered hydrogel as a novel therapeutic target for streptozotocin-induced Alzheimer’s disease in Wistar rats, Curr. Res. Pharmacol. Drug Discov. source

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    • cites [112] Kaur, 2022, Galantamine: A Review Update, J. Drug Deliv. Ther. source

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    • cites [113] Santos, 2020, Use of galantamine in the treatment of Alzheimer’s disease and strategies to optimize its biosynthesis using the in vitro culture technique, Plant Cell Tissue Organ Cult. (PCTOC) source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DMTs are intended to delay progression of long-term conditions such as AD and ultimately improve patient's quality of life.

    “DMTs are intended to delay the progression of long-term conditions such as AD and ultimately improve the patient’s quality of life [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Morató, X., Pytel, V., Jofresa, S., Ruiz, A., and Boada, M. (2022). Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach. Int. J. Mol. Sci., 23. source

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    Premisecitation

    Aβ buildup can start 15-20 years before clinical symptoms appear, indicating therapy effectiveness may depend on early intervention.

    “Studies have shown that Aβ buildup can start 15–20 years before clinical symptoms appear, indicating that therapy effectiveness may depend on early intervention [88,89].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [88] Panza, 2019, A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease, Nat. Rev. Neurol. source

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    • cites [89] Shi, M., Chu, F., Zhu, F., and Zhu, J. (2022). Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab. Front. Aging Neurosci., 14. source

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    Premisecitation

    While lowering Aβ levels can decrease cognitive deterioration, not all patients will definitely see improved clinical outcomes from this strategy.

    “While lowering Aβ levels can decrease cognitive deterioration, not all patients will definitely see improved clinical outcomes from this strategy, according to certain research [86,93].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] Zhang, 2023, Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future, Signal Transduct. Target. Ther. source

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    • cites [93] Wu, 2024, Targeting aging and age-related diseases with vaccines, Nat. Aging source

      Not checked in the free run.

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    Premisecitation

    Memantine is safe and well-tolerated and is used to treat moderate-to-severe AD alone or in combination with AChEI.

    “Memantine is safe and well-tolerated; it is used to treat moderate-to-severe AD alone or in combination with AChEI [124,125,126].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [124] Marotta, G., Basagni, F., Rosini, M., and Minarini, A. (2020). Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease. Molecules, 25. source

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    • cites [125] Turcu, 2022, Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer’s disease, Eur. J. Med. Chem. source

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    • cites [126] Wu, 2021, Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer’s disease, Aging Cell source

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    Premisecitation

    Aducanumab is the first disease-modifying medication for AD, a recombinant monoclonal antibody targeting amyloid beta specifically, and functions by lowering amyloid deposits or brain plaques.

    “The first disease-modifying medication for AD is a recombinant monoclonal antibody called aducanumab, also known by the brand name Aduhelm. It targets amyloid beta specifically [37]. It functions by lowering the quantity of amyloid deposits or brain plaques [130,131].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

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    • cites [130] Rahman, 2023, Aducanumab for the treatment of Alzheimer’s disease: A systematic review, Psychogeriatrics source

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    • cites [131] Wojtunik-Kulesza, K., Rudkowska, M., and Orzeł-Sajdłowska, A. (2023). Aducanumab—Hope or Disappointment for Alzheimer’s Disease. Int. J. Mol. Sci., 24. source

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    Premisecitation

    Compared to oral pills, transdermal patches are more pleasant and provide a smaller dosage, leading to fewer side effects.

    “Compared to oral pills, transdermal patches are more pleasant and provide a smaller dosage, which leads to fewer side effects.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [119] Rompicherla, 2021, Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease, Naunyn-Schmiedeberg S Arch. Pharmacol. source

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    • cites [120] Guo, 2024, Rivastigmine nasal spray for the treatment of Alzheimer’s Disease: Olfactory deposition and brain delivery, Int. J. Pharm. source

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    • cites [121] Ezzat, S.M., Salem, M.A., Mahdy, N.M.E., and Ragab, M.F. (2021). Rivastigmine. Naturally Occurring Chemicals Against Alzheimer’s Disease, Elsevier. source

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    Premisecitation

    Reduction in amyloid-beta brain plaques and encouraging clinical outcomes in one of two pivotal Phase III trials were factors cited for aducanumab's expedited approval.

