Pub Date : 2025-12-18DOI: 10.1016/j.arr.2025.103001
Lorenzo Pini , Bruno P. Imbimbo , Alessandra Griffa , Gilles Allali , Nunzio Pomara
Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Based on these insights, this review explores the potential of off-label FDA-approved drug repositioning as a cost-effective strategy to identify therapeutic approaches for AD. We examine the neurophysiological effects of certain repurposed drugs that modulate synaptic activity, reduce inflammation, enhance metabolic pathways and gut-brain axis interactions, in preclinical and clinical models. Emerging evidence suggests that these drugs (e.g., anticonvulsants, anti-diabetics, anti-inflammatory, and gastrointestinal agents) can influence brain connectivity and activity, mitigating cognitive deficits. By integrating connectivity-focused biomarkers into clinical trials, researchers can advance the development of disease-modifying treatments. This review underscores the importance of a connectivity-driven framework for repurposing existing drugs to address need for new treatments for AD.
{"title":"Targeting brain connectivity in Alzheimer’s disease with repurposed drugs","authors":"Lorenzo Pini , Bruno P. Imbimbo , Alessandra Griffa , Gilles Allali , Nunzio Pomara","doi":"10.1016/j.arr.2025.103001","DOIUrl":"10.1016/j.arr.2025.103001","url":null,"abstract":"<div><div>Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Based on these insights, this review explores the potential of off-label FDA-approved drug repositioning as a cost-effective strategy to identify therapeutic approaches for AD. We examine the neurophysiological effects of certain repurposed drugs that modulate synaptic activity, reduce inflammation, enhance metabolic pathways and gut-brain axis interactions, in preclinical and clinical models. Emerging evidence suggests that these drugs (e.g., anticonvulsants, anti-diabetics, anti-inflammatory, and gastrointestinal agents) can influence brain connectivity and activity, mitigating cognitive deficits. By integrating connectivity-focused biomarkers into clinical trials, researchers can advance the development of disease-modifying treatments. This review underscores the importance of a connectivity-driven framework for repurposing existing drugs to address need for new treatments for AD.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 103001"},"PeriodicalIF":12.4,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer's disease (AD) is the most chronic neurodegenerative disease. The pathological hallmark of AD includes the accumulation of amyloid-beta plaques (Aβ), oxidative stress as well as chronic inflammatory reactions. Current treatments, such as acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and recently approved monoclonal antibodies, offer symptomatic relief or slightly slow down progression. However, they too are constrained by high cost, side effects and limited activity. Proteins and peptides are emerging focus of attention as promising therapeutics, due to their higher selectivity, participation in many pathological pathways, and are lesser toxicity than other therapies in recent years. These biomolecules mediate their effect by decreasing amyloid aggregation, preventing tau hyperphosphorylation, regulating oxidative damage and repairing synapses. Various proteins and peptides such as SS31, LPfFFD-PEG, SEN1576, α sheet peptides, D-(PGKLVYA), RI-OR2-TAT, TFP5, SEN304, PP-Leu, Ac-Leu-Pro-Phe-Phe-Asp-NH2 (iAb5p), and Cyclo (17, 21)- (Lys17, Asp21) Aβ (1−28) have been used in the treatment of AD. Nonetheless, these peptides have a limited clinical translatability due to their vulnerability to enzymatic degradation, systemic circulation instability, low bioavailability, and limited penetration across the blood-brain barrier (BBB). To overcome these challenges, nanotechnology-based treatments have become a revolutionary solution. Both functionalized and non-functionalized protein and peptide-loaded nanoparticles provide protection against degradation, cross the BBB, and allow sustained and targeted delivery of neuronal tissues. The ligand-functionalized nanoparticle systems increase the accumulation of therapeutics in the brain as they cross the blood-brain barrier more efficiently. These are also able to protect the circulatory proteins and peptides, and eventually lead to improved therapeutic results in preclinical models. The present review highlights the therapeutic and delivery potential of protein- and peptide-based nanocarriers as dual therapeutic and delivery vectors with disease-modifying capability and precision targeting. Together, these advances have placed nanotechnology-based protein and peptide therapeutics for better management of AD.
