Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update
Open accessAbstract
Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.
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Written from the paper’s full text.
TL;DR
This 2020–2023 update reviews Alzheimer disease drug trials listed on ClinicalTrials.gov and highlights the FDA approvals of aducanumab and lecanemab. It finds that trials increasingly focus on disease-modifying anti-amyloid/anti-tau therapies and earlier disease stages, while symptomatic, anti-neuroinflammation, and other approaches remain active.
Key findings
- The FDA granted accelerated approval to aducanumab in June 2021, accelerated approval to lecanemab on January 6, 2023, and traditional approval to lecanemab on July 6, 2023; donanemab had an application for full approval.
- In the lecanemab Clarity AD trial, CDR-SB difference was −0.45 (95% CI −0.67 to −0.23), amyloid PET burden difference was −59.1 (95% CI −62.6 to −55.6), ADAS-Cog14 mean difference was −1.44 (95% CI −2.27 to −0.61), ADCOMS mean difference was −0.050 (95% CI −0.074 to −0.027), and ADCS-MCI-ADL mean difference was 2.0 (95% CI 1.2 to 2.8); ARIA-E occurred in 12.6% and infusion-related reactions in 26.4%.
- In TRAILBLAZER-ALZ 2, donanemab produced iADRS change of −6.02 vs −9.27 for placebo in the low/medium tau group and −10.2 vs −13.1 in the combined population, with a reported 60% reduction in decline in early-stage AD; ARIA occurred in 24% vs 2.1% and infusion-related reactions in 8.7% vs 0.5%. In TRAILBLAZER-ALZ 4, 38% of donanemab-treated patients vs 2% of aducanumab-treated patients were below the amyloid positivity threshold at 6 months, plasma pTau217 decreased by 25% with donanemab but not with aducanumab, and ARIA-edema occurred in 22% of both groups.
- The review reports that most trials continue to target amyloid and tau, with a shift toward prodromal/preclinical populations; BIIB080 produced dose-dependent 30%–50% reductions in CSF total tau and pTau181. Among trials newly registered in the last 4 years, four articles from two trials were published, and both trials had overall low risk of bias.
Methods
- Narrative review/update of Alzheimer disease clinical trials listed on ClinicalTrials.gov, covering 2020–2023, with tables summarizing ongoing phase 2, phase 3, and phase 4 trials by mechanism.
- The paper describes trial agents, targets, designs, outcomes, and status; for published results, it identified four articles pertaining to two trials newly registered in the last 4 years and assessed methodological quality using the Cochrane risk of bias tool, version 2.
- No systematic search, meta-analysis, or pooled effect estimate is described.
Limitations
- The paper does not state a formal limitations section. Evident from the text: it is a descriptive review relying on ClinicalTrials.gov listings and selected published results, without a systematic search or quantitative synthesis.
- Many cited trials are ongoing or not yet recruiting, so efficacy and safety results are unavailable; the review notes challenges including limited indications for anti-amyloid monoclonal antibodies, administration and monitoring costs, need for specialized facilities and imaging, and unmet needs for BPSD and cognitive enhancement.
- Risk-of-bias assessment was limited to four published articles from two trials; other trial data were not quality-assessed.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 50 cited sources checked · 0 supported · 0 flagged
- Findingcitation
A double-blind, placebo-controlled phase 2 trial recruited 856 patients with AD with MCI or mild dementia and verified amyloid pathology through amyloid PET or CSF Aβ1-42.
“A double-blind, placebo-controlled phase 2 trial recruited 856 patients with AD with mild cognitive impairment (MCI) or mild dementia and verified amyloid pathology through amyloid PET or CSF Aβ1-42 [42].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RY, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021;13(1):80. source
Not checked in the free run.
- Findingcitation
In TRAILBLAZER-ALZ 4 preliminary results, 38% of patients on donanemab exhibited amyloid levels below the amyloid positivity threshold after 6 months, whereas only 2% of patients on aducanumab had such findings.
“The preliminary results were presented at the 2022 Clinical Trial of AD (CTAD) conference: 38% of the patients on donanemab exhibited amyloid levels below the amyloid positivity threshold after 6 months, whereas only 2% of the patients on aducanumab has such findings.”
Quote in the paperNot a substantial claim - Findingcitation
Clarity AD reported favorable outcomes for all primary and secondary measures, including ADAS-Cog14, ADCOMS, and ADCS-MCI-ADL scores.
“It reported favorable outcomes for all primary and secondary measures, including ADAS-Cog14, AD Composite Score (ADCOMS), and ADCS-MCI-ADL scores [43].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. source
Not checked in the free run.
- Findingcitation
An exploratory analysis revealed that a subgroup of participants in the ENGAGE trial who received a high dose of aducanumab exhibited slow decline similar to that observed in the EMERGE trial.
“An exploratory analysis revealed that a subgroup of the participants in the ENGAGE trial who received a high dose of aducanumab exhibited slow decline, which was similar to that observed among the participants in the EMERGE trial.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dunn B, Stein P, Cavazzoni P. Approval of aducanumab for Alzheimer disease—the FDA’s perspective. JAMA Intern Med. 2021;181(10):1276–8. source
Not checked in the free run.
- Findingcitation
The US FDA granted traditional approval for Leqembi (lecanemab-irmb) on July 6, 2023, for the treatment of AD, based on Phase 3 data from the Clarity AD clinical trial.
“On July 6, 2023, Leqembi (lecanemab-irmb) received traditional approval from the US FDA for the treatment of AD based on Phase 3 data from the Clarity AD clinical trial [17].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval-Action Follows Confirmatory Trial to Verify Clinical Benefit. 2023.
Not checked in the free run.
- Findingcitation
In TRAILBLAZER-ALZ 2, adverse effects included amyloid-related imaging problems (24% donanemab vs. 2.1% placebo).
“Adverse effects included amyloid-related imaging problems (24% donanemab vs. 2.1% placebo) and infusion-related reactions (8.7% donanemab vs. 0.5% placebo).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. source
Not checked in the free run.
- Findingcitation
The phase 2 trial results revealed a significant and dose-dependent reduction of amyloid plaques in the lecanemab group (10 mg/kg, intravenous infusion every 2 weeks) from baseline to week 79 compared with the placebo group.
“The results revealed a significant and dose-dependent reduction of amyloid plaques in the lecanemab group (10 mg/kg, intravenous infusion every 2 weeks) from baseline to week 79 compared with the placebo group.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RY, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021;13(1):80. source
Not checked in the free run.
- Findingcitation
In the EMERGE trial, the findings reached statistical significance.
“However, the findings of the EMERGE trial reached statistical significance, whereas the primary endpoint was not reached in the ENGAGE trial.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Dunn B, Stein P, Cavazzoni P. Approval of aducanumab for Alzheimer disease—the FDA’s perspective. JAMA Intern Med. 2021;181(10):1276–8. source
Not checked in the free run.
- Findingreasoning
The US FDA approved aducanumab in June 2021 on the basis of the data of the EMERGE and ENGAGE trials.
“The US FDA approved aducanumab in June 2021 on the basis of the data of the EMERGE and ENGAGE trials.”
Quote in the paperNot a substantial claim - Findingcitation
Donanemab reduced the tau burden in the temporal, parietal, and frontal lobes.
“Donanemab reduced the tau burden in the temporal, parietal, and frontal lobes and significantly decreased plasma pTau217 by 24% in the treatment group, whereas the placebo group exhibited a 6% increase in plasma pTau217 at the end of the trial [49].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Pontecorvo MJ, Lu M, Burnham SC, Schade AE, Dage JL, Shcherbinin S, et al. Association of donanemab treatment with exploratory plasma biomarkers in early symptomatic Alzheimer disease: a secondary analysis of the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. 2022;79(12):1250–9. source
Not checked in the free run.
- Findingcitation
In TRAILBLAZER-ALZ 2, donanemab achieved significant cognitive improvement in the combined population (change: −10.2 vs. −13.1 placebo).
“Donanemab achieved significant cognitive improvement in the low/medium tau group (iADRS change: − 6.02 vs. − 9.27 placebo) and combined population (change: − 10.2 vs. − 13.1 placebo).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. source
Not checked in the free run.
- Findingnone given
In TRAILBLAZER-ALZ 4 preliminary results, the side effect of ARIA-edema occurred in 22% of participants in both groups.
“The side effect of ARIA-edema occurred in 22% of the participants in both groups.”
Quote in the paperNot a substantial claim - Findingcitation
In TRAILBLAZER-ALZ 2, donanemab achieved significant cognitive improvement in the low/medium tau group (iADRS change: −6.02 vs. −9.27 placebo).
“Donanemab achieved significant cognitive improvement in the low/medium tau group (iADRS change: − 6.02 vs. − 9.27 placebo) and combined population (change: − 10.2 vs. − 13.1 placebo).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. source
Not checked in the free run.
- Findingcitation
Donanemab reduced decline by 60% in patients with early-stage AD.
“The drug notably reduced decline by 60% in patients with early-stage AD, supporting the efficacy of short-term dosing.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. source
Not checked in the free run.
- Findingcitation
In TRAILBLAZER-ALZ 2, adverse effects included infusion-related reactions (8.7% donanemab vs. 0.5% placebo).
“Adverse effects included amyloid-related imaging problems (24% donanemab vs. 2.1% placebo) and infusion-related reactions (8.7% donanemab vs. 0.5% placebo).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. source
Not checked in the free run.
- Findingcitation
Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers.
“Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers [48].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Shcherbinin S, Evans CD, Lu M, Andersen SW, Pontecorvo MJ, Willis BA, et al. Association of amyloid reduction after donanemab treatment with tau pathology and clinical outcomes: the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. 2022;79(10):1015–24. source
Not checked in the free run.
- Findingcitation
In the phase 2 TRAILBLAZER-ALZ study, donanemab met its primary endpoint of delaying decline by 32% compared with placebo, determined on the basis of iADRS scores.
“The trial met its primary endpoint of delaying decline—which was determined on the basis of iADRS scores—by 32% compared with placebo.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Shcherbinin S, Evans CD, Lu M, Andersen SW, Pontecorvo MJ, Willis BA, et al. Association of amyloid reduction after donanemab treatment with tau pathology and clinical outcomes: the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. 2022;79(10):1015–24. source
Not checked in the free run.
- Findingcitation
In the ENGAGE trial, the primary endpoint was not reached.
“However, the findings of the EMERGE trial reached statistical significance, whereas the primary endpoint was not reached in the ENGAGE trial.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dunn B, Stein P, Cavazzoni P. Approval of aducanumab for Alzheimer disease—the FDA’s perspective. JAMA Intern Med. 2021;181(10):1276–8. source
Not checked in the free run.
- Findingown data
Trials that do not target specific pathophysiologies are becoming fewer in all phases.
“Trials that do not target specific pathophysiologies are becoming fewer in all phases (Figs. 2 and 3).”
Quote in the paperSubstantial claim - Findingnone given
Outcome measurement tools have become more diverse.
“Outcome measurement tools have also become more diverse, which has enabled meaningful improvements in AD and the efficacy of treatments to be clearly determined in clinical trials.”
Quote in the paperSubstantial claim - Findingreasoning
There has been a significant reduction in the number of anti-amyloid phase 3 trials since 2019.
“Additionally, the validity of the amyloid hypothesis has been contested, resulting in a significant reduction in the number of anti-amyloid phase 3 trials since 2019.”
Quote in the paperSubstantial claim - Findingown data
An increasing number of phase 1 trials involving DMTs, particularly those targeting both anti-amyloid and anti-tau mechanisms, has been noted.
“Similarly, an increasing number of phase 1 trials involving DMTs, particularly those targeting both anti-amyloid and anti-tau mechanisms, has been noted, indicating the importance of basic research (Fig. 3).”
