Alzheimer's disease drug development pipeline: 2021

Cummings, Jeffrey L.; Lee, Garam; Zhong, Kate; Fonseca, Jorge; Taghva, Kazem

doi:10.1002/trc2.12179

Cited by 398 publications

(435 citation statements)

References 38 publications

(59 reference statements)

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“…It cannot be excluded that mechanisms other than modulating glutamatergic and GABAergic signaling contribute to the neuroprotective effects of the compounds described above. Moreover, current strategies and novel drug approaches for AD were described, including modulatory effects of autophagy on APP processing, as a potential treatment target for AD [190][191][192] (Table 3). As mentioned in this review, the metabolism of glutamate and GABA is very complex.…”

Section: Therapeutic Compounds Affecting Glutamate/gaba Neurotransmission In Microglial-neuron Communicationmentioning

confidence: 99%

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Czapski

Strosznajder

2021

IJMS

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The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.

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Section: Therapeutic Compounds Affecting Glutamate/gaba Neurotransmission In Microglial-neuron Communicationmentioning

confidence: 99%

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Czapski

Strosznajder

2021

IJMS

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“…Alzheimer’s disease is costly and marked by accumulation of pathological hallmarks such as amyloid plaques and neuronal tangles of hyperphosphorylated tau. Because Aβ plaques have shown poor correlation with AD progression, there has been a rise in the exploration and development of therapeutics that are not based on amyloid (Cummings et al, 2021). This shift in focus has resulted in numerous potential therapies that have made it into clinical trials, but so far there have been limitations on the impact of these potential therapies.…”

Section: Discussionmentioning

confidence: 99%

“…The first FDA-approved drug to treat Alzheimer’s disease (AD) in nearly two decades, Aduhelm®, shows a preferential affinity for all aggregated forms of amyloid beta (Aβ), rather than targeting only the toxic AβOs. Currently, there are more than 126 agents in clinical trials, with most aimed at disease modification (Cummings, 2021; Cummings et al, 2021). While less than 10% of these target Aβ, there remains evidence that Aβ is a significant target for therapeutic development.…”

Section: Discussionmentioning

confidence: 99%

The therapeutic and diagnostic potential of amyloid β oligomers (AβOs) selective antibodies to treat Alzheimer’s disease

Viola

Bicca

Bebenek

et al. 2021

Preprint

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Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques- species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce a promising anti-AβO diagnostic probe capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 hours. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.

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“…Apart from the biological options, 24 approaches with small molecules in phase 3 trial stage, 13 of which can be considered disease-modifying and the 11 others rather symptomatic. 51 In this review, every included combination therapy uses standard ChEI treatment as part of the combined approach. ChEI, despite their limited efficacy on cognition outcomes, play a very important role in AD treatment strategies and will most likely continue to do so in coming years.…”

Section: Outlook On Future Research Aimsmentioning

confidence: 99%

“…Caffeine, for example, has been associated with a significantly reduced risk of developing AD 56 and is currently investigated in a phase 3 trial in mild to moderate AD. 51 In terms of efficacy, there is still a long way to go. Also, as stated earlier, a critical issue is study duration.…”

Section: Outlook On Future Research Aimsmentioning

confidence: 99%

Alzheimer’s Disease: Efficacy of Mono- and Combination Therapy. A Systematic Review

Knorz

Quante

2021

J Geriatr Psychiatry Neurol

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Importance: Alzheimer’s disease (AD) is a complex neurodegenerative disorder and the most prevalent cause of dementia. In spite of the urgent need for more effective AD drug therapy strategies, evidence of the efficacy of combination therapy with existing drugs remains unclear. Objective: To assess the efficacy of combined drug therapy on cognition and progress in patients with AD in comparison to single agent drug therapy. Methods: The electronic databases MEDLINE and EMBASE were systematically searched to identify relevant publications. Only randomized controlled clinical trials were included, but no limits were applied to language or time published. Data were extracted from May 27th until December 29th, 2020. Results: Three trials found that a combination of ChEI with additional memantine provides a slight benefit for patients with moderate to severe AD over ChEI monotherapy and placebo. However, a further 4 trials could not replicate this effect. One trial reported benefits of add-on Gingko biloba in donepezil-treated patients with moderate AD (using a formula containing Gingko and other antioxidants) compared to donepezil with placebo. A further trial found no significant effect of combining EGb 761® and donepezil in patients with probable AD over donepezil with placebo. Approaches with idalopirdine, atorvastatin or vitamin supplementation in combination with ChEI have not proven effective and have not been retried since. Fluoxetine and ST101 have shown partial benefits in combination with ChEI over ChEI monotherapy and placebo. However, these effects must be replicated by further research. Conclusion: Additional memantine in combination with ChEI might be of slight benefit in patients with moderate to severe AD, but evidence is ambiguous. Longer trials are needed. No major cognitive benefit is missed, if solely appropriate ChEI monotherapy is initiated.

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Alzheimer's disease drug development pipeline: 2021

Cited by 398 publications

References 38 publications

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

The therapeutic and diagnostic potential of amyloid β oligomers (AβOs) selective antibodies to treat Alzheimer’s disease

Alzheimer’s Disease: Efficacy of Mono- and Combination Therapy. A Systematic Review

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