A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Salloway, Stephen; Farlow, Martin R.; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre‐Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan; Santacruz, Anna; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley; Cruchaga, Carlos; Goate, Alison; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine J.; Surti, Ghulam M.; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jiménez‐Velázquez, Ivonne Z.; Roberson, Erik D.; Dyck, Christopher H. van; Honig, Lawrence S.; Castilla, Joaquı́n; Brooks, William S.; Gauthier, Serge; Galasko, Douglas; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging‐Yuek Robin; Jayadev, Suman; Formaglio, Maïté; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R.; Koeppe, Robert A.; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, R.; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.

doi:10.1038/s41591-021-01369-8

Cited by 245 publications

(239 citation statements)

References 58 publications

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“…In support of the concept of a need for earlier intervention of Aβ therapeutics, the effect of gantenerumab on plaque reduction and downstream biomarkers of tau pathology and neuronal injury appeared to be larger in the asymptomatic group vs. the symptomatic group-though the small number of participants limited the statistical power of these findings. Although no cognitive or clinical benefit was observed, these findings suggest that removal of amyloid plaques may be a viable strategy in preventing or slowing the biological progression of AD if introduced at an optimal time [43].…”

Section: Review Of Amyloid Prevention Approachesmentioning

confidence: 72%

The informed road map to prevention of Alzheimer Disease: A call to arms

McDade,

Llibre-Guerra,

Holtzman

et al. 2021

Mol Neurodegeneration

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Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.

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Section: Review Of Amyloid Prevention Approachesmentioning

confidence: 72%

The informed road map to prevention of Alzheimer Disease: A call to arms

McDade,

Llibre-Guerra,

Holtzman

et al. 2021

Mol Neurodegeneration

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“…Dental anxiety was also identified as a major barrier to accessing dental treatment for people with ID [ 31 ]. Mentally challenged individuals tend to be less cooperative than the regular patient and dentists experience more difficulty in managing them during treatment sessions [ 32 ]. Friendly encounters with dental professionals during SO-SS events may contribute to enhance the dental compliance of SO athletes.…”

Section: Discussionmentioning

confidence: 99%

Ecological Study on the Oral Health of Romanian Intellectually Challenged Athletes

et al. 2022

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This study aimed to give an image of the oral health status and treatment needs of intellectually challenged athletes taking part in Special Olympics—Special Smiles (SO-SS) events organized in Romania during 2011–2019 and to find potential associations with socio-economic factors. An observational ecological retrospective study was conducted, and 1860 oral examinations were performed on participants aged 8 to 30 years in nine SS-SO events. Oral examination was performed under field conditions. Percentage of caries-free subjects, mean DMF-T index and its components (D = decayed; M = missing; F = filled; T = teeth), restoration index RI = [F/(F + D) × 100]%, and Plaque Index were calculated for each of the nine groups. Caries-free subjects ranged between 5.90% and 21.70%. DMF-T ranged from 4.27 to 7.71. Higher values for “F” component (range 0.66–1.69) and RI (range 13.02–27.74%) were found in events held in cities from regions with higher reported Gross Domestic Product. Sealants were present in 0 to 8.4% of the subjects. In areas with lower numbers of inhabitants per dentist, more sealants were found (p < 0.001). Romanian SO athletes exhibited relatively poor oral health, limited access to dental treatment, and low level of prevention. Targeted prevention and treatment programs adjusted to specific conditions in each geo-economic region are needed.

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“…On the 21st June 2021, results from a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with dominantly inherited AD (DIAD) across asymptomatic and symptomatic disease stages were disclosed. Despite both drugs demonstrated convincing Aβ target engagement, gantenerumab failed to show a beneficial effect on cognitive measures, whereas solanezumab-treated group even exhibited a greater cognitive decline on some measures compared to placebo [9]. One week later, a cross sectional study conducted on 598 amyloid-positive participants patients was published and revealed that soluble Aβ 42 levels above 800 pg/ml were correlated with normal cognition irrespective of (and despite increasing) brain amyloid burden, implying that increasing soluble Aβ 42 , rather than reducing Aβ plaques, might represent a better therapeutic option [11].…”

Section: Discussionmentioning

confidence: 92%

Aducanumab for Alzheimer’s disease: A regulatory perspective

Nisticò

Borg

2021

Pharmacological Research

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On June 7th 2021, the Food and Drug Administration (FDA) granted approval for Aduhelm (aducanumab) for the treatment of Alzheimer's disease under its accelerated approval program. Aducanumab is the first putative disease-modifying therapy (DMT) approved for the treatment of AD with a great potential for clinical benefit over current symptomatic therapies. The scientific community has been largely confounded by this historical decision since this has been based on the reduction of a surrogate marker (amyloid beta) and not on data showing clinical efficacy. Here we provide a regulatory perspective on the topic and discuss potential similarities and differences between the FDA's and EMA's evaluative processes.

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A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Abstract: Code availabilityAll code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.

Cited by 245 publications

References 58 publications

The informed road map to prevention of Alzheimer Disease: A call to arms

The informed road map to prevention of Alzheimer Disease: A call to arms

Ecological Study on the Oral Health of Romanian Intellectually Challenged Athletes

Aducanumab for Alzheimer’s disease: A regulatory perspective

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