Quote in the paperSubstantial claim - Findingcitation
The targets of both phase 1 and phase 2 trials are diverse.
“However, the targets of both phase 1 and phase 2 trials are diverse, with a noticeable increase in the number of phase 1 trials focusing on neuroprotection and phase 2 trials focusing on anti-neuroinflammation [85].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [85] Huang L-K, Chao S-P, Hu C-J. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020;27(1):18. source
Not checked in the free run.
- Findingown data
Among the clinical trials newly registered in the last 4 years, four articles pertaining to two trials have been published in peer-reviewed scientific journals.
“Among the clinical trials newly registered in the last 4 years, four articles pertaining to two trials have been published in peer-reviewed scientific journals.”
Quote in the paperNot a substantial claim - Findingnone given
Successful phase 3 trials such as Clarity AD (lecanemab) and EMERGE (aducanumab) have evaluated anti-amyloid treatment in mild AD.
“Successful phase 3 trials such as Clarity AD (lecanemab) and EMERGE (aducanumab) have evaluated anti-amyloid treatment in mild AD (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
In terms of the number of AD drug trials and the number of recruited participants, the majority of trials continue to focus on mechanisms involving amyloid and tau.
“This review documented that in terms of the number of AD drug trials and the number of recruited participants, the majority of trials continue to focus on mechanisms involving amyloid and tau.”
Quote in the paperSubstantial claim - Findingcitation
There has been a noticeable increase in the number of phase 2 trials focusing on anti-neuroinflammation.
“However, the targets of both phase 1 and phase 2 trials are diverse, with a noticeable increase in the number of phase 1 trials focusing on neuroprotection and phase 2 trials focusing on anti-neuroinflammation [85].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [85] Huang L-K, Chao S-P, Hu C-J. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020;27(1):18. source
Not checked in the free run.
- Findingcitation
There has been a noticeable increase in the number of phase 1 trials focusing on neuroprotection.
“However, the targets of both phase 1 and phase 2 trials are diverse, with a noticeable increase in the number of phase 1 trials focusing on neuroprotection and phase 2 trials focusing on anti-neuroinflammation [85].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [85] Huang L-K, Chao S-P, Hu C-J. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020;27(1):18. source
Not checked in the free run.
- Findingown data
An increasing number of early-phase trials of therapies for symptoms, including cognitive enhancers and agents for relieving BPSD, are being conducted.
“However, an increasing number of early-phase trials of therapies for symptoms, including cognitive enhancers and agents for relieving BPSD, are being conducted.”
Quote in the paperSubstantial claim - Premisecitation
APOE4 allele carriers, especially APOE4 homozygotes, are at a high risk of ARIAs.
“APOE4 allele carriers, especially APOE4 homozygotes, are at a high risk of ARIAs.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [44] Cummings J, Rabinovici G, Atri A, Aisen P, Apostolova L, Hendrix S, et al. Aducanumab: appropriate use recommendations update. J Prev Alzheimers Di s. 2022;9(2):221–30.
Not checked in the free run.
- cites [45] Cummings J, Apostolova L, Rabinovici G, Atri A, Aisen P, Greenberg S, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2023;10(3):362–77.
Not checked in the free run.
- Premisecitation
NFTs and quantitative neuronal loss may be more closely correlated with disease severity and dementia progression than the amyloid plaque burden.
“NFTs and quantitative neuronal loss may be more closely correlated with disease severity and dementia progression than the amyloid plaque burden [20–22].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [20] Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;41(1):17–24. source
Not checked in the free run.
- cites [21] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42(3 Pt 1):631–9. source
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- cites [22] Bierer LM, Hof PR, Purohit DP, Carlin L, Schmeidler J, Davis KL, et al. Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol. 1995;52(1):81–8. source
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- Premisecitation
Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms.
“Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms [8].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Sperling R, Mormino E, Johnson K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron. 2014;84(3):608–22. source
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- Interpretationreasoning
The approval of lecanemab affirms the pathophysiological significance of amyloid in AD.
“The approval of this treatment not only affirms the pathophysiological significance of amyloid in AD but also marks a notable advance in clinical approaches to AD treatment, remedying the scarcity of new drugs in the market for nearly two decades.”
Quote in the paperSubstantial claim - Premisecitation
In the lecanemab Clarity AD trial, lecanemab reduced CDR-SB score compared to placebo (difference: −0.45; 95% CI: -0.67 to −0.23).
“CDR-SB Score(difference: − 0.45; 95% CI: -0.67 to − 0.23)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dyck et al. [2023] source
Not checked in the free run.
- Study design and conductown data
The overall risk of bias was low for the Dyck [2023] trial.
“| Dyek [2023] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |”
Quote in the paperNot a substantial claim - Interpretationreasoning
The increasing number of early-phase trials of therapies for symptoms reflects the unmet clinical need for such therapies.
“This reflects the unmet clinical need for such therapies (Figs. 2 and 3).”
Quote in the paperSubstantial claim- Rests on an assumption: There is an unmet clinical need for therapies for symptoms including cognitive enhancers and agents for relieving BPSD.
- Premisecitation
In the DIAN-TU-001 trial, the solanezumab-treated group had greater cognitive decline on some measures relative to placebo.
“The results indicated that the solanezumab-treated group had greater cognitive decline on some measures relative to placebo”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96. source
Not checked in the free run.
- Premisenone given
BIIB080 led to dose-dependent reductions of 30%-50% in total tau and pTau181 levels in CSF.
“BIIB080 led to a dose-dependent reductions of 30%–50% in total tau and pTau181 levels in CSF.”
Quote in the paperNot a substantial claim - Premisecitation
In the phase 3 trial EXPEDITION-3, 400 mg solanezumab administered every 4 weeks did not have significant effects on cognitive decline in patients with mild Alzheimer disease.
“Similarly, the phase 3 trial EXPEDITION-3 demonstrated that 400 mg solanezumab administered every 4 weeks did not have significant effects on cognitive decline in patients with mild AD [52].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321–30. source
Not checked in the free run.
- Study design and conductown data
The overall risk of bias was low for the Bateman [2018] trial.
“| Bateman [2018] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |”
Quote in the paperNot a substantial claim - Interpretationown data
The increasing number of phase 1 trials involving DMTs indicates the importance of basic research.
“Similarly, an increasing number of phase 1 trials involving DMTs, particularly those targeting both anti-amyloid and anti-tau mechanisms, has been noted, indicating the importance of basic research (Fig. 3).”
Quote in the paperSubstantial claim - Premiseown data
In the ACI-35 phase 1b/2a trial, participants who received ACI-35.030 exhibited a strong and sustained immune response against pathological tau proteins (pTau) and nonphosphorylated tau (ePHF), particularly in the mid- and low-dose groups.
“The results indicated that participants who received ACI-35.030 exhibited a strong and sustained immune response against pathological tau proteins (pTau) and nonphosphorylated tau (ePHF), particularly in the mid- and low-dose groups.”
Quote in the paperNot a substantial claim - Study design and conductown data
The overall risk of bias was low for the Tahami Monfared [2023] trial.
“| Tahami Monfared 2023] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |”
Quote in the paperNot a substantial claim - Interpretationcitation
The impact of amyloid and consequent pathological alterations is likely to become the main focus of clinical trials.
“Since the positive outcomes in terms of slow decline in cognitive abilities in the lecanemab Clarity AD trial [43] and the donanemab trial TRAILBLAZER-ALZ [86], the impact of amyloid and consequent pathological alterations is likely to become the main focus of clinical trials.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [43] Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. source
Not checked in the free run.
- cites [86] Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384(18):1691–704. source
Not checked in the free run.
- Study design and conductown data
The overall risk of bias was low for the Salloway [2021] trial.
“| Salloway [2021] | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |”
Quote in the paperNot a substantial claim - Premisecitation
In phase 3 trials EXPEDITION-1 and EXPEDITION-2, which enrolled 2,052 patients with mild-to-moderate Alzheimer disease, solanezumab did not improve ADAS-Cog11 or ADCS-ADL scores, the primary outcome measures.
“Phase 3 trials of solanezumab, including EXPEDITION-1 and EXPEDITION-2, which enrolled 2,052 patients with mild-to-moderate AD, did not reveal improvements in ADAS-Cog11 and ADCS-ADL scores, which were the primary outcome measures.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321–30. source
Not checked in the free run.
- Premisecitation
In the BIIB080 trial, intrathecal injection of BIIB080 at either of three doses every month for 3 months or two high-dose injections 3 months apart produced no serious adverse events.
“revealing no serious adverse events from the intrathecal injection of BIIB080 at either of three doses every month for 3 months or two high-dose injections 3 months apart.”
Quote in the paperNot a substantial claim - Premisecitation
In the DIAN-TU-001 trial, solanezumab treatment did not exert any beneficial effects on downstream biomarkers.
“and that solanezumab treatment did not exert any beneficial effects on downstream biomarkers”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96. source
Not checked in the free run.
- Premisenone given
In the DIAN-TU-001 trial, the primary endpoint-treatment-related changes on the DIAN-Multivariate Cognitive Endpoint-was not achieved.
“However, on February 10, 2020, the study investigators announced that the primary endpoint was not achieved in the trial, namely treatment-related changes on the DIAN-Multivariate Cognitive Endpoint.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 13
- May combine two claims. 18
Classified as probably not a substantial claim. May combine two claims.
Findingnone givenClinical trials of early or preventive interventions based on amyloid/tau theory and those targeting other pathophysiologies are ongoing or have been initiated.
“Clinical trials of early or preventive interventions based on amyloid/tau theory and those targeting other pathophysiologies are ongoing or have been initiated.”
Quote in the paperSubstantial claim- Rests on an assumption: The key event in AD pathogenesis is Aβ accumulation.
May combine two claims.
FindingcitationDonanemab significantly decreased plasma pTau217 by 24% in the treatment group, whereas the placebo group exhibited a 6% increase in plasma pTau217 at the end of the trial.
“Donanemab reduced the tau burden in the temporal, parietal, and frontal lobes and significantly decreased plasma pTau217 by 24% in the treatment group, whereas the placebo group exhibited a 6% increase in plasma pTau217 at the end of the trial [49].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Pontecorvo MJ, Lu M, Burnham SC, Schade AE, Dage JL, Shcherbinin S, et al. Association of donanemab treatment with exploratory plasma biomarkers in early symptomatic Alzheimer disease: a secondary analysis of the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. 2022;79(12):1250–9. source
Not checked in the free run.
May combine two claims.
FindingcitationBoth EMERGE and ENGAGE trials presented evidence of an intermediate effect of aducanumab on biomarkers, indicating amyloid removal, which is likely linked to the clinical benefit of aducanumab.
“Both trials presented evidence of an intermediate effect of the drug on biomarkers, indicating amyloid removal, which is likely linked to the clinical benefit of aducanumab.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dunn B, Stein P, Cavazzoni P. Approval of aducanumab for Alzheimer disease—the FDA’s perspective. JAMA Intern Med. 2021;181(10):1276–8. source
Not checked in the free run.
May combine two claims.
FindingcitationThe US FDA approved lecanemab on January 6, 2023, through an accelerated approval pathway on the basis of evidence of amyloid removal in a phase 2 trial and because it had a likelihood of having clinical benefits.
“The US FDA approved it on January 6, 2023, through an accelerated approval pathway on the basis of evidence of amyloid removal in a phase 2 trial (NCT01767311) and because it had a likelihood of having clinical benefits [41]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Canady VA. FDA approves new treatment for Alzheimer’s disease. Ment Heal Wkly. 2023;33(3):6–7. source
Not checked in the free run.
May combine two claims.