    “The reduction in amyloid-beta brain plaques, a purported surrogate endpoint that indicates the “progression” of AD, and the encouraging clinical outcomes in one of the two pivotal Phase III trials were two of the factors cited for aducanumab’s expedited approval [130,134,135,136].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [130] Rahman, 2023, Aducanumab for the treatment of Alzheimer’s disease: A systematic review, Psychogeriatrics source

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    • cites [134] Dunn, 2021, Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective, JAMA Intern. Med. source

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    • cites [135] Mullard, 2023, FDA approves second anti-amyloid antibody for Alzheimer disease, Nat. Rev. Drug Discov. source

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    • cites [136] Reardon, 2023, FDA approves Alzheimer’s drug lecanemab amid safety concerns, Nature source

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    Premisecitation

    CAD106 is an active Aβ immunotherapy currently undergoing clinical development, involving multiple doses of whole Aβ1-6 peptide linked to ADP-Q carrier, a virus-like particle that generates high-titer anti-Aβ antibodies.

    “CAD106, a further active Aβ immunotherapy, is presently undergoing clinical development. It involves administering multiple doses of the whole Aβ1–6 peptide linked to the ADP-Q carrier, a virus-like particle that generates high-titer anti-Aβ antibodies [140,141,153,154].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [140] Bhadane, 2024, Immunotherapeutic approaches for Alzheimer’s disease: Exploring active and passive vaccine progress, Brain Res. source

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    • cites [141] Parrocha, 2022, Current peptide vaccine and immunotherapy approaches against Alzheimer’s disease, Pept. Sci. source

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    • cites [153] Riviere, 2023, Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes, Alzheimer’s Dement. source

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    • cites [154] Thakur, 2023, Attempts to Develop Vaccines Against Alzheimer’s Disease: A Systematic Review of Ongoing and Completed Vaccination Trials in Humans, Cureus

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    Premisecitation

    Lecanemab is a humanized IgG1 monoclonal antibody specifically targeting aggregated forms of amyloid beta and was given fast approval by the FDA.

    “Lecanemab (LEQEMBI, brand name), a different monoclonal antibody known as humanized immunoglobulin G1 (IgG1), which specifically targets aggregated forms of amyloid beta, was also given fast approval by the FDA earlier in the year [134,135,136].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [134] Dunn, 2021, Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective, JAMA Intern. Med. source

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    • cites [135] Mullard, 2023, FDA approves second anti-amyloid antibody for Alzheimer disease, Nat. Rev. Drug Discov. source

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    • cites [136] Reardon, 2023, FDA approves Alzheimer’s drug lecanemab amid safety concerns, Nature source

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    Premisecitation

    CNP520 (umibecestat) has been shown to reduce burden of amyloid-beta plaques in preclinical animals and is currently undergoing testing phases.

    “Similar to other BACE-1 inhibitors, CNP520 (umibecestat (labeled as 11, Figure 5)) has been shown to reduce the burden of amyloid-beta plaques in preclinical animals; it is presently undergoing testing phases [157,166,167].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [157] Piton, 2018, Alzheimer’s Disease: Advances in Drug Development, J. Alzheimer’s Dis. source

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    • cites [166] Machauer, 2021, Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer’s Disease, J. Med. Chem. source

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    • cites [167] Neumann, 2018, The BACE -1 inhibitor CNP 520 for prevention trials in Alzheimer’s disease, EMBO Mol. Med. source

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    Premisecitation

    Rivastigmine is authorized for use in mild-to-moderate Parkinson's disease dementia and mild-to-moderate AD.