阿尔茨海默病（AD）是最慢性的神经退行性疾病。AD的病理特征包括淀粉样斑块（Aβ）的积累、氧化应激以及慢性炎症反应。目前的治疗方法，如乙酰胆碱酯酶抑制剂、n -甲基- d -天冬氨酸（NMDA）受体拮抗剂和最近批准的单克隆抗体，可以缓解症状或略微减缓进展。然而，它们也受到高成本、副作用和有限活动的限制。近年来，由于蛋白质和多肽具有较高的选择性，参与许多病理途径，并且毒性比其他治疗方法小，因此它们作为有前景的治疗方法正成为人们关注的焦点。这些生物分子通过减少淀粉样蛋白聚集、防止tau过度磷酸化、调节氧化损伤和修复突触来调节其作用。各种蛋白和肽如SS31、LPfFFD-PEG、SEN1576、α片肽、D-(PGKLVYA)、RI-OR2-TAT、TFP5、SEN304、PP-Leu、ac - leu - pro - ph - ph - asp - nh2 （iAb5p）和Cyclo (17,21)- (Lys17, Asp21) Aβ(1−28)已被用于治疗AD。然而，由于这些多肽易受酶降解、体循环不稳定、生物利用度低以及穿过血脑屏障（BBB）的渗透有限，它们的临床可翻译性有限。为了克服这些挑战，基于纳米技术的治疗已经成为一种革命性的解决方案。功能化和非功能化的蛋白质和肽负载纳米颗粒都提供抗降解保护，穿过血脑屏障，并允许持续和靶向递送神经元组织。配体功能化的纳米颗粒系统可以更有效地通过血脑屏障，从而增加治疗药物在大脑中的积累。这些也能够保护循环蛋白和肽，并最终在临床前模型中改善治疗结果。目前的综述强调了基于蛋白质和肽的纳米载体作为具有疾病修饰能力和精确靶向的双重治疗和递送载体的治疗和递送潜力。总之，这些进展使基于纳米技术的蛋白质和肽疗法更好地管理阿尔茨海默病。
{"title":"Protein and peptide based nanotherapeutics for the management of Alzheimer’s disease: Current insights and future directions","authors":"Sandeep Kumar Das , Bushra Bashir , Kaustubh Ajit Kolekar , Vancha Harish , Deepshikha Patle , Sukriti Vishwas , Neeraj Mittal , Saurabh Kumar Jha , Puneet Kumar , Gaurav Gupta , Harish Dureja , Kamal Dua , Dennis Chang , Gowthamarajan Kuppusamy , Sachin Kumar Singh","doi":"10.1016/j.arr.2025.103000","DOIUrl":"10.1016/j.arr.2025.103000","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the most chronic neurodegenerative disease. The pathological hallmark of AD includes the accumulation of amyloid-beta plaques (Aβ), oxidative stress as well as chronic inflammatory reactions. Current treatments, such as acetylcholinesterase inhibitors, N-methyl-<span>D</span>-aspartate (NMDA) receptor antagonists, and recently approved monoclonal antibodies, offer symptomatic relief or slightly slow down progression. However, they too are constrained by high cost, side effects and limited activity. Proteins and peptides are emerging focus of attention as promising therapeutics, due to their higher selectivity, participation in many pathological pathways, and are lesser toxicity than other therapies in recent years. These biomolecules mediate their effect by decreasing amyloid aggregation, preventing tau hyperphosphorylation, regulating oxidative damage and repairing synapses. Various proteins and peptides such as SS31, LPfFFD-PEG, SEN1576, α sheet peptides, D-(PGKLVYA), RI-OR2-TAT, TFP5, SEN304, PP-Leu, Ac-Leu-Pro-Phe-Phe-Asp-NH2 (iAb5p), and Cyclo (17, 21)- (Lys17, Asp21) Aβ (1−28) have been used in the treatment of AD. Nonetheless, these peptides have a limited clinical translatability due to their vulnerability to enzymatic degradation, systemic circulation instability, low bioavailability, and limited penetration across the blood-brain barrier (BBB). To overcome these challenges, nanotechnology