Findingnone givenIn TRAILBLAZER-ALZ 4 preliminary results, plasma pTau217 levels decreased by 25% for participants receiving donanemab, but not at all for those receiving aducanumab.
“Plasma pTau217 levels decreased by 25% for the participants receiving donanemab, but not at all for those receiving aducanumab.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone givenClinical trials related to AD have exhibited a shift in focus toward the earlier stages of AD, such as MCI, or even cognitively healthy participants for developing prevention interventions.
“Clinical trials related to AD have also exhibited a shift in focus toward the earlier stages of AD, such as MCI, or even cognitively healthy participants for developing prevention interventions.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningThe focus of research has shifted toward populations in the prodromal or preclinical stage with positive results for diagnostic biomarkers.
“This shift in perspective has led to a change in the focus of research toward populations in the prodromal or preclinical stage with positive results for diagnostic biomarkers.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone givenThe scope of indications for novel anti-amyloid monoclonal antibody therapy remains limited.
“However, despite this expansion of research areas, the scope of indications for novel anti-amyloid monoclonal antibody therapy remains limited.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationTwo articles reported the results of NCT03887455, and the other two reported the results of NCT01760005.
“Two articles reported the results of NCT03887455 [43, 84], and the other two reported the results of NCT01760005 [53, 83].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [43] Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. source
Not checked in the free run.
- cites [84] Tahami Monfared AA, Ye W, Sardesai A, Folse H, Chavan A, Aruffo E, et al. A path to improved Alzheimer’s care: simulating long-term health outcomes of lecanemab in early Alzheimer’s disease from the CLARITY AD trial. Neurol Ther. 2023;12(3):863–81. source
Not checked in the free run.
- cites [53] Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96. source
Not checked in the free run.
- cites [83] Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: Adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8–19. source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
FindingreasoningThe field of AD clinical trials is evolving.
“Overall, the field of AD clinical trials is evolving, and additional promising treatments for AD are likely to be developed in the near future.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe articles pertaining to the two trials were published between 2018 and 2023.
“The articles were published between 2018 and 2023.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationnone givenMany ongoing clinical trials on AD are focused on disease-modifying therapies (DMTs) that target the causes and can change the course of AD.
“Many ongoing clinical trials on AD are focused on disease-modifying therapies (DMTs) that target the causes and can change the course of AD.”
Quote in the paperSubstantial claim- Rests on an assumption: The key event in AD pathogenesis is Aβ accumulation.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDonanemab is a humanized monoclonal antibody that recognizes Aβ (3-42), an aggregated form of Aβ found in amyloid plaques.
“It recognizes Aβ (3–42), an aggregated form of Aβ found in amyloid plaques [46].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Irizarry MC, Sims JR, Lowe SL, Nakano M, Hawdon A, Willis BA, et al. 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. Alzheimers Dement. 2016;12:P352–3. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAcetylcholine (ACh) plays a vital role in memory function, including memory encoding, consolidation, and retrieval processes.
“Acetylcholine (ACh) plays a vital role in memory function, including memory encoding, consolidation, and retrieval processes, and increasing Ach levels by using cholinesterase inhibitors (AChEIs) has become a standard therapy for the symptoms of AD [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379–97. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreasing Ach levels by using cholinesterase inhibitors (AChEIs) has become a standard therapy for the symptoms of AD.
“Acetylcholine (ACh) plays a vital role in memory function, including memory encoding, consolidation, and retrieval processes, and increasing Ach levels by using cholinesterase inhibitors (AChEIs) has become a standard therapy for the symptoms of AD [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379–97. source
Not checked in the free run.
May combine two claims.
PremisecitationAducanumab is a high-affinity, fully human IgG1 monoclonal antibody that binds to the N-terminus of Aβ fibrils and blocks amyloid aggregation.
“Aducanumab (brand name: Aduhelm) is a high-affinity, fully human immunoglobulin gamma 1 (IgG1) monoclonal antibody that binds to the N-terminus of Aβ fibrils and blocks amyloid aggregation [38].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Arndt JW, Qian F, Smith BA, Quan C, Kilambi KP, Bush MW, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8(1):6412. source
Not checked in the free run.
May combine two claims.
PremisecitationLecanemab is a humanized IgG1 antibody derived from mAb158 that selectively binds to soluble Aβ protofibrils.
“Lecanemab (brand name: Leqembi), a humanized IgG1 antibody derived from mAb158, selectively binds to soluble Aβ protofibrils [40].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Tucker S, Möller C, Tegerstedt K, Lord A, Laudon H, Sjödahl J, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43(2):575–88. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone givenOther ongoing trials involve symptomatic treatments-for example, enhancing cognitive function and relieving BPSD.
“The other trials involve symptomatic treatments—for example, enhancing cognitive function and relieving BPSD (Fig. 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe AURs for lecanemab and aducanumab highlight the importance of patient selection, surveillance for adverse events, and clinician preparedness.
“The appropriate use recommendations (AURs) for lecanemab and aducanumab highlight the importance of patient selection, surveillance for adverse events, and clinician preparedness [44, 45].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [44] Cummings J, Rabinovici G, Atri A, Aisen P, Apostolova L, Hendrix S, et al. Aducanumab: appropriate use recommendations update. J Prev Alzheimers Di s. 2022;9(2):221–30.
Not checked in the free run.
- cites [45] Cummings J, Apostolova L, Rabinovici G, Atri A, Aisen P, Greenberg S, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2023;10(3):362–77.
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe approval of lecanemab marks a notable advance in clinical approaches to AD treatment, remedying the scarcity of new drugs in the market for nearly two decades.
“The approval of this treatment not only affirms the pathophysiological significance of amyloid in AD but also marks a notable advance in clinical approaches to AD treatment, remedying the scarcity of new drugs in the market for nearly two decades.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn the A4 study, solanezumab did not slow cognitive decline or clear amyloid plaques in individuals with preclinical Alzheimer disease.
“On March 8, 2023, Eli Lilly and Company reported that solanezumab did not slow cognitive decline or clear amyloid plaques in individuals with preclinical AD in the A4 study.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningAdditional promising treatments for AD are likely to be developed in the near future.
“Overall, the field of AD clinical trials is evolving, and additional promising treatments for AD are likely to be developed in the near future.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductcitationBoth trials NCT03887455 and NCT01760005 had an overall low risk of bias.
“Both trials (NCT03887455 and NCT01760005) had a overall low risk of bias [43, 53, 83, 84].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [43] Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. source
Not checked in the free run.
- cites [53] Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96. source
Not checked in the free run.
- cites [83] Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: Adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8–19. source
Not checked in the free run.
- cites [84] Tahami Monfared AA, Ye W, Sardesai A, Folse H, Chavan A, Aruffo E, et al. A path to improved Alzheimer’s care: simulating long-term health outcomes of lecanemab in early Alzheimer’s disease from the CLARITY AD trial. Neurol Ther. 2023;12(3):863–81. source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
InterpretationreasoningThe diversity of outcome measurement tools has enabled meaningful improvements in AD and the efficacy of treatments to be clearly determined in clinical trials.
“Outcome measurement tools have also become more diverse, which has enabled meaningful improvements in AD and the efficacy of treatments to be clearly determined in clinical trials.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIn the DIAN-TU-001 trial, participants were offered an open-label extension with high-dose gantenerumab because of its positive effects on imaging and other biomarkers, such as normalized CSF Aβ42, and because it reduced CSF total tau and pTau181 levels.
“The participants were offered an open-label extension with high-dose gantenerumab because of its positive effects on imaging and other biomarkers, such as normalized CSF Aβ42, and because it reduced CSF total tau and pTau181 levels.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn the DIAN-TU-001 trial, gantenerumab significantly reduced amyloid plaques, CSF total tau, and phospho-tau181 and attenuated increases in neurofilament light chain.
“whereas gantenerumab significantly reduced amyloid plaques, CSF total tau, and phospho-tau181 and attenuated increases in neurofilament light chain [53].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96. source
Not checked in the free run.
May combine two claims.
Premiseown dataIn the ACI-35 phase 1b/2a trial, recipients of JACI-35.054 displayed a robust immune response against ePHF and pTau, but without a clear dose-effect relationship.
“Recipients of JACI-35.054 also displayed a robust immune response against ePHF and pTau, but without a clear dose–effect relationship.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The key event in AD pathogenesis is Aβ accumulation.
“The key event in AD pathogenesis is believed to be Aβ accumulation.”
The paper relies on this without support.
Remternetug is a monoclonal antibody that recognizes a pyroglutamated form of Aβ that aggregates into amyloid plaques.
“Remternetug is a monoclonal antibody that recognizes a pyroglutamated form of Aβ that aggregates into amyloid plaques.”
The paper relies on this without support.
The validity of the amyloid hypothesis has been contested.
“Additionally, the validity of the amyloid hypothesis has been contested, resulting in a significant reduction in the number of anti-amyloid phase 3 trials since 2019.”
The paper relies on this without support.
There is an unmet clinical need for therapies for symptoms including cognitive enhancers and agents for relieving BPSD.
“This reflects the unmet clinical need for such therapies (Figs. 2 and 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?
Phase III trials include 48 trials that tested 32 medications.
“Phase III trials, including 48 trials that tested 32 medications [37,183,184].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [184]
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.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [184]
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].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [184]
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).”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [184]
In Phase I, there are 26 trials assessing 25 agents.
“In Phase I, there are 26 trials assessing 25 agents.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [184]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
ACI-35 is classified as passive immunotherapy but described as a vaccine
MinorTable 4 classifies ACI-35 as passive immunotherapy, while the text describes it as a vaccine that elicits an immune response.
“| ACI-35 | AC Immune SA | Tau Morphomer | Immunotherapy (passive) | NCT04445831 | Active, not recruiting |”
“ACI-35 is a liposome-based vaccine that targets pathological conformations of phosphorylated tau.”
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“During the course of AD, many behavioral and psychological symptoms of dementia (BPSD) occur [2–4].”
BackgroundNIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537 · see citing works
Neurotoxic reactive astrocytes are induced by activated microglia
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“However, activated microglia induce neurotoxic A1 astrocyte reactivity through the release of IL-1α, C1q, and TNF-α, resulting in a feedback loop of dysregulated inflammation in AD [28].”
BackgroundLecanemab in early Alzheimer's disease
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212948 · Cited by 5,678 · see citing works
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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
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“The accumulation of NFTs might be initiated between the accumulation of Aβ and the development of clinical symptoms of AD [19].”
BackgroundThe precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Amyloid plaque core protein in Alzheimer disease and Down syndrome.
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Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
Sims, J. R., Zimmer, J. A., Evans, C. D., Lu, M., Ardayfio, P., Sparks, J., Wessels, A. M., Shcherbinin, S., Wang, H., Monkul Nery, E. S., et al. (2023) · JAMA · doi:10.1001/jama.2023.13239 · Cited by 2,932 · cited 1× · see citing works
“The study findings indicated the potential of donanemab to slow AD progression, particularly in the early stage [50].”
BackgroundThe molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708 · cited 2× · see citing works
“In familial AD, mutant autosomal-dominant genes, including the genes for amyloid precursor protein ( APP ), presenilin-1 ( PSEN1 ), and presenilin-2 ( PSEN2 ), encode the major proteins involved in amyloid metabolism [13–15].”
BackgroundNeurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
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Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
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A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Feldman, H. H., Frisoni, G. B., Hampel, H., Jagust, W. J., Johnson, K. A., Knopman, D. S., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002923 · Cited by 1,864 · cited 1× · see citing works
“The analysis of a combination of biomarkers such as amyloid, tau, and neurodegeneration (collectively, ATN classification) has been proposed by research on AD [24, 25].”