    “It is authorized for use in mild-to-moderate Parkinson’s disease dementia and mild-to-moderate AD [116,117,118].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [116] Ray, 2020, Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease, Transl. Psychiatry source

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    • cites [117] Vicente-Zurdo, D., Rosales-Conrado, N., León-González, M.E., Brunetti, L., Piemontese, L., Pereira-Santos, A.R., Cardoso, S.M., Madrid, Y., Chaves, S., and Santos, M.A. (2022). Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease. Biomedicines, 10. source

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    • cites [118] Shamsi, 2020, Probing the interaction of Rivastigmine Tartrate, an important Alzheimer’s drug, with serum albumin: Attempting treatment of Alzheimer’s disease, Int. J. Biol. Macromol. source

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    Premisecitation

    Methylene blue was tried in Phase II clinical trials for mild-to-moderate AD for suppressing tau aggregation and has drawn criticism due to binding efficiency problems showing blue discolorations in urine.

    “Due to problems with binding efficiency, which show up as blue discolorations in urine, methylene blue (labeled as 12, Figure 5), which was also tried in Phase II clinical trials for mild-to-moderate AD (for suppressing tau aggregation), has drawn a lot of criticism [168,169,170].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [168] Soeda, 2019, Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease, J. Alzheimer’s Dis. source

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    • cites [169] Berrocal, M., Caballero-Bermejo, M., Gutierrez-Merino, C., and Mata, A.M. (2019). Methylene Blue Blocks and Reverses the Inhibitory Effect of Tau on PMCA Function. Int. J. Mol. Sci., 20. source

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    • cites [170] How, 2018, Exploring the effects of methylene blue on amyloid fibrillogenesis of lysozyme, Int. J. Biol. Macromol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Phase II trials include 90 studies and 81 medicines.

    “Phase II trials (90 studies, 81 medicines): these trials continue to investigate the drugs’ safety and efficacy.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

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    • cites [183] Cummings, 2024, Alzheimer’s disease drug development pipeline: 2024, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

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    • cites [184] Huang, L.-K., Kuan, Y.-C., Lin, H.-W., and Hu, C.-J. (2023). Clinical trials of new drugs for Alzheimer disease: A 2020–2023 update. J. Biomed. Sci., 30. source

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    Premisecitation

    Saracatinib (AZD0530) is a tyrosine kinase inhibitor undergoing Phase II trials and has been demonstrated to improve memory in transgenic mice models of AD.

    “The tyrosine kinase inhibitor saracatinib (AZD0530 (labeled as 14, Figure 5)) is undergoing Phase II trials [174,175,176] and has been demonstrated to improve memory in transgenic mice models of AD.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [174] Fagiani, 2020, Targeting dementias through cancer kinases inhibition, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

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    • cites [175] Ramos, R., and Vale, N. (2024). Dual Drug Repurposing: The Example of Saracatinib. Int. J. Mol. Sci., 25. source

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    • cites [176] Tridente, G., Jana, A., Nath, A., and Ashraf, G.M. (2023). Protein kinase inhibitors as therapeutics in neurodegenerative and psychiatric disorders. Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders, Academic Press. source

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    Premisecitation

    The mean difference in brain amyloid between lecanemab and placebo was −73.5 centiloides and −0.31 SUVR units.

    “In particular, a mean difference of −73.5 centiloides and −0.31 standardized uptake value ratio (SUVR) units was found between the lecanemab and placebo treatment groups.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [187] Mukhopadhyay, 2021, A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer’s Disease, J. Alzheimer’s Dis. source

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    • cites [188] Swanson, 2021, A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody, Alzheimer’s Res. Ther. source

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    Premisecitation

    PDE4 inhibitors include roflumilast, an oral small compound that selectively inhibits PDE4, an enzyme involved in controlling cAMP levels, and may lessen inflammation and increase neuronal survival.

