Advancing combination therapy for Alzheimer's disease

Salloway, Stephen; Sevingy, Jeff; Budur, Kumar; Pederson, Jan; DeMattos, Ronald B.; Rosenstiel, Philipp von; Páez, Antonio; Evans, Rebecca; Weber, Christopher J.; Hendrix, James A.; Worley, Susan; Bain, Lisa J.; Carrillo, María C.

doi:10.1002/trc2.12073

Cited by 32 publications

(29 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Anti-tau agents already are in clinical trial, leading to consideration of combining anti-amyloid and anti-tau therapies [154]. Other potential combinations of therapies that have diverse mechanisms of action could include agents that address neuroinflammation, apolipoprotein E, mitochondrial modifiers, free radicals, autophagy, or the disrupted blood-brain barrier [44,155]. In addition, future studies should explore the potential role of human induced pluripotent stem cells (hiPSCs) in AD treatment, however to improve the interpretation of hiPSC experiments, more effective animal models and access to primary or age-matched cells from the human CNS are needed (Table 3).…”

Section: Combination Therapies In Prevention Trialsmentioning

confidence: 99%

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

McDade,

Llibre-Guerra,

Holtzman

et al. 2021

Mol Neurodegeneration

View full text Add to dashboard Cite

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.

show abstract

Section: Combination Therapies In Prevention Trialsmentioning

confidence: 99%

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

McDade,

Llibre-Guerra,

Holtzman

et al. 2021

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“… 30 , 43 , 44 Thus, single‐target therapies effective in reducing risk of AD will not necessarily be effective for treatment for AD. 45 , 46 However, combination therapies tailored to the cascade of risk factors still hold potential. Because risk factor biology is linked to the pathophysiology of AD, combination therapy that targets the preclinical risk factor profile could provide a combinatorial strategy to treat AD.…”

Section: Discussionmentioning

confidence: 99%

Preventing Alzheimer's disease within reach by 2025: Targeted‐risk‐AD‐prevention (TRAP) strategy

Vitali

Branigan

Brinton

2021

A&D Transl Res & Clin Interv

View full text Add to dashboard Cite

Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disease that currently affects 6.2 million people in the United States and is projected to impact 12.7 million worldwide in 2050 with no effective disease‐modifying therapeutic or cure. In 2011 as part of the National Alzheimer's Project Act, the National Plan to Address Alzheimer's Disease was signed into law which proposed to effectively prevent AD by 2025, which is rapidly approaching. The preclinical phase of AD can begin 20 years prior to diagnosis, which provides an extended window for preventive measures that would exert a transformative impact on incidence and prevalence of AD. Methods A novel combination of text‐mining and natural language processing strategies to identify (1) AD risk factors, (2) therapeutics that can target risk factor pathways, and (3) studies supporting therapeutics in the PubMed database was conducted. To classify the literature relevant to AD preventive strategies, a relevance score (RS) based on STRING (search tool for the retrieval of interacting genes/proteins) score for protein–protein interactions and a confidence score (CS) on Bayesian inference were developed. To address mechanism of action, network analysis of protein targets for effective drugs was conducted. Collectively, the analytic approach, referred to as a targeted‐risk‐AD‐prevention (TRAP) strategy, led to a ranked list of candidate therapeutics to reduce AD risk. Results Based on TRAP mining of 9625 publications, 364 AD risk factors were identified. Based on risk factor indications, 629 Food and Drug Administration‐approved drugs were identified. Computation of ranking scores enabled identification of 46 relevant high confidence (RS & CS > 0.7) drugs associated with reduced AD risk. Within these candidate therapeutics, 16 had more than one clinical study supporting AD risk reduction. Top‐ranked therapeutics with high confidence emerged within lipid‐lowering, anti‐inflammatory, hormone, and metabolic‐related drug classes. Discussion Outcomes of our novel bioinformatic strategy support therapeutic targeting of biological mechanisms and pathways underlying relevant AD risk factors with high confidence. Early interventions that target pathways associated with increased risk of AD have the potential to support the goal of effectively preventing AD by 2025.

show abstract

“…24 Therefore, the identification of combinatorial drug targets emerges as an essential approach to develop an effective combinatorial strategy in combating neurodegenerative tauopathies. 25 This indicated that dmyc and gsk3β can be exploited as a combinatorial drug target to accomplish an efficient amelioration against tau toxicity. In our subsequent investigations, we established that dmyc and gsk3β functions in a linear pathway to curb tau etiology.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, it is worth mentioning that the complex nature of tauopathies, which is primarily due to the contribution of multiple cellular cascades affected by pathogenic tau molecules, a single genetic modifier or a molecule is unlikely to be efficient enough to drive a complete rescue. 10,[22][23][24][25] Therefore, the need of the hour is to identify more than one candidate gene(s), which can act synergistically to alleviate the toxic effects of human tau protein.…”

Section: Introductionmentioning

confidence: 99%

Shaggy functions downstream of dMyc and their concurrent downregulation confers additive rescue against tau toxicity in Drosophila

Pragati

Sarkar

2021

BioFactors

View full text Add to dashboard Cite

Neurodegenerative tauopathies such as Alzheimer's and Parkinson's diseases are characterized by hyperphosphorylation of tau protein and their subsequent aggregation in the forms of paired helical filaments and/or neurofibrillary tangles in specific areas of the brain. Despite several attempts, it remains a challenge to develop reliable biomarkers or effective drugs against tauopathies. It is increasingly evident now that due to the involvement of multiple cellular cascades affected by the pathogenic tau molecules, a single genetic modifier or a molecule is unlikely to be efficient enough to provide an inclusive rescue. Hence, multitargets based combinatorial approach(s) have been suggested to provide an efficient rescue against tauopathies. We have reported earlier that targeted downregulation of dmyc (a Drosophila homolog of human cmyc proto-oncogene) restricts tau etiology by limiting tau hyperphosphorylation and heterochromatin loss. Although, dmyc generates a significant rescue; however, it is not proficient enough to provide a complete alleviation against tauopathies. Here, we report that tissue-specific concurrent downregulation of dmyc and gsk3β conveys a near-complete rescue against tau toxicity in Drosophila. We noted that combinatorial downregulation of dmyc and gsk3β reduces tau hyperphosphorylation, restricts the formation of neurofibrillary tangles, and restores heterochromatin loss to the physiological level. Our subsequent investigations revealed that dmyc regulates gsk3β via protein phosphatase 2A (dPP2A) in a dose-dependent manner to regulate tau pathogenesis. We propose that dmyc and gsk3β candidates can be utilized in a synergistic manner for the development of an efficient combinatorial therapeutic approach against the devastating human tauopathies.

show abstract

Advancing combination therapy for Alzheimer's disease

Cited by 32 publications

References 42 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

Preventing Alzheimer's disease within reach by 2025: Targeted‐risk‐AD‐prevention (TRAP) strategy

Shaggy functions downstream of dMyc and their concurrent downregulation confers additive rescue against tau toxicity in Drosophila

Contact Info

Product

Resources

About