BackgroundDonanemab in Early Alzheimer’s Disease
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., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2100708 · Cited by 1,728 · cited 4× · see citing works
“The trial started in October 2022; 1,500 participants will be recruited by using the same criteria as those of TRAILBLAZER-ALZ 2 from 148 sites across China, Korea, Taiwan, and Europe; and the trial is expected to run until mid-2025.”
BackgroundInfluentialNeuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
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“NFTs and quantitative neuronal loss may be more closely correlated with disease severity and dementia progression than the amyloid plaque burden [20–22].”
BackgroundThe spectrum of behavioral changes in Alzheimer's disease
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Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease
Honig, L. S., Vellas, B., Woodward, M., Boada, M., Bullock, R., Borrie, M., Hager, K., Andreasen, N., Scarpini, E., Liu-Seifert, H., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1705971 · Cited by 1,049 · cited 2× · see citing works
“Similarly, the phase 3 trial EXPEDITION-3 demonstrated that 400 mg solanezumab administered every 4 weeks did not have significant effects on cognitive decline in patients with mild AD [52].”
BackgroundLecanemab: Appropriate Use Recommendations
Cummings, J., Apostolova, L., Rabinovici, G. D., Atri, A., Aisen, P., Greenberg, S., Hendrix, S., Selkoe, D., Weiner, M., Petersen, R. C., et al. (2023) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2023.30 · Cited by 961 · cited 1× · see citing works
“The appropriate use recommendations (AURs) for lecanemab and aducanumab highlight the importance of patient selection, surveillance for adverse events, and clinician preparedness [44, 45].”
BackgroundSwanson, C. J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R. Y. K., Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00813-8 · Cited by 847 · cited 2× · see citing works
“The US FDA approved it on January 6, 2023, through an accelerated approval pathway on the basis of evidence of amyloid removal in a phase 2 trial (NCT01767311) and because it had a likelihood of having clinical benefits [41] A double-blind, placebocontrolled phase 2 trial recruited 856 patients with AD with mild cogni…”
BackgroundRaina, P., Santaguida, P., Ismaila, A., Patterson, C., Cowan, D., Levine, M., Booker, L., & Oremus, M. (2008) · Annals of Internal Medicine · doi:10.7326/0003-4819-148-5-200803040-00009 · Cited by 771 · cited 1× · see citing works
“Acetylcholine (ACh) plays a vital role in memory function, including memory encoding, consolidation, and retrieval processes, and increasing Ach levels by using cholinesterase inhibitors (AChEIs) has become a standard therapy for the symptoms of AD [37].”
BackgroundThe Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials
Sperling, R., Mormino, E., & Johnson, K. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.038 · Cited by 725 · cited 1× · see citing works
“Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms [8].”
BackgroundClinical trials of new drugs for Alzheimer disease
Huang, L.-K., Chao, S.-P., & Hu, C.-J. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-019-0609-7 · Cited by 702 · cited 1× · see citing works
“However, the targets of both phase 1 and phase 2 trials are diverse, with a noticeable increase in the number of phase 1 trials focusing on neuroprotection and phase 2 trials focusing on anti-neuroinflammation [85].”
BackgroundSelf-citationLian, H., Yang, L., Cole, A., Sun, L., Chiang, A. C.-A., Fowler, S. W., Shim, D. J., Rodriguez-Rivera, J., Taglialatela, G., Jankowsky, J. L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.018 · Cited by 697 · cited 1× · see citing works
“Subsequently, by binding to C3a receptors, C3 causes neuronal dysfunction and microglial activation [27].”
BackgroundAlzheimer’s disease drug development pipeline: 2022
Cummings, J., Lee, G., Nahed, P., Kambar, M. E. Z. N., Zhong, K., Fonseca, J., & Taghva, K. (2022) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12295 · Cited by 665 · cited 1× · see citing works
“BPDO-1603 is a potential cognitive-enhancing drug for AD, but its mechanism of action remains unknown [61].”
BackgroundLee, J.-H., Yang, D.-S., Goulbourne, C. N., Im, E., Stavrides, P., Pensalfini, A., Chan, H., Bouchet-Marquis, C., Bleiwas, C., Berg, M. J., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01084-8 · Cited by 638 · cited 1× · see citing works
“These formations constitute the primary source of the majority of amyloid plaques found in mouse models of AD [35].”
BackgroundAlzheimer's disease drug development pipeline: 2017
Cummings, J., Lee, G., Mortsdorf, T., Ritter, A., & Zhong, K. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.05.002 · Cited by 549 · see citing works
Hamelin, L., Lagarde, J., Dorothée, G., Leroy, C., Labit, M., Comley, R. A., de Souza, L. C., Corne, H., Dauphinot, L., Bertoux, M., et al. (2016) · Brain · doi:10.1093/brain/aww017 · Cited by 519 · cited 1× · see citing works
“The excessive accumulation of Aβ or other toxic compounds activates proinflammatory phenotypes, resulting in neuronal damage [29].”
BackgroundNeocortical Neurofibrillary Tangles Correlate With Dementia Severity in Alzheimer's Disease
Bierer, L. M., Hof, P. R., Purohit, D. P., Carlin, L., Schmeidler, J., Davis, K. L., & Perl, D. P. (1995) · Archives of Neurology · doi:10.1001/archneur.1995.00540250089017 · Cited by 514 · cited 1× · see citing works
“NFTs and quantitative neuronal loss may be more closely correlated with disease severity and dementia progression than the amyloid plaque burden [20–22].”
BackgroundThe amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy
McGeer, P. L., & McGeer, E. G. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1177-7 · Cited by 467 · cited 1× · see citing works
“The inadequate clearance of Aβ along with the aggregation of tau disrupts microglial defense mechanisms, resulting in sustained and harmful microglial activation [32].”
BackgroundFrequency of hippocampal formation atrophy in normal aging and Alzheimer's disease
De Leon, M. J., George, A. E., Golomb, J., Tarshish, C., Convit, A., Kluger, A., De Santi, S., Mc Rae, T., Ferris, S. H., Reisberg, B., et al. (1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(96)00213-8 · Cited by 429 · cited 1× · see citing works
“Brain atrophy, particularly in the hippocampus, is major indicator of early Aβ accumulation, particularly in the presubiculum [9, 10].”
BackgroundNeuronal Cell Death Mechanisms in Major Neurodegenerative Diseases
Chi, H., Chang, H.-Y., & Sang, T.-K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103082 · Cited by 412 · cited 1× · see citing works
“Neuroprotective therapies, including free radical scavengers, regeneration enhancers, and the suppression of excitable amino acid signaling pathways, have been proposed for preventing neuronal death or brain atrophy caused by amyloid, tau, and neuroinflammation [36].”
BackgroundStructural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β
Arndt, J. W., Qian, F., Smith, B. A., Quan, C., Kilambi, K. P., Bush, M. W., Walz, T., Pepinsky, R. B., Bussière, T., Hamann, S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-24501-0 · Cited by 364 · cited 1× · see citing works
“Aducanumab (brand name: Aduhelm) is a high-affinity, fully human immunoglobulin gamma 1 (IgG1) monoclonal antibody that binds to the N-terminus of Aβ fibrils and blocks amyloid aggregation [38].”
BackgroundA trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
Salloway, S., Farlow, M., McDade, E., Clifford, D. B., Wang, G., Llibre-Guerra, J. J., Hitchcock, J. M., Mills, S. L., Santacruz, A. M., Aschenbrenner, A. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01369-8 · Cited by 359 · cited 4× · see citing works
“Both trials (NCT03887455 and NCT01760005) had a overall low risk of bias [43, 53, 83, 84].”
BackgroundResultInfluentialBateman, R. J., Benzinger, T. L., Berry, S., Clifford, D. B., Duggan, C., Fagan, A. M., Fanning, K., Farlow, M. R., Hassenstab, J., McDade, E. M., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.07.005 · Cited by 303 · cited 3× · see citing works
“Both trials (NCT03887455 and NCT01760005) had a overall low risk of bias [43, 53, 83, 84].”
BackgroundResultTucker, S., Möller, C., Tegerstedt, K., Lord, A., Laudon, H., Sjödahl, J., Söderberg, L., Spens, E., Sahlin, C., Waara, E. R., et al. (2015) · Journal of Alzheimer’s Disease · doi:10.3233/jad-140741 · Cited by 272 · cited 1× · see citing works
“Lecanemab (brand name: Leqembi), a humanized IgG1 antibody derived from mAb158, selectively binds to soluble Aβ protofibrils [40].”
BackgroundPontecorvo, M. J., Lu, M., Burnham, S. C., Schade, A. E., Dage, J. L., Shcherbinin, S., Collins, E. C., Sims, J. R., & Mintun, M. A. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.3392 · Cited by 261 · see citing works
Apostolova, L. G. (2016) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000000307 · Cited by 253 · see citing works
Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective
Dunn, B., Stein, P., & Cavazzoni, P. (2021) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2021.4607 · Cited by 246 · cited 1× · see citing works
“Further trials must be conducted to confirm the potential benefit of aducanumab [39].”
BackgroundXiao, S., Chan, P., Wang, T., Hong, Z., Wang, S., Kuang, W., He, J., Pan, X., Zhou, Y., Ji, Y., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00795-7 · Cited by 224 · see citing works
Beyreuther, K., & Masters, C. L. (1991) · Brain Pathology · doi:10.1111/j.1750-3639.1991.tb00667.x · Cited by 221 · cited 1× · see citing works
“Aβ accumulation was discovered to be crucial by three independent research groups in 1991 [11–13].”
BackgroundShcherbinin, 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., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.2793 · Cited by 210 · cited 1× · see citing works
“Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers [48].”
BackgroundAducanumab: Appropriate Use Recommendations Update
Cummings, J. L., Rabinovici, G. D., Atri, A., Aisen, P. S. S., Apostolova, L. G., Hendrix, S. B., Sabbagh, M. N., Selkoe, D. J., Weiner, M. W., & Salloway, S. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2022.34 · Cited by 198 · cited 1× · see citing works
“The appropriate use recommendations (AURs) for lecanemab and aducanumab highlight the importance of patient selection, surveillance for adverse events, and clinician preparedness [44, 45].”
BackgroundThe precursor of Alzheimer??s disease amyloid A4 protein resembles a cell-surface receptor
Kang, J.-M., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Kh, G., Multhaup, G., Beyreuther, K. T., & Müller‐Hill, B. (1987) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-198701030-00032 · Cited by 194 · see citing works
Tau Proteins and Neurofibrillary Degeneration
Goedert, M., Spillantini, M. G., & Crowther, R. A. (1991) · Brain Pathology · doi:10.1111/j.1750-3639.1991.tb00671.x · Cited by 178 · cited 1× · see citing works
“Although the exact causes of AD remain unclear, the disease has two pathological hallmarks: plaques composed of amyloid-beta (Aβ) fibrils and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein [5–7].”
BackgroundRandomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease
Herrmann, N., Ruthirakuhan, M. T., Gallagher, D., Verhoeff, N. P. L. G., Kiss, A., Black, S. E., & Lanctôt, K. L. (2019) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2019.05.002 · Cited by 172 · cited 1× · see citing works
“Nabilone is a partial agonist of cannabinoid receptor 1 (CB1) and CB2 in the brain and in peripheral tissues, and it has been reported to provide effective treatment for agitation in patients with AD [78].”
BackgroundThe role of extracellular Tau in the spreading of neurofibrillary pathology
Medina, M., & Avila, J. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00113 · Cited by 161 · cited 1× · see citing works
“As the disease progresses, the gradual spread of tau pathology throughout brain regions has been suggested to be caused by the transfer of abnormal types of tau protein from one neuron to another [18].”