    “PDE4 inhibitors, which are oral small compounds that selectively inhibit PDE4, an enzyme involved in controlling cAMP levels, include roflumilast (15, Figure 5), which may lessen inflammation and increase neuronal survival [177,178,179,180].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [177] Wang, 2020, The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer’s Disease: A Preclinical Study in APP/PS1 Transgenic Mice, Int. J. Neuropsychopharmacol. source

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    • cites [178] Sugin, 2020, Roflumilast: A potential drug for the treatment of cognitive impairment?, Neurosci. Lett. source

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    • cites [179] Hu, 2019, Synthesis and evaluation of clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of Alzheimer’s disease, Eur. J. Med. Chem. source

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    • cites [180] Hasan, 2022, Roflumilast Reduces Pathological Symptoms of Sporadic Alzheimer’s Disease in Rats Produced by Intracerebroventricular Streptozotocin by Inhibiting NF-κB/BACE-1 Mediated Aβ Production in the Hippocampus and Activating the cAMP/BDNF Signalling Pathway, Neurotox. Res. source

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    Premisecitation

    Of these trials, 41% look into disease-modifying small molecule medications, 34% look into biological agents that change disease, and the remaining trials focus on treatments that improve cognitive function or address neuropsychiatric symptoms linked to AD.

    “Of these trials, 41% look into disease-modifying small molecule medications, 34% look into biological agents that change disease, and the remaining trials focus on treatments that improve cognitive function or address neuropsychiatric symptoms linked to ADs [68,70,71,182,183,184].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [68] Cummings, 2022, Alzheimer’s disease drug development pipeline: 2022, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

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    • cites [70] Cummings, 2020, Alzheimer’s disease drug development pipeline: 2020, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

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    • cites [71] Cummings, 2023, Alzheimer’s disease drug development pipeline: 2023, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

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    • cites [182] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

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    • cites [183] Cummings, 2024, Alzheimer’s disease drug development pipeline: 2024, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [184] Huang, L.-K., Kuan, Y.-C., Lin, H.-W., and Hu, C.-J. (2023). Clinical trials of new drugs for Alzheimer disease: A 2020–2023 update. J. Biomed. Sci., 30. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 2024 AD drug development pipeline includes 164 trials, of which 127 are exploring possible treatments or medicines.

    “The most recent list of studies was provided by the 2024 AD drug development pipeline, which includes 164 trials (of which 127 are exploring possible treatments or medicines).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [68] Cummings, 2022, Alzheimer’s disease drug development pipeline: 2022, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [70] Cummings, 2020, Alzheimer’s disease drug development pipeline: 2020, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [71] Cummings, 2023, Alzheimer’s disease drug development pipeline: 2023, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [182] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [183] Cummings, 2024, Alzheimer’s disease drug development pipeline: 2024, Alzheimer’s Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [184] Huang, L.-K., Kuan, Y.-C., Lin, H.-W., and Hu, C.-J. (2023). Clinical trials of new drugs for Alzheimer disease: A 2020–2023 update. J. Biomed. Sci., 30. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The BBB is impermeable to 98% of small molecules and around 100% of large molecules in relevant quantities.

    “The BBB is impermeable to 98% of small molecules and around 100% of large molecules in relevant quantities.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [193] Conrado, 2020, Challenges in Alzheimer’s Disease Drug Discovery and Development: The Role of Modeling, Simulation, and Open Data, Clin. Pharmacol. Ther. source

      Not checked in the free run.

    • cites [194] Abduljawad, A.A., Elawad, M.A., Elkhalifa, M.E.M., Ahmed, A., Hamdoon, A.A.E., Salim, L.H.M., Ashraf, M., Ayaz, M., Hassan, S.S.U., and Bungau, S. (2022). Alzheimer’s Disease as a Major Public Health Concern: Role of Dietary Saponins in Mitigating Neurodegenerative Disorders and Their Underlying Mechanisms. Molecules, 27. source

      Not checked in the free run.

    • cites [195] Ribba, B. (2023). Reinforcement learning as an innovative model-based approach: Examples from precision dosing, digital health and computational psychiatry. Front. Pharmacol., 13. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The phenomenon of slow/no progressors is most likely caused by uncertainties in AD pathophysiology, such as lack of validated diagnostic biomarkers and low specificity of clinical diagnosis.

    “This phenomenon is most likely caused by uncertainties in AD pathophysiology, such as the lack of validated diagnostic biomarkers and the low specificity of clinical diagnosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The treatment effect of lecanemab increased in a dose- and exposure-dependent manner, with 25% AUC therapy probably superior to placebo by >0.64.

