Advancements in the development of multi-target directed ligands for the treatment of Alzheimer’s disease

Bioorganic & Medicinal Chemistry, Год журнала: 2022, Номер 61, С. 116742 - 116742

Опубликована: Апрель 5, 2022

Язык: Английский

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High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects

Revue Neurologique, Год журнала: 2022, Номер 178(10), С. 1011 - 1030

Опубликована: Сен. 29, 2022

In 2021, aducanumab, an immunotherapy targeting amyloid-β, was approved for Alzheimer's disease (AD) by the US Food and Drug Administration thanks to positive results on a putative biological surrogate marker. This approval has raised unprecedented controversy. It followed refusal of European Medicine Agency, which does not allow marketing drugs solely arguments safety issues, important coverage limitations Centers Medicare & Medicaid Services. Two other anti-amyloid immunotherapies showed significant regarding clinical outcome in phase 2 trials, five are being studied 3 trials. Compared those tested previous trials 2010s, common feature novelty these is their ability induce high clearance amyloid load, as measured with positron emission tomography, brain early-stage biomarker-proven AD patients. Here, we review available evidence efficacy data medico-economical aspects high-clearance immunotherapies. We also perform frequentist Bayesian meta-analyses highest dose groups from two aducanumab donanemab lecanemab When pooled together, confirm statistically effect cognitive decline after 18 months (difference CDR-SB between vs. placebo = −0.24 points; P 0.04, random-effect model), ADAS-Cog most robust. However, this remains below previously established minimal clinically relevant values. parallel, significantly increased occurrence amyloid-related imaging abnormalities-edema (ARIA-E: risk ratio 13.39; < 0.0001), ARIA-hemorrhage (risk 2.78; 0.0002), symptomatic serious ARIA (7/1321 0.53% versus 0/1446 groups; 6.44; 0.04). The risk/benefit early so far questionable months. Identifying subgroups better responders, perspective combination therapies, longer follow-up may help improve relevance. Finally, preliminary analyses seems indicate that current cost reasonable alignment its benefits.

Язык: Английский

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Glucose Metabolism, Neural Cell Senescence and Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(8), С. 4351 - 4351

Опубликована: Апрель 14, 2022

Alzheimer’s disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, burdening diseases. To date, pathogenesis AD has not been fully illustrated. Emerging studies have revealed that cellular senescence abnormal glucose metabolism in brain are early hallmarks AD. Moreover, disturbance patients may precede amyloid-β deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia astrocytes be novel strategy for intervention treatment. Here, we recapitulate relationships between neural cell (e.g., insulin signaling, lactate metabolism) We then discuss potential perspective towards intervention, providing theoretical basis further exploration therapeutic approach toward

Язык: Английский

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Alzheimer’s disease clinical trial update 2019–2021

Journal of Neurology, Год журнала: 2021, Номер 269(2), С. 1038 - 1051

Опубликована: Окт. 5, 2021

Язык: Английский

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BACE1 Inhibitors for Alzheimer’s Disease: The Past, Present and Any Future?

Molecules, Год журнала: 2022, Номер 27(24), С. 8823 - 8823

Опубликована: Дек. 12, 2022

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and common cause of dementia in elderly. The complexity AD has hindered development either a cure or disease-modifying therapy to halt progression. Numerous hypotheses were presented order explain mechanisms underlying pathogenesis AD. Introduced 1992, “Amyloid Cascade Hypothesis” had huge impact on field inspired rise various drug candidates, especially amyloid-beta (Aβ)-directed drugs; including beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. Adopted by number pharmaceutical companies, BACE1 inhibitors gained momentum past decade with promising results from experimental early clinical-phase studies. Nevertheless, nearly all failed later phases clinical trials, due safety and/or efficacy issues, others discontinued favor second-generation small-molecule candidates. This paper aims provide comprehensive review ever reach we discuss challenges different perspectives whether are be reconsidered revitalized future.

Язык: Английский

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