BackgroundPost-mortem analysis of neuroinflammatory changes in human Alzheimer’s disease
Gomez-Nicola, D., & Boche, D. (2015) · Alzheimer's Research & Therapy · doi:10.1186/s13195-015-0126-1 · Cited by 147 · cited 1× · see citing works
“Sustained inflammation has been observed in the brains of patients with AD [30, 31].”
BackgroundHey, J. A., Yu, Y., Versavel, M., Abushakra, S. R., Kočiš, P., Power, A., Kaplan, P. L., Amedio, J. C., & Tolar, M. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0608-3 · Cited by 130 · cited 1× · see citing works
“The participants were offered an open-label extension with high-dose gan-tenerumab because of its positive effects on imaging and other biomarkers, such as normalized CSF Aβ42, and because it reduced CSF total tau and pTau181 levels.”
BackgroundNilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer’s Disease
Turner, R. S., Hebron, M. L., Lawler, A., Mundel, E. E., Yusuf, N., Starr, J. N., Anjum, M., Pagan, F., Torres‐Yaghi, Y., Shi, W., et al. (2020) · Annals of Neurology · doi:10.1002/ana.25775 · Cited by 126 · see citing works
Tracking neuroinflammation in Alzheimer’s disease: the role of positron emission tomography imaging
Zimmer, E. R., Leuzy, A., Benedet, A. L., Breitner, J., Gauthier, S., & Rosa-Neto, P. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-120 · Cited by 121 · cited 1× · see citing works
“Sustained inflammation has been observed in the brains of patients with AD [30, 31].”
BackgroundGrundman, M., Morgan, R. E., Lickliter, J. D., Schneider, L. S., DeKosky, S. T., Izzo, N. J., Guttendorf, R. J., Higgin, M., Pribyl, J., Mozzoni, K., et al. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.11.001 · Cited by 111 · cited 1× · see citing works
“CT1812 is a ligand that targets the component 1 subunit of the sigma2/progesterone membrane receptor.”
BackgroundMahapatra, M. K., Karuppasamy, M., & Sahoo, B. M. (2022) · Pharmaceutical Research · doi:10.1007/s11095-022-03302-1 · Cited by 110 · cited 1× · see citing works
“GLP-1 receptors are involved in cognition, synaptic transmission in hippocampal neurons, and cell apoptosis; thus, they may serve as targets for exploring candidate drugs with neuroprotective and cognition-enhancing effects [72].”
BackgroundSauder, C. L., Allen, L. A., Baker, E. K., Miller, A., Paul, S. M., & Brannan, S. K. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02254-9 · Cited by 108 · cited 1× · see citing works
“It is reported that KarXT improves cognition in patients with AD and schizophrenia [67].”
BackgroundReading, C. L., Ahlem, C. N., & Murphy, M. F. (2021) · Neurodegenerative Disease Management · doi:10.2217/nmt-2021-0022 · Cited by 84 · cited 1× · see citing works
“The primary outcome measures are changes in ADAS-Cog12 and ADCS-CGIC scores from baseline to week 30 [76].”
BackgroundLi, N., Zhou, T. G., & Fei, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158281 · Cited by 83 · cited 1× · see citing works
“Metformin, a commonly prescribed antidiabetic medication, has been reported to improve cognition or mood in many neurological disorders [68, 69].”
BackgroundPresenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo
Gunawardena, S., Yang, G., & Goldstein, L. S. B. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt237 · Cited by 66 · cited 1× · see citing works
“In familial AD, mutant autosomal-dominant genes, including the genes for amyloid precursor protein ( APP ), presenilin-1 ( PSEN1 ), and presenilin-2 ( PSEN2 ), encode the major proteins involved in amyloid metabolism [13–15].”
BackgroundReducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A
Wang, H.-Y., Bakshi, K. P., Frankfurt, M., Stucky, A., Goberdhan, M., Shah, S. M., & Burns, L. H. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0354-12.2012 · Cited by 64 · cited 1× · see citing works
“Simufilam (PTI-125) is a drug that binds to filamin, a scaffolding protein that stabilizes the interaction between soluble Aβ42 and the α7 nicotinic acetylcholine receptor [55].”
BackgroundDehghan, E., Goodarzi, M., Saremi, B., Lin, R., & Mirzaei, H. (2019) · Nature Communications · doi:10.1038/s41467-019-12425-w · Cited by 63 · see citing works
Lues, I., Weber, F., Meyer, A., Uli, B., Hoffmann, T., Kühn‐Wache, K., Manhart, S., Heiser, U. F., Pokorny, R., Chiesa, J., et al. (2015) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2015.08.002 · Cited by 62 · cited 1× · see citing works
“Varoglutamstat (PQ912) is a glutaminyl cyclase inhibitor that reduces pGlu-Aβ generation [56].”
BackgroundFang, C., Hernandez, P., Liow, K. K., Damiano, E., Zetterberg, H., Blennow, K., Feng, D., Chen, M., & Maccecchini, M. L. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2022.84 · Cited by 62 · cited 1× · see citing works
“Buntanetap is a novel translational inhibitor of multiple neurotoxic proteins, including APP, tau, and α-synuclein, by enhancing the binding of the atypical iron response element in the 5′UTR regions of the mRNA of the neurotoxic proteins to iron regulatory protein 1 [62].”
BackgroundAlzheimer’s dementia: pathogenesis and impact of cardiovascular risk factors on cognitive decline
Wanleenuwat, P., Iwanowski, P. S., & Kozubski, W. P. (2019) · Postgraduate Medicine · doi:10.1080/00325481.2019.1657776 · Cited by 57 · cited 1× · see citing works
“Vascular risk factors can also lead to inflammation in the brain, which damages neuronal cells and further increases the likelihood of AD dementia [34].”
BackgroundLi, T., Martin, E., Abada, Y.-S. K., Boucher, C., Cès, A., Youssef, I., Fenaux, G., Forand, Y., Legrand, A., Nadkarni, N. A., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200466 · Cited by 51 · cited 1× · see citing works
“Anti‐neuroinflammation therapy Masitinib, an oral tyrosine kinase inhibitor, exerts effects by inhibiting mast cell and microglia/macrophage activity, with significant CNS penetration [74].”
BackgroundGardener, S. L., Rainey‐Smith, S. R., Villemagne, V. L., Fripp, J., Doré, V., Bourgeat, P., Taddei, K., Fowler, C. J., Masters, C. L., Maruff, P. T., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.744872 · Cited by 47 · cited 1× · see citing works
“Caffeine is an adenosine receptor antagonist that has been reported to be associated with slower cognitive decline and lower cerebral amyloid accumulation [63].”
BackgroundLockhart, S. N., Schaich, C. L., Craft, S., Sachs, B. C., Rapp, S. R., Jung, Y., Whitlow, C. T., Sai, K. K. S., Cleveland, M. L., Williams, B. J., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12429 · Cited by 44 · see citing works
Paul, S., Haskali, M. B., Liow, J., Zoghbi, S. S., Barth, V., Comly, M., Bond, M. R., Morse, C. L., Gladding, R. L., Frankland, M. P., et al. (2018) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.213231 · Cited by 41 · cited 1× · see citing works
“LY3372689 is a small-molecule inhibitor of O-GlcN-Acase, which promotes tau glycosylation and prevents tau aggregation [58].”
BackgroundKang, B. W., Kim, F., Cho, J., Kim, S., Rhee, J., & Choung, J. J. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01034-3 · Cited by 41 · cited 1× · see citing works
“It can rescue long-term potentiation impairment and cognitive dysfunction in animal models of AD [60].”
Monfared, A. A. T., Ye, W., Sardesai, A., Folse, H., Chavan, A., Aruffo, E., & Zhang, Q. (2023) · Neurology and Therapy · doi:10.1007/s40120-023-00473-w · Cited by 36 · cited 5× · see citing works
“Two articles reported the results of NCT03887455 [43, 84], and the other two reported the results of NCT01760005 [53, 83].”
BackgroundResultInfluentialParker, T. D., Cash, D. M., Lane, C., Lu, K., Malone, I. B., Nicholas, J. M., James, S., Keshavan, A., Murray‐Smith, H., Wong, A., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224030 · Cited by 35 · see citing works
Khaleghi-Mehr, M., Delshad, A.-A., Shafie-Damavandi, S., & Roghani, M. (2023) · Metabolic Brain Disease · doi:10.1007/s11011-023-01170-1 · Cited by 35 · cited 1× · see citing works
“Metformin, a commonly prescribed antidiabetic medication, has been reported to improve cognition or mood in many neurological disorders [68, 69].”
BackgroundWessels, A. M., Dennehy, E. B., Dowsett, S. A., Dickson, S. P., & Hendrix, S. B. (2023) · Neurology Clinical Practice · doi:10.1212/cpj.0000000000200127 · Cited by 35 · cited 1× · see citing works
“placebo), thus demonstrating clinical efficacy [51].”
Wu, C., Gong, W.-G., Wang, Y., Sun, J., Zhou, H., Zhang, Z., & Ren, Q. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.03.011 · Cited by 34 · cited 1× · see citing works
“activity and the insulin receptor substrate/glycogen synthase kinase-3β signaling pathway [79].”
BackgroundLu, J., Pan, Q., Zhou, J., Weng, Y., Chen, K., Shi, L., Zhu, G., Chen, C., Li, L., Geng, M., et al. (2021) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2021.06.001 · Cited by 29 · see citing works
Applications of tau PET imaging
Okamura, N., & Yanai, K. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.38 · Cited by 26 · cited 1× · see citing works
“Positron emission tomography (PET) investigations have revealed a strong correlation between the binding characteristics of tau tracers and the severity of clinical manifestations in individuals with AD [23].”
BackgroundIrizarry, M. C., Sims, J. R., Lowe, S. L., Nakano, M. H., Hawdon, A., Willis, B. A., Gonzales, C., Liu, P., Fujimoto, S., Dean, R. A., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.665 · Cited by 25 · cited 1× · see citing works
“It recognizes Aβ (3–42), an aggregated form of Aβ found in amyloid plaques [46].”
Bouter, Y., Liekefeld, H., Pichlo, S., Westhoff, A. C., Fenn, L., Bakrania, P., & Bayer, T. A. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02418-3 · Cited by 25 · cited 1× · see citing works
“It was discovered to be bound to approximately one-third of amyloid plaques in postmortem brain samples of patients with AD or Down syndrome, and it strongly reacted with the plaque core [47].”
BackgroundNirogi, R. V. S., Jayarajan, P., Benade, V. S., Shinde, A. K., Goyal, V., Jetta, S., Ravula, J., Abraham, R., Ramalingayya, G. V., Subramanian, R., et al. (2022) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.5813 · Cited by 18 · cited 1× · see citing works
“Masupirdine, a selective 5 ‐ HT6 receptor antagonist with favorable physicochemical properties and absorption, distribution, metabolism, and excretion properties, may have beneficial effects on agitation, aggression, and psychosis in patients with moderate AD [77].”
BackgroundJohnston, J. L., Reda, S. M., Setti, S. E., Taylor, R. W., Berthiaume, A.-A., Walker, W. E., Wu, W., Moebius, H. J., & Church, K. J. (2023) · Neurotherapeutics · doi:10.1007/s13311-022-01325-5 · Cited by 18 · cited 1× · see citing works
“The active metabolite of fosgonimeton (ATH-1017) is a positive modulator of hepatocyte growth factor (HGF)/ MET signaling [59].”
BackgroundChhunchha, B., Kubo, E., Krueger, R. R., & Singh, D. P. (2023) · Antioxidants · doi:10.3390/antiox12010140 · Cited by 18 · cited 1× · see citing works
“…it activates the Nrf2 pathway, which involves more than 200 antioxidant proteins; improves mitochondrial function; and increases respiration capacity and the production of adenosine triphosphate; hydralazine also activates autophagy, which aids in the clearance of intra-cellular aggregates [64–66].”