    “Additionally, the treatment impact increased in a dose- and exposure-dependent manner; a 25% AUC therapy was probably superior to a placebo by >0.64.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [187] Mukhopadhyay, 2021, A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer’s Disease, J. Alzheimer’s Dis. source

      Not checked in the free run.

    • cites [188] Swanson, 2021, A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody, Alzheimer’s Res. Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One regulatory obstacle in creating DMTs for AD is insufficient knowledge and ability of regional regulatory organizations, in addition to post-study medication administration and sustained treatment supply.

    “One of the regulatory obstacles in creating DMTs for AD is the insufficient knowledge and ability of regional regulatory organizations, in addition to post-study medication administration and sustained treatment supply.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [196] Ndebele, 2014, Regulatory Challenges Associated with Conducting Multicountry Clinical Trials in Resource-Limited Settings, JAIDS J. Acquir. Immune Defic. Syndr. source

      Not checked in the free run.

    • cites [197] Alemayehu, 2018, Barriers for conducting clinical trials in developing countries—A systematic review, Int. J. Equity Health source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The goal of tau treatments is to prevent tau from aggregating and spreading.

    “The goal of tau treatments is to prevent tau from aggregating and spreading.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [198] Sinsky, J., Pichlerova, K., and Hanes, J. (2021). Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies. Int. J. Mol. Sci., 22. source

      Not checked in the free run.

    • cites [199] Alquezar, C., Arya, S., and Kao, A.W. (2021). Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation. Front. Neurol., 11. source

      Not checked in the free run.

    • cites [200] Yang, J., Zhi, W., and Wang, L. (2024). Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review. Molecules, 29. source

      Not checked in the free run.

    • cites [201] Sigurdsson, 2018, Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1, J. Alzheimer’s Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both aducanumab and lecanemab slowed cognitive decline and reduced amyloid plaques, but were more likely to cause ARIAs, thought to be the most significant side effect of both drugs.

    “While both aducanumab and lecanemab slowed cognitive decline and reduced amyloid plaques, they were more likely to cause amyloid-related imaging abnormalities (ARIAs), which are thought to be the most significant side effect of both drugs.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

      Not checked in the free run.

    • cites [92] Qiao, 2024, Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer’s Disease: A Systematic Review and Network Meta-Analysis, CNS Drugs source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are several review levels with conflicting results and different guidelines for participant reimbursement for trial-related injuries.

    “Moreover, there are several review levels with conflicting results and different guidelines for participant reimbursement for trial-related injuries.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [196] Ndebele, 2014, Regulatory Challenges Associated with Conducting Multicountry Clinical Trials in Resource-Limited Settings, JAIDS J. Acquir. Immune Defic. Syndr. source

      Not checked in the free run.

    • cites [197] Alemayehu, 2018, Barriers for conducting clinical trials in developing countries—A systematic review, Int. J. Equity Health source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Even more targeted strategies are being developed to enhance neurotransmitter activity.

    “Even more targeted strategies are being developed to enhance neurotransmitter activity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [209] Pham, 2023, Novel approaches to increase synaptic resilience as potential treatments for Alzheimer’s disease, Semin. Cell Dev. Biol. source

      Not checked in the free run.

    • cites [210] Skaper, 2017, Synaptic Plasticity, Dementia and Alzheimer Disease, CNS Neurol. Disord.—Drug Targets source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PSEN1 and PSEN2 mutations are important genetic factors closely associated with early-onset AD and impact γ-secretase cleavage products such as Aβ.

    “PSEN1 and PSEN2 mutations, which are closely associated with early-onset AD and impact the γ-secretase cleavage products, such as Aβ, are important genetic factors.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

      Not checked in the free run.

    • cites [213] AlMansoori, M.E., Jemimah, S., Abuhantash, F., and AlShehhi, A. (2024). Predicting early Alzheimer’s with blood biomarkers and clinical features. Sci. Rep., 14. source

      Not checked in the free run.

