Small-molecule theranostics in Alzheimer's disease DOI Creative Commons
Álvaro Sarabia-Vallejo,

Pilar López‐Alvarado,

J. Carlos Menéndez

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 255, P. 115382 - 115382

Published: April 22, 2023

Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed countries, due to rising life expectancy and, moreover, represents a considerable economic burden worldwide. All efforts at discovery new diagnostic and therapeutic tools last decades have invariably met with failure, making AD an incurable illness underscoring need approaches. In recent years, theranostic agents emerged as interesting strategy. They are molecules able simultaneously provide information deliver activity, allowing assessment molecule organism response pharmacokinetics. This makes these compounds promising streamlining research on drugs their application personalized medicine. We review here field small-molecule development novel resources against AD, highlighting positive significant impact that theranostics can be expected near future clinical practice.

Language: Английский

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments DOI Creative Commons
Jun Guo, Xiuqing Huang, Lin Dou

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

Citations

773
Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup DOI Creative Commons
Clifford R. Jack,

J. Scott Andrews,

Thomas G. Beach

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5143 - 5169

Published: June 27, 2024

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 single 2012 2018 to create recommendations for diagnosis characterization of disease (AD). present document updates research framework response several recent developments. Defining diseases biologically, rather than based syndromic presentation, has long been standard many areas medicine (e.g., oncology), is becoming a unifying concept common all neurodegenerative diseases, not just AD. consistent with this principle. Our intent objective criteria staging AD, incorporating advances biomarkers, serve as bridge between clinical care. These are intended provide step‐by‐step practice guidelines workflow or specific treatment protocols, but general principles inform AD that reflect current science. Highlights We define (AD) be biological process begins appearance neuropathologic change (ADNPC) while people asymptomatic. Progression burden leads later progression symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid accurate plasma [especially phosphorylated tau 217]) map onto either amyloid beta tauopathy pathway; however, these presence ADNPC more generally (i.e., both neuritic plaques tangles). An abnormal biomarker result sufficient establish decision making throughout continuum. Later‐changing 2 (biofluid PET) can prognostic information, when abnormal, will increase confidence contributing integrated scheme described accommodates fact copathologies, cognitive reserve, resistance may modify relationships stages.

Language: Английский

Citations

598
Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs DOI
Francesca M. Alves, Paweł Kalinowski, Scott Ayton

et al.

Neurology, Journal Year: 2023, Volume and Issue: 100(20)

Published: March 27, 2023

To evaluate brain volume changes caused by different subclasses of anti-β-amyloid (Aβ) drugs trailed in patients with Alzheimer disease.

Language: Английский

Citations

134
Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment DOI Creative Commons
Katherine O. Kopp, Elliot J. Glotfelty, Yazhou Li

et al.

Pharmacological Research, Journal Year: 2022, Volume and Issue: 186, P. 106550 - 106550

Published: Nov. 11, 2022

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for diseases. Interestingly, increased inflammation risk been associated with type 2 diabetes mellitus (T2DM) insulin resistance (IR), suggesting that mitigate T2DM pathology may successful treating well. Glucagon-like peptide-1 (GLP-1) an incretin hormone promotes healthy signaling, regulates blood sugar levels, suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs developed approved by the US Food Drug Administration (FDA) related global regulatory authorities treatment T2DM. Furthermore, GLP-1R anti-inflammatory, neurotrophic, neuroprotective properties disorder preclinical models, hence hold promise repurposing In this review, we discuss pathways, intersections between neuroinflammation, brain IR, diseases, focus on AD PD. We additionally overview current FDA-approved agents development, including unimolecular single, dual, triple agonists, highlight those trials treatment. propose already-approved agonists safe, efficacious, cost-effective strategy ameliorating PD quelling neuroinflammation.

Language: Английский

Citations

130
The amyloid cascade hypothesis: an updated critical review DOI
Kasper P. Kepp,

Nikolaos K. Robakis,

Poul Flemming Høilund‐Carlsen

et al.

Brain, Journal Year: 2023, Volume and Issue: 146(10), P. 3969 - 3990

Published: May 15, 2023

Results from recent clinical trials of antibodies that target amyloid-β (Aβ) for Alzheimer's disease have created excitement and been heralded as corroboration the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging biochemical data suggest a more complex aetiology. Here we review history weaknesses hypothesis in view new evidence obtained anti-amyloid antibodies. These indicate treatments either no or uncertain effect on cognition. Despite importance definition argue point playing minor aetiological role. We also discuss suggesting concerted activity many pathogenic factors propose evolving multi-factor models will better underpin search effective strategies treat disease.

Language: Английский

Citations

125
Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial DOI
Mitzi M. Gonzales, Valentina R. Garbarino, Tiffany F. Kautz

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(10), P. 2481 - 2488

Published: Sept. 7, 2023

Language: Английский

Citations

125
Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials DOI Creative Commons
Adam L. Boxer, Reisa A. Sperling

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4757 - 4772

Published: Oct. 1, 2023

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as selection patients at relatively early stages disease. Biomarkers target pathologies, including tau PET, insights from past were also critical successes. Moving forward, challenge will be develop more efficacious greater efficiency. Novel trial designs, combination umbrella basket protocols, accelerate development. Better diversity inclusivity participants are needed, blood-based biomarkers may help improve access medically underserved groups. Incentivizing innovation in both academia industry through public-private partnerships, collaborative mechanisms, creation career paths build momentum exciting times.

Language: Английский

Citations

87
A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease DOI Creative Commons
Yongjin Yoo,

Gernot Neumayer,

Yohei Shibuya

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(8), P. 1043 - 1053.e6

Published: Aug. 1, 2023

Language: Английский

Citations

56
Alzheimer's disease pathophysiology in the Retina DOI Creative Commons
Bhakta Prasad Gaire,

Yosef Koronyo,

Dieu‐Trang Fuchs

et al.

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 101, P. 101273 - 101273

Published: May 15, 2024

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks AD, including amyloid β-protein (Aβ) deposits abnormal tau protein isoforms, in retinas AD patients animal models. Moreover, structural functional vascular abnormalities such as reduced blood flow, Aβ deposition, blood-retinal barrier damage, along with inflammation neurodegeneration, been described mild cognitive impairment dementia. Histological, biochemical, clinical studies demonstrated that nature severity pathologies brain correspond. Proteomics analysis revealed a similar pattern dysregulated proteins biological pathways patients, enhanced inflammatory neurodegenerative processes, impaired oxidative-phosphorylation, mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific deposits, well vasculopathy neurodegeneration living suggesting alterations at different stages links to pathology. Current exploratory ophthalmic modalities, optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, hyperspectral imaging, may offer promise assessment AD. However, further research needed deepen our understanding AD's impact on its progression. To advance this field, future require replication larger diverse cohorts confirmed biomarkers standardized retinal techniques. This will validate aiding early screening monitoring.

Language: Английский

Citations

28
Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank DOI Creative Commons
Xiaofei Wang, Ziyan Shi, Yuhan Qiu

et al.

BMC Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 13, 2024

Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP NfL levels elevated in the pre-clinical phase Alzheimer's disease (AD) dementia. However, predictive value for dementia requires more evidence from population-based cohorts.

Language: Английский

Citations

27