BackgroundLi, Z., Ramirez, G., Tang, R., Paul, C. K. X., Nair, M., Henderson, S. T., Morimoto, B. H., Liu, J. X., Kaasgaard, T., Boyd, B. J., et al. (2022) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2022.11.022 · Cited by 16 · cited 1× · see citing works
“Tricaprilin, a semisynthetic medium-chain triglyceride, is hydrolyzed to octanoic acid after administration and is further metabolized to ketones, which serve as an alternative energy substrate for the brain [73].”
BackgroundFDA approves new treatment for Alzheimer's disease
Canady, V. A. (2023) · Mental Health Weekly · doi:10.1002/mhw.33505 · Cited by 14 · cited 1× · see citing works
“…pathway on the basis of evidence of amyloid removal in a phase 2 trial (NCT01767311) and because it had a likelihood of having clinical benefits [41] A double-blind, placebo-controlled phase 2 trial recruited 856 patients with AD with mild cognitive impairment (MCI) or mild dementia and…”
BackgroundSchneider, L. S., Laudon, M., Nir, T., Caceres, J., Ianniciello, G., Capulli, M., & Zisapel, N. (2022) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2021.61 · Cited by 13 · cited 1× · see citing works
“Piromelatine is a melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptor agonist and was developed as a treatment for mild AD [71].”
BackgroundChang, T., & Chen, J. (2022) · Antioxidants · doi:10.3390/antiox11112224 · Cited by 13 · see citing works
The NIA-AA revised clinical criteria for Alzheimer’s disease: are they too advanced?
Bianchetti, A., Ikeda, M., Mateos, R., Mondini, S., Rabheru, K., Serrati, C., & Leo, D. D. (2023) · International Psychogeriatrics · doi:10.1017/s1041610223000868 · Cited by 9 · see citing works
Mehdipour, M., Emamghoreishi, M., Farrokhi, M. R., Fard, E. A., & Keshavarz, M. (2021) · Advanced Pharmaceutical Bulletin · doi:10.34172/apb.2022.065 · Cited by 8 · see citing works
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- Reading CL, Ahlem CN, Murphy MF. NM101 Phase III study of NE3107 in Alzheimer’s disease: rationale, design and therapeutic modulation of neuroinflammation and insulin resistance. Neurodegener Dis Manag. 2021;11(4):289–98. · DOI · Paper page
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Dementia Prevention and Treatment
Reuben, D. B., Kremen, S. A., & Maust, D. T. (2024) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2023.8522 · Cited by 214 · see citing works
Imam, F. B., Saloner, R., Vogel, J. W., Krish, V. S., Abdel-Azim, G., Ali, M., An, L., Anastasi, F., Bennett, D. A. A., Binette, A. P., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03834-0 · Cited by 134 · see citing works
“Until recently, treatment options were limited to managing symptoms, but approvals for disease-modifying drugs for AD and genetic forms of ALS point to considerable progress 2,3 .”
Terao, I., & Kodama, W. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102203 · Cited by 134 · see citing works
Alzheimer’s disease: a review on the current trends of the effective diagnosis and therapeutics
Manap, A. S. A., Almadodi, R., Sultana, S., Sebastian, M. G., Kavani, K. S., Lyenouq, V. E., & Shankar, A. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1429211 · Cited by 62 · see citing works
Novelties on Neuroinflammation in Alzheimer’s Disease–Focus on Gut and Oral Microbiota Involvement
Popescu, C., Munteanu, C., Anghelescu, A., Ciobanu, V., Spînu, A., Andone, I., Mandu, M., Bistriceanu, R., Băilă, M., Postoiu, R.-L., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011272 · Cited by 56 · see citing works
“Some clinical trials have shown promising results, such as improved cognitive function and reduced inflammatory markers following probiotic supplementation [142,143].”
BackgroundRecent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R. (2024) · Molecules · doi:10.3390/molecules29215131 · Cited by 56 · see citing works
“Phase III trials, including 48 trials that tested 32 medications [37,183,184].”
BackgroundGrabowska, W. A., Bijak, M., Szelenberger, R., Gorniak, L., Podogrocki, M., Harmata, P., & Cichoń, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178726 · Cited by 62 · see citing works
“However, very few multifunctional AChE inhibitors have progressed to clinical trials [9,24,25], highlighting the ongoing challenge of translating preclinical efficacy into safe and effective therapies for humans.”
Asghar, S., Mushtaq, N., Ahmed, A., Anwar, L., Munawar, R., & Akhtar, S. (2024) · Molecules · doi:10.3390/molecules29020490 · Cited by 48 · see citing works
“Similarly, lecanemab has demonstrated the ability to diminish pathogenic A β , prevent A β deposition, and selectively reduce A β protofibrils in both the brain and cerebrospinal fluid (CSF) of AD animal models [13,14].”
BackgroundGheidari, D., Mehrdad, M., & karimelahi, Z. (2024) · Scientific Reports · doi:10.1038/s41598-024-75292-6 · Cited by 44 · see citing works
Newer Therapeutic Approaches in Treating Alzheimer’s Disease: A Comprehensive Review
Sree, R. R., Kalyan, M., Anand, N., Mani, S., Gorantla, V. R., Sakharkar, M. K., Song, B., & Chidambaram, S. B. (2025) · ACS Omega · doi:10.1021/acsomega.4c05527 · Cited by 45 · see citing works
Muolokwu, C. E., Chaulagain, B., Gothwal, A., Mahanta, A. K., Tagoe, B., Lamsal, B., & Singh, J. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1405423 · Cited by 42 · see citing works
2023 China Alzheimer’s disease: facts and figures
Xiao, J., Li, J., Wang, J., Zhang, X., Wang, C., Peng, G., Hu, H., Liu, H., Liu, J., Shen, L., et al. (2023) · Human Brain · doi:10.37819/hb.3.1771 · Cited by 40 · see citing works
Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies
Meng, X., Zhang, H., Zhao, Z., Li, S., Zhang, X., Guo, R., Li, H., Yuan, Y., Li, W., Song, Q., et al. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01101-z · Cited by 43 · see citing works
Amyloid β oligomer induces cerebral vasculopathy via pericyte-mediated endothelial dysfunction
Chen, S., Guo, D., Zhu, Y., Xiao, S., Xie, J., Zhang, Z., Hu, Y., Huang, J., Ma, X., Ning, Z., et al. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01423-w · Cited by 41 · see citing works
“Most clinical treatments targeted glial and neuronal impairment in AD, such as cholinesterase inhibitors, memantine and some anti-neuroinflammatory drugs [4–6], could only enhance cognitive symptoms for a limited time period and are unable to reverse the disease course.”
BackgroundAutophagy-lysosomal pathway impairment and cathepsin dysregulation in Alzheimer’s disease
Mançano, A. S. F., Pina, J. G., Froes, B. R., & Sciani, J. M. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1490275 · Cited by 44 · see citing works
“One such study involves hydralazine, which is in phase 3 clinical trials for mild-to-moderate AD and, among various mechanisms, activates autophagy (Huang et al., 2023).”
Puranik, N., & Song, M. (2024) · Molecules · doi:10.3390/molecules29235744 · Cited by 45 · see citing works
“Sodium oligomannate is still in phase IV clinical trial [185].”
Daraban, B. S., Popa, A. S., & Stan, M. S. (2024) · Molecules · doi:10.3390/molecules29174056 · Cited by 36 · see citing works
Sighencea, M. G., Popescu, R. Ș., & Trifu, S. C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212311 · Cited by 32 · see citing works
“Therefore, a multitude of molecules have been found to exhibit antioxidant properties, functioning not only as activators of Nrf2, such as sulforaphane and hydralazine (the latter also inducing autophagy), but also as mimics of glutathione peroxidase, exemplified by ebselen [8,47].”
Yan, H., Wang, W., Cui, T., Shao, Y., Li, M., Fang, L., & Feng, L. (2024) · ImmunoTargets and Therapy · doi:10.2147/itt.s455881 · Cited by 30 · see citing works
Navigating the dementia landscape: Biomarkers and emerging therapies
Maheshwari, S., Singh, A., Ansari, V. A., Mahmood, T., Wasim, R., Akhtar, J., & Verma, A. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102193 · Cited by 30 · see citing works
Natural products targeting amyloid-β oligomer neurotoxicity in Alzheimer's disease
Gonçalves, P. B., Sodero, A. C. R., & Cordeiro, Y. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116684 · Cited by 26 · see citing works
Approved drugs and natural products at clinical stages for treating Alzheimer’s disease
Ma, Y., Liu, S., Zhou, Q., Zhong-hua, L., ZHANG, Z., & Yu, B. (2024) · Chinese Journal of Natural Medicines · doi:10.1016/s1875-5364(24)60606-0 · Cited by 26 · see citing works
Trisal, A., & Singh, A. K. (2024) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-024-01493-2 · Cited by 23 · see citing works
“This can lead to a decline in the reported efficacy of the treatment as no changes in the outcome measures will be observed in such individuals (Huang et al. 2023).”
BackgroundToward a biological definition of neuronal and glial synucleinopathies
Soto, C. A., Mollenhauer, B., Hansson, O., Kang, U. J., Alcalay, R. N., Standaert, D. G., Trenkwalder, C., MAREK, K. L., Galasko, D. R., & Poston, K. L. (2025) · Nature Medicine · doi:10.1038/s41591-024-03469-7 · Cited by 22 · see citing works
“Indeed, drugs are increasingly being tested in asymptomatic individuals, and some recently approved drugs were (to some extent) based on biomarker changes in patients enrolled at early stages of the disease 40,41 .”
Tang, C., Border, J. J., Zhang, H., Gregory, A., Bai, S., Fang, X., Liu, Y., Wang, S., Hwang, S. H., Gao, W., et al. (2025) · GeroScience · doi:10.1007/s11357-025-01550-8 · Cited by 22 · see citing works
“Kisunla™ (donanemab-azbt) received FDA approval in July 2024 for the treatment of early symptoms of AD [62].”
Qin, Y., Yang, P. C., He, W., Li, D., Zeng, L., Li, J., Zhou, T., Peng, J., Cao, L., & Huang, W. G. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01650-w · Cited by 26 · see citing works
“The FDA has approved Adu-canumab and Lecanemab, which are antibodies against amyloids that may prevent or reverse the progression of AD [8].”
BackgroundInfluentialJia, C., Chai, J., Zhang, S., Sun, Y., He, L., Sang, Z., Chen, D., & Zheng, X. (2025) · Marine Drugs · doi:10.3390/md23030091 · Cited by 21 · see citing works
“Existing therapeutic approaches [18,19] largely target singular aspects of AD pathology, such as A β aggregation, yet they have demonstrated limited clinical efficacy and often come with considerable side effects.”
Nrf2/Bach1 signaling axis: A promising multifaceted therapeutic strategy for Alzheimer's disease
Soni, P., Sharma, S. M., Pieper, A. A., Paul, B. D., & Thomas, B. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00586 · Cited by 22 · see citing works
“Many clinical trials enroll subjects in the later stages of AD, at which point signi fi cant neuronal loss and cognitive impairment have already occurred [113,114].”
Chhabra, A., Solanki, S., Saravanabawan, P., Venkiteswaran, A., Nimmathota, N., & Modi, N. M. (2024) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2024.2416947 · Cited by 20 · see citing works
“With conventional treatment usually limited to Cholinesterase Inhibitors and memantine, along with supportive care [13], the need for more targeted therapies that alter disease progression or induce disease remission is necessary.”