    • cites [214] Kesu, S.M.R., Sinha, N., and Ramasangu, H. (2024). Cellular Automata Framework for Dementia Classification Using Explainable AI. Eng. Proc., 68. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 agonists are being investigated as potential therapeutic agents because they reduce inflammation and encourage amyloid-beta microglial phagocytosis.

    “TREM2 agonists are being investigated as potential therapeutic agents since they reduce inflammation and encourage amyloid-beta microglial phagocytosis [202,203,204,205].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [202] Yang, 2020, TREM2 ectodomain and its soluble form in Alzheimer’s disease, J. Neuroinflamm. source

      Not checked in the free run.

    • cites [203] Huang, W., Huang, J., Huang, N., and Luo, Y. (2023). The role of TREM2 in Alzheimer’s disease: From the perspective of Tau. Front. Cell Dev. Biol., 11. source

      Not checked in the free run.

    • cites [204] Shi, Q., Gutierrez, R.A., and Bhat, M.A. (2024). Microglia, Trem2, and Neurodegeneration. Neuroscientist, 10738584241254118. source

      Not checked in the free run.

    • cites [205] Pocock, 2024, Microglia and TREM2, Neuropharmacology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Finding preventative drugs derived from conventional herbal remedies is one approach to treating AD.

    “Finding preventative drugs derived from conventional herbal remedies is one approach to treating AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These AI systems have demonstrated notable advances in diagnostic performance, particularly in radiology.

    “These systems have demonstrated notable advances in diagnostic performance, particularly in radiology.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

      Not checked in the free run.

    • cites [213] AlMansoori, M.E., Jemimah, S., Abuhantash, F., and AlShehhi, A. (2024). Predicting early Alzheimer’s with blood biomarkers and clinical features. Sci. Rep., 14. source

      Not checked in the free run.

    • cites [216] Forloni, 2020, Alzheimer’s disease: From basic science to precision medicine approach, BMJ Neurol. Open source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This neuroimaging allows for disease stratification and may facilitate an earlier diagnosis.

    “This allows for disease stratification and may even facilitate an earlier diagnosis [214,215].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [214] Kesu, S.M.R., Sinha, N., and Ramasangu, H. (2024). Cellular Automata Framework for Dementia Classification Using Explainable AI. Eng. Proc., 68. source

      Not checked in the free run.

    • cites [215] Arafah, A., Khatoon, S., Rasool, I., Khan, A., Rather, M.A., Abujabal, K.A., Faqih, Y.A.H., Rashid, H., Rashid, S.M., and Ahmad, S.B. (2023). The Future of Precision Medicine in the Cure of Alzheimer’s Disease. Biomedicines, 11. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Certain dysregulated proteostasis, dysregulated circadian rhythms, inflammation, oxidative stress, tau proteinopathies, and dysregulated metabolism may all be treated therapeutically with some DMTs.

    “Certain dysregulated proteostasis, dysregulated circadian rhythms, inflammation, oxidative stress, tau proteinopathies, and dysregulated metabolism may all be treated therapeutically with some DMTs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Combination therapy targets different pharmacologic targets (such as tau and amyloid) or targets pathways sequentially by using successive combinations.

    “Combination therapy is another example; it targets different pharmacologic targets (such as tau and amyloid) or targets pathways sequentially by using successive combinations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Cummings, 2019, Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options, J. Alzheimer’s Dis. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    New advances in synthetic biology and genomics open up new avenues for discovering and using the medicinal properties of plants.

    “New advances in synthetic biology and genomics open up new avenues for discovering and using the medicinal properties of plants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These blood-based markers provide information about the underlying pathophysiology of AD and are crucial for detecting the disease, especially in those with memory problems.

    “These markers provide information about the underlying pathophysiology of AD and are crucial for detecting the disease, especially in those who have memory problems.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [214] Kesu, S.M.R., Sinha, N., and Ramasangu, H. (2024). Cellular Automata Framework for Dementia Classification Using Explainable AI. Eng. Proc., 68. source

      Not checked in the free run.