Hsu, C., Hsu, T., Kao, Y., Lin, Y., Thompson, T., Carvalho, A. F., Stubbs, B., Tseng, P., Yang, F., Tsai, C., et al. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100195 · Cited by 20 · see citing works
“These mABs target amyloid-𝛽 plaques which was seen as disease-modifying therapies based on the amyloid hypothesis of AD [ 9 , 10 ].”
Therapeutic Advances in Targeting the Amyloid-β Pathway for Alzheimer’s Disease
Zhang, B., Li, Y., Li, H., Shen, X., & Zhu, Z. (2025) · Brain Sciences · doi:10.3390/brainsci15101101 · Cited by 19 · see citing works
“This represents a milestone in AD drug development, as no other pathological pathway has yet achieved regulatory validation of clinical efficacy [14].”
Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases
Wu, Y.-F., Ma, B., Liu, C. Y., Li, D., & Sui, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251810187 · Cited by 18 · see citing works
“Thus, early diagnosis is crucial to identify the susceptible individuals before the commencement or at the early stages of the diseases [280].”
BackgroundBhardwaj, V., Kumari, S., Dhapola, R., Sharma, P., Beura, S. K., Singh, S. K., Vellingiri, B., & HariKrishnaReddy, D. (2024) · Inflammopharmacology · doi:10.1007/s10787-024-01598-6 · Cited by 17 · see citing works
“They mainly target activated immune cells of the CNS (mast cells and microglia) (Dubois et al. 2023; Huang et al. 2023).”
Dubey, Y. K., Bhongade, A., Palsodkar, P., & Fulzele, P. R. (2024) · Diagnostics · doi:10.3390/diagnostics14242770 · Cited by 21 · see citing works
The Potential Role of Phytochemicals in Alzheimer’s Disease
Baranowska‐Wójcik, E., Gajowniczek-Ałasa, D., Pawlikowska-Pawlęga, B., & Szwajgier, D. (2025) · Nutrients · doi:10.3390/nu17040653 · Cited by 17 · see citing works
Advancements in the treatment of Alzheimer's disease: a comprehensive review
Rajanna, S., Gundale, P. P., & Mahadevaiah, A. D. (2025) · Dementia & Neuropsychologia · doi:10.1590/1980-5764-dn-2024-0204 · Cited by 16 · see citing works
“Many promising treatments have been associated with significant side effects, such as ARIA in amyloid-target-ing therapies 51 .”
Fagla, B. M., & Buhimschi, I. A. (2024) · Molecules · doi:10.3390/molecules29030610 · Cited by 17 · see citing works
“ER stress modulators, autophagy-enhancing drugs, gene therapy, and anti-amyloid immunotherapy are also being examined as therapeutic approaches in the treatment of AD [146,220–222].”
Park, M., Ahn, J., Kim, Y.-J., Lee, J., Lee, J.-C., Hwang, S., & Kim, K. (2024) · Cells · doi:10.3390/cells13131085 · Cited by 16 · see citing works
“This figure is projected to increase to 82 million by 2030 and 150 million by 2050, with nearly 10 million new cases emerging annually [1–3].”
BackgroundMandino, F., Shen, X., Desrosiers-Grégoire, G., O’Connor, D. A., Mukherjee, B., Owens, A., Qu, A., Onofrey, J. A., Papademetris, X., Chakravarty, M. M., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02779-z · Cited by 18 · see citing works
“Vitally, treatment is given during very late-stage disease which is in stark contrast to existing anti-amyloid drugs which have only shown ef fi cacy during early (asymptomatic) illness [32].”
Mulumba, J., Duan, R., Luo, B., Wu, J., Sulaiman, M., Wang, F., & Yang, Y. (2025) · Exploration of neuroscience · doi:10.37349/en.2025.100675 · Cited by 22 · see citing works
Immunotherapeutic approaches for Alzheimer’s disease: Exploring active and passive vaccine progress
Bhadane, P., Roul, K., Belemkar, S., & Kumar, D. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149018 · Cited by 15 · see citing works
Cataldo, A., Criscuolo, S., Benedetto, E. D., Masciullo, A., Pesola, M., & Schiavoni, R. (2024) · Bioengineering · doi:10.3390/bioengineering11040324 · Cited by 15 · see citing works
“Nowadays, some drugs can slow the progression of AD, but a definitive cure does not yet exist [3].”
BackgroundRecent Advances in the Search for Effective Anti-Alzheimer’s Drugs
Ogoś, M., Stary, D., & Bajda, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms26010157 · Cited by 16 · see citing works
Park, M., Ahn, J., Lim, J., Han, M., Lee, J., Lee, J.-C., Hwang, S., & Kim, K. (2024) · Cells · doi:10.3390/cells13221920 · Cited by 15 · see citing works
“This number is projected to increase to 82 million by 2030 and 150 million by 2050, with nearly 10 million new cases Cells 2024 , 13 , 1920. https://doi.org/10.3390/cells13221920 https://www.mdpi.com/journal/cells Cells 2024 , 13 , 1920 2 of 24 each year [1–3].”
InfluentialThe Evolution of AChE Inhibitors in Alzheimer's Disease: From Single‐Target to Multi‐Target Ligands
Mehta, N. V., Kapadia, A., Khambete, M., & Abhyankar, A. N. (2025) · ChemBioChem · doi:10.1002/cbic.202500053 · Cited by 17 · see citing works
Gao, C., Liu, Y., Zhang, T., Luo, Y., Gao, J., Chu, J., Gong, B., Chen, X., Yin, T., Zhang, J., et al. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s436774 · Cited by 14 · see citing works
“70 However, AD is a complicated disease that may develop through the combination of multiple pathological mechanisms.”
BackgroundImpact of Peptide Transport and Memory Function in the Brain
Cheng, L., Shi, C., Li, X., & Matsui, T. (2024) · Nutrients · doi:10.3390/nu16172947 · Cited by 13 · see citing works
“However, the exact mechanism should be further investigated in the future.”
BackgroundAdvances in next-generation sequencing (NGS) applications in drug discovery and development
Wang, H., Huang, J., Fang, X., Liu, M., Fan, X., & Li, Y. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2481262 · Cited by 14 · see citing works
“This design increased the probability of participants receiving active treatment to 75%, as opposed to the 50% typical in traditional trials, thus enhancing the likelihood of achieving positive outcomes with a limited sample size [70] and contributing to high participant satisfaction [71].”
Gopalakrishna, P. K., Nassir, C. M. N. C. M., Anandan, S., Hussan, F., Dandala, K. C. R., Sura, S., Jagadeesan, S., Moklas, M. A. M., Vishnumukkala, T., & Hein, Z. M. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01671-4 · Cited by 22 · see citing works
Mitochondria, Autophagy and Inflammation: Interconnected in Aging
Silva, R. C. M. C. (2024) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-024-01231-x · Cited by 12 · see citing works
“Unfortunately, the levels of methylglyoxal were not evaluated, but hydralazine also activates autophagy, improves mitochondrial function, possesses antioxidant effects [32] and can regulate in fl am-mation to promote regeneration [33], being a fascinating drug for anti-ageing therapies.”
Das, B., Baidya, A. T. K., Chakrabarti, S., Chouhan, D., Thakur, B., Darreh‐Shori, T., Chen, G., Tiwari, V. K., & Kumar, R. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107373 · Cited by 12 · see citing works
Schreiner, T. G., Croitoru, C. G., Hodorog, D. N., & Cuciureanu, D. I. (2024) · Biomedicines · doi:10.3390/biomedicines12051096 · Cited by 12 · see citing works
“Currently being tested on participants with MCI or mild AD in a phase 1 clinical trial, initial results show a successful shift from PET-positive to PET-negative cerebral A β load [92].”
BackgroundAlzheimer's disease approaches - Focusing on pathology, biomarkers and clinical trial candidates
Hroudová, J., & Fišar, Z. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111069 · Cited by 13 · see citing works
Dendrimers—Novel Therapeutic Approaches for Alzheimer’s Disease
Mroziak, M., Kozłowski, G., Kołodziejczyk, W., Pszczołowska, M., Walczak, K., Beszłej, J. A., & Leszek, J. (2024) · Biomedicines · doi:10.3390/biomedicines12081899 · Cited by 12 · see citing works
“It is a humanized monoclonal antibody that recognizes A β , an aggregated form of A β in amyloid plaques and bound up to one-third of plaques [52].”
BackgroundFrança, V. L. B., BEZERRA, E. M., da COSTA, R. F., Carvalho, H. F., Freire, V. N., & Matos, G. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00453 · Cited by 12 · see citing works
Kanuri, S. H., & Sirrkay, P. J. (2024) · Brain Circulation · doi:10.4103/bc.bc_113_23 · Cited by 12 · see citing works
Clinical Applications of PET Imaging in Alzheimer’s Disease
Patil, S., Ayubcha, C., Teichner, E. M., Subtirelu, R. C., Cho, J. H., Ghonim, M., Ghonim, M., Werner, T. J., Høilund‐Carlsen, P. F., Alavi, A., et al. (2024) · PET Clinics · doi:10.1016/j.cpet.2024.09.015 · Cited by 13 · see citing works
Khedraoui, M., Guerguer, F. Z., Karim, E. M., Errougui, A., & Chtita, S. (2025) · Current Pharmaceutical Analysis · doi:10.1016/j.cpan.2025.03.005 · Cited by 14 · see citing works
Ashmawy, R. E., Okesanya, O. J., Ukoaka, B. M., Daniel, F. M., Ezedigwe, S. G., Agboola, A. O., Ahmed, M. M., Ogaya, J. B., Amisu, B. O., Adigun, O. A., et al. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251331640 · Cited by 12 · see citing works
Hossain, M. M., Adhikari, J., Dutta, A., Khandaker, A., Islam, S., Rahman, M. M., & Shibly, A. Z. (2025) · PLOS One · doi:10.1371/journal.pone.0331339 · Cited by 11 · see citing works
“Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia, affecting over 55 million individuals globally, a number projected to reach 139 million by 2050 due to an aging population [1,2].”
Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer’s Disease
Lalwani, R. C., Volmar, C., Wahlestedt, C., Webster, K. A., & Shehadeh, L. A. (2023) · Biomedicines · doi:10.3390/biomedicines11123232 · Cited by 11 · see citing works
“…the tests of time and remains the predominant hypothesis for AD progression and a promising pharmacological target, as evidenced by the recent FDA approval of two monoclonal antibodies (mAb), aducanumab and lecanemab, that target A β plaques and soluble A β O protofibrils, respectively [148,149].”
BackgroundWang, P.-H., Lin, H.-W., Nguyen, T. T. T., Hu, C., Huang, L.-K., Tam, K., & Kuan, Y. (2024) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2024.105199 · Cited by 11 · see citing works
Self-citationCalcineurin inhibition prevents synaptic plasticity deficit induced by brain-derived tau oligomers
Scaduto, P., Marcatti, M., Bhatt, N. N., Kayed, R., & Taglialatela, G. (2024) · Brain Communications · doi:10.1093/braincomms/fcae277 · Cited by 11 · see citing works
“Specifically, in comparison with the BDTO + FK506 group, the CTRL group exhibited an upregulation of 10 pro-inflammatory genes, including H2-M5 , known for its role in antigen presentation [1], [2] and Pla2g3 , implicated in the biosynthesis of pro-inflammatory eicosanoids [3].”
ResultNovel techniques for early diagnosis and monitoring of Alzheimer’s disease
Parul, P., Singh, A. K., & Shukla, S. (2024) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2024.2415985 · Cited by 13 · see citing works
“Involving people at different stages of the disease is essential to understand how the disease is progressing and creating novel treatment approaches [31].”
Swain, S., & Metya, A. K. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c00106 · Cited by 12 · see citing works
Yang, H., Yang, J., Park, N., Hwang, D., Park, S.-Y., Kim, S., & Bae, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413682 · Cited by 10 · see citing works
“This highlights the need for a more comprehensive approach targeting other pathological mechanisms, such as tau proteins and inflammation [2].”
Path integration impairments reveal early cognitive changes in subjective cognitive decline
Segen, V., Kabir, M. R., Streck, A., Slavík, J., Glanz, W., Butryn, M., Newman, E. L., Tiganj, Z., & Wolbers, T. (2025) · Science Advances · doi:10.1126/sciadv.adw6404 · Cited by 10 · see citing works
“Earlier identification is particularly important, as it opens a window for potential interventions at a stage when treatment could be more effective, potentially altering the disease trajectory ( 10 , 11 ).”
Targeting protein misfolding in Alzheimer’s disease: The emerging role of molecular chaperones
Sharma, A., Srivastava, S., Gupta, P., Sridhar, S. B., Tariq, M., Rao, G. K., Kumar, S., & Malik, T. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118531 · Cited by 10 · see citing works
McInvale, J. J., Canoll, P., & Hargus, G. (2024) · Brain Pathology · doi:10.1111/bpa.13231 · Cited by 11 · see citing works
“Given the need for effective treatments for AD, numerous therapeutics are in various stages of development from preclinical characterization to clinical trials [17].”
BackgroundMechanistic Approach to Immunity and Immunotherapy of Alzheimer’s Disease: A Review
Islam, M. R., Rabbi, M. A., Hossain, T., Sultana, S., & Uddin, S. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00360 · Cited by 10 · see citing works
Gomez-Sequeda, N., Jiménez-Del-Río, M., & Velez‐Pardo, C. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00472 · Cited by 10 · see citing works
Mitochondria-targeting by small molecules against Alzheimer's disease: A mechanistic perspective
Pal, C. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167617 · Cited by 12 · see citing works
Zhang, Y., Zhang, X., Zhou, J., Li, Y., Kai, T., & Zhang, L. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.140758 · Cited by 11 · see citing works
Hu, F., Peng, J., Wang, W., Shen, L., & Jia, M. (2025) · Complementary Therapies in Clinical Practice · doi:10.1016/j.ctcp.2025.101968 · Cited by 11 · see citing works
Bergamo, G., & Liguori, C. (2025) · Sleep And Breathing · doi:10.1007/s11325-025-03421-0 · Cited by 10 · see citing works
“The field continues to evolve, emphasizing the impor - tance of basic research on AD pathophysiology, prevention, and early intervention [4 ].”
Biologics as Therapeutical Agents Under Perspective Clinical Studies for Alzheimer’s Disease
Li, H., Shen, X., Zhang, B., & Zhu, Z. (2025) · Molecules · doi:10.3390/molecules30173479 · Cited by 10 · see citing works
“The most clinically advanced class of biologics in AD are mAbs targeting A β , with Aducanumab, Lecanemab, and Donanemab each reaching Phase III trials or receiving conditional approval [155–157].”
Ferritin nanocage-enabled detection of pathological tau in living human retinal cells
Barolo, L., Gigante, Y., Mautone, L., Ghirga, S., Soloperto, A., Giorgi, A., Ghirga, F., Pitea, M., Incocciati, A., Mura, F., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-62188-8 · Cited by 9 · see citing works
“There are currently about 200 active clinical trials worldwide assessing 140 novel treatments for AD, requiring a total enrollment of more than 60,000 participants 1–3 .”
Supplementation with NAD+ Precursors for Treating Alzheimer’s Disease: A Metabolic Approach
Alghamdi, M. A., & Braidy, N. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231277 · Cited by 10 · see citing works
Phytomedicine Potential of Oroxylum indicum Root and Its Constituents: Targeting Alzheimer’s Disease
Summat, R., Waiwut, P., Daodee, S., Nualkaew, N., Phemphunananchai, K., Arsito, P. N., Chulikhit, Y., Monthakantirat, O., Khamphukdee, C., & Boonyarat, C. (2025) · Plants · doi:10.3390/plants14020223 · Cited by 10 · see citing works
Multi-Omic Blood Biomarkers as Dynamic Risk Predictors in Late-Onset Alzheimer’s Disease
Bhalala, O. G., Watson, R., & Yassi, N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021231 · Cited by 10 · see citing works
“Such a shift in the utilization of blood biomarkers may also shed light on the effects of existing treatments, such as cholinesterase inhibitors and memantine, as well as molecules currently under investigation—an area of research where insufficient data exist [177,178].”
BackgroundDevelopment of Triphenylmethane Dyes for In Vivo Fluorescence Imaging of Aβ Oligomers
Nagashima, K., Watanabe, H., Akasaka, T., & Ono, M. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00053 · Cited by 9 · see citing works
Şimşek, H., & Uçar, A. (2024) · Clinical Nutrition Open Science · doi:10.1016/j.nutos.2024.05.012 · Cited by 10 · see citing works
Mosalam, E. M., Elberri, A. I., Abdallah, M. S., Abdel‐Bar, H. M., Zidan, A. A., Batakoushy, H. A., & Mansour, H. E. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147790 · Cited by 9 · see citing works
Functionalized Nanoparticles: A Promising Approach for Effective Management of Alzheimer’s Disease
Bogadi, S., Bhaskaran, M., Ravichandran, V., Nesamony, J., Selvam, C., Kuppusamy, G., Prakash, G., Karri, V. V. S. R., Mallick, S., Farahim, F., et al. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04917-2 · Cited by 10 · see citing works
Wang, K., Zan, S., Xu, J., Sun, W., Li, C., Zhang, W., Ni, D., Cheng, R., Li, L., Yu, Z., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e35800 · Cited by 9 · see citing works
Psychological Stress and Cognitive Brain Health: Policies to Reduce Dementia Risk
Graham‐Engeland, J. E., Sliwinski, M. J., Almeida, D. M., & Engeland, C. G. (2024) · Policy Insights from the Behavioral and Brain Sciences · doi:10.1177/23727322241303761 · Cited by 7 · see citing works
“Although recent advances in pharmacological treatments offer some hope in slowing the progression of ADRD (e.g., Huang et al., 2023), no treatment has proved capable of halting or reversing the disease.”
Gao, Q.-L., Zha, H.-W., Liu, Z.-J., Wang, M.-M., Zhang, Y.-Q., Bi, J.-R., Wu, T.-Y., Liu, Z.-J., Wu, H., & Sun, D. (2025) · Cell & Bioscience · doi:10.1186/s13578-025-01420-y · Cited by 11 · see citing works
“Although the therapeutic drugs for AD have been studied for many years, the side effects and safety concerns pro-foundly limit their clinical application [4].”
Gomez-Sequeda, N., Jiménez-Del-Río, M., & Velez‐Pardo, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094925 · Cited by 7 · see citing works
“Based on these observations, several drugs that work by reducing amyloid plaques and/or A β loads are currently in clinical trials [11,12] or have already been approved by the FDA (e.g., aducanumab [13], lecanemab [14]).”
BackgroundLiu, Z., Li, X., Huang, M., et al. (2024) · Medicinal Chemistry Research · doi:10.1007/s00044-024-03250-y · Cited by 7 · see citing works
“Clinical drugs approved by the FDA for anti-AD use include cholinesterase inhibitors (rivastigmine, donepezil, and galantamine), NMDA receptor antagonists (memantine), and monoclonal antibodies (Aducanumab and Leca-nemab) [2, 3].”
Coffee and Alzheimer's disease
Mirzaei, F., Agbaria, L., Bhatnagar, K., Sirimanne, N., A'amar, N. O., Jindal, V., Thilagendra, A. G., & Raba, F. T. (2024) · Progress in brain research · doi:10.1016/bs.pbr.2024.06.002 · Cited by 7 · see citing works
Ramey, G. D., Tang, A., Phongpreecha, T., Yang, M. M., Woldemariam, S. R., Oskotsky, T., Montine, T. J., Allen, I. E., Miller, Z., Aghaeepour, N., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.101980 · Cited by 7 · see citing works
Brain patterns and risk factors in the FINGER RCT multimodal lifestyle intervention
Lorenzon, G., Marseglia, A., Mohanty, R., Lehtisalo, J., Poulakis, K., Ngandu, T., Solomon, A., Kivipelto, M., & Westman, E. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100390 · Cited by 6 · see citing works
“While pharmacological solutions continue to be investigated [2], prevention remains the most effective strategy [1,3].”
Feldman, S. J., Blasco, D., Mones, M., & Roberts, J. S. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.69 · Cited by 6 · see citing works
“Further, the advent of precision medicine has also led to a rise in clinical trials of anti-amyloid-β and tau protein drug therapies available only to participants with specific APOE genotypes (9, 10, 11).”
Does Physical Exercise Modify the Pathophysiology of Alzheimer's Disease in Older Persons?
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“Various strategies to prevent AD have been developed, including drug therapy trials (7) as well as lifestyle interventions comprising cognitive stimulation, diet regulation, and physical exercise (8).”
BackgroundAlmeaqli, M. T., Alaidaa, Y., Alnajjar, F. M., Shararh, A. S. A., Alharbi, D. S., Almslmani, Y. I., Alotibi, Y. A., Alrashidi, H. S., Alshehri, W. A., Hassan, H. M., et al. (2024) · Current Alzheimer Research · doi:10.2174/0115672050333388240801043509 · Cited by 6 · see citing works
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Distinct inflammatory profiles in young‐onset versus late‐onset Alzheimer's disease
Thapa, S., Anastassiadis, C., Vasilevskaya, A., Taghdiri, F., Jurišica, I., Hadian, M., Salwierz, P., Robbani, F., Kivisäkk, P., Hyman, B. T., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70509 · Cited by 5 · see citing works
“18–21 Similarly, A β plaques and tau pathology disrupt the neuroprotective functions of astrocytes, which depend on well-regulated cytokine secretion.”
Photodynamic and Photothermal Therapies using Nanotechnology Approach in Alzheimer's Disease
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“The removal of amyloid and its promising potential for clinical benefits are supported by evidence from the phase 2 trial [40, 41].”
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“Further phase-3 trials are underway to evaluate its safety and efficacy in larger groups of patients [80].”
Plasma phosphorylated tau and neuropsychiatric symptoms in dementia with Lewy bodies
Gibson, L. L., González, M. C., Ashton, N. J., Tovar, D., Blanc, F., Pilotto, A., Lemstra, A. W., Paquet, C., Ballard, C. G., Zetterberg, H., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14434 · Cited by 5 · see citing works
“54,71 The presence of NPSs early in the course of DLB may be an additional differentiator to support the enrichment of clinical trial populations.”
- Authors
- Huang, L.-K., Kuan, Y.-C., Lin, H.-W., & Hu, C.-J.
- Affiliations
- Taipei Medical University-Shuang Ho Hospital (TW)
- National Taiwan University (TW)
- Taipei Medical University (TW)
- Corresponding author
- Hu, Chaur-Jong
- Venue
- Journal of Biomedical Science
- Published
- 2023-10-02
- Volume
- 30
- Issue
- 1
- Pages
- 83-83
- ISSN
- 1021-7770 (ISSN-L)
- 1423-0127
- PMC
- PMC10544555
- OpenAlex
- W4387259038
- Semantic Scholar
- c0688229e547b86cdf80c6678871dd16ba30491e
- Cited by
- 252
- References
- 86
- Citations by year
- 2026: 54 · 2025: 88 · 2024: 105 · 2023: 5
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Journal of Biomedical Science (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, clinical trials, new drug development, aducanumab, lecanemab, disease-modifying therapy, amyloid accumulation, neuroinflammation, clinical trial design
- MeSH terms
- Alzheimer Disease, Humans, Amyloid beta-Peptides
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