    • cites [215] Arafah, A., Khatoon, S., Rasool, I., Khan, A., Rather, M.A., Abujabal, K.A., Faqih, Y.A.H., Rashid, H., Rashid, S.M., and Ahmad, S.B. (2023). The Future of Precision Medicine in the Cure of Alzheimer’s Disease. Biomedicines, 11. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AI systems are very good at finding patterns, assessing large volumes of data, and forecasting the likelihood of developing diseases.

    “These AI systems are very good at finding patterns, assessing large volumes of data, and forecasting the likelihood of developing diseases.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

      Not checked in the free run.

    • cites [213] AlMansoori, M.E., Jemimah, S., Abuhantash, F., and AlShehhi, A. (2024). Predicting early Alzheimer’s with blood biomarkers and clinical features. Sci. Rep., 14. source

      Not checked in the free run.

    • cites [216] Forloni, 2020, Alzheimer’s disease: From basic science to precision medicine approach, BMJ Neurol. Open source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AI systems have been approved by the FDA for enhancing medical imaging assessments, including the identification of suspicious lesions.

    “AI systems have been approved by the US Food and Drug Administration (FDA) for enhancing medical imaging assessments, including the identification of suspicious lesions [37,213,216].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25. source

      Not checked in the free run.

    • cites [213] AlMansoori, M.E., Jemimah, S., Abuhantash, F., and AlShehhi, A. (2024). Predicting early Alzheimer’s with blood biomarkers and clinical features. Sci. Rep., 14. source

      Not checked in the free run.

    • cites [216] Forloni, 2020, Alzheimer’s disease: From basic science to precision medicine approach, BMJ Neurol. Open source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multifunctional compounds incorporate several activities or targets into a single medication.

    “Another type of combination therapy is represented by multifunctional compounds, which incorporate several activities or targets into a single medication.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Cummings, 2019, Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options, J. Alzheimer’s Dis. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Combining pharmacological therapies with lifestyle changes, cognitive training, and psychosocial support becomes a comprehensive care paradigm.

    “It becomes a comprehensive care paradigm when pharmacological therapies are combined with lifestyle changes, cognitive training, and psychosocial support.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [220] Strac, 2021, Personalizing the Care and Treatment of Alzheimer’s Disease: An Overview, Pharmacogenom. Pers. Med.

      Not checked in the free run.

    • cites [221] Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate-Armand, C., Yen, F.T., and Arab-Tehrany, E. (2022). Alzheimer’s Disease: Treatment Strategies and Their Limitations. Int. J. Mol. Sci., 23. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The search for new leads in AD treatment could be fruitful if herbal remedies are evaluated for lead chemicals based on their physicochemical properties and predicted BBB actions.

    “The search for new leads in AD treatment could be fruitful if herbal remedies are evaluated for lead chemicals based on their physicochemical properties and predicted BBB actions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    A DMT with a particular therapeutic target may be more effective than other DMTs with different targets due to the complex and all-encompassing pathogenesis of AD, particularly if the therapeutic target aligns with the most salient pathological findings of the subpopulation.

    “A DMT with a particular therapeutic target may be more effective than other DMTs with different targets due to the complex and all-encompassing pathogenesis of AD, particularly if the therapeutic target of the DMT being administered aligns with the most salient pathological findings of the subpopulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pharmacodynamic agent combinations for AD may consist of DMTs, which change the course of the disease, or symptomatic medicines, which reduce symptoms without changing the course.

    “Pharmacodynamic agent combinations for AD may consist of DMTs, which change the course of the disease, or symptomatic medicines, which reduce the symptoms without changing the course of the disease.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [217] Cummings, 2019, Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options, J. Alzheimer’s Dis. source

      Not checked in the free run.

    • cites [218] Horani, 2015, Anticancer Prodrugs—Three Decades of Design, World J. Pharm. Pharm. Sci.

      Not checked in the free run.

    • cites [219] Dudchenko, 2024, Combination Drug Therapy for the Management of Alzheimer’s Disease, Russ. J. Geriatr. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    This comprehensive care approach is adaptable enough to be customized for every single patient, ensuring optimal treatment outcomes.

    “This approach is adaptable enough to be customized for every single patient, ensuring optimal treatment outcomes [220,221].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [220] Strac, 2021, Personalizing the Care and Treatment of Alzheimer’s Disease: An Overview, Pharmacogenom. Pers. Med.

      Not checked in the free run.

    • cites [221] Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate-Armand, C., Yen, F.T., and Arab-Tehrany, E. (2022). Alzheimer’s Disease: Treatment Strategies and Their Limitations. Int. J. Mol. Sci., 23. source

      Not checked in the free run.

81 of 81

  • The paper relies on this without support.

    Only a small percentage of AD patients benefit from the two DMTs currently approved for therapy.

    “Only a small percentage of AD patients benefit from the two DMTs that are currently approved for therapy.”

  • The paper relies on this without support.

    Several natural compounds have demonstrated potential for treating AD in both in vitro and in vivo studies.

    “Nevertheless, several natural compounds have demonstrated potential for treating AD in both in vitro and in vivo studies.”

  • The paper relies on this without support.

    Humans and animals in studies differ physiologically.

    “because humans and animals in studies differ physiologically”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cholinesterase inhibitors rivastigmine, donepezil, galantamine, and tacrine work by increasing acetylcholine levels, improving cognition and memory, though they do not alter disease progression.

    “Several drugs focus on symptom management such as cholinesterase inhibitors (ChEIs): rivastigmine, donepezil, galantamine, and tacrine work by increasing ACh levels, improving cognition and memory, though they do not alter the disease’s progression.”

    From Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer’s Treatment: Systematic Review (2025) · cites this paper as [9]

    Section 3, “AD Current Treatment Drugs” (page not provided), says cholinesterase inhibition raises acetylcholine levels and enhances cognitive performance without affecting the disease’s course. It identifies donepezil, galantamine, and rivastigmine, but our copy does not identify tacrine as one of the drugs covered by this account. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Current treatments for Alzheimer's disease offer limited symptom relief, especially in early to moderate stages, but do not halt disease progression or address underlying neurodegeneration.

    “Current treatments for AD, including cholinesterase inhibitors and memantine, offer limited symptom relief, especially in the early to moderate stages, but do not halt disease progression or address the underlying neurodegeneration.”

    From Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer’s Treatment: Systematic Review (2025) · cites this paper as [9]

    The Introduction (§1.1) says cholinesterase inhibitors have limited efficacy and do not halt progression; §3 says they improve cognitive performance without affecting the disease’s course. The Future Directions section distinguishes symptomatic medicines, including standard-of-care memantine and cholinesterase inhibitors, from disease-modifying treatments that address underlying causes. The stage qualifier is too broad for the named drugs: §3 says memantine is used for moderate-to-severe AD, not especially early-to-moderate AD. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

1 retracted

Flagged first, then by citations

7 of the 227 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Horani, 2015, Anticancer Prodrugs—Three Decades of Design, World J. Pharm. Pharm. Sci., 4, 1751

Cited by

Sorted by citations

Related

Authors
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R.
Affiliations
  • Birzeit University (PS)
  • Al-Quds University (PS)
  • University of Basilicata (IT)
Corresponding author
Karaman, Rafik
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2024-10-30
Volume
29
Issue
21
Pages
5131
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules29215131
PMC
PMC11547905
OpenAlex
W4403924413
Semantic Scholar
3b5aac7de909b8d17998af8b07fc6969ccab0114
Cited by
56
References
227
Citations by year
2026: 24 · 2025: 30 · 2024: 2
FWCI
3.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
Alzheimer's disease, disease-modifying therapy, amyloid-beta, tau protein, neuroinflammation, anti-amyloid therapy, neuroprotective therapy, neurogenesis, cognitive decline, FDA-approved drugs, clinical trials, small molecule drugs, biologics
MeSH terms
Alzheimer Disease, Animals, Clinical Trials as Topic, Humans, Amyloid beta-Peptides, tau Proteins, Neuroprotective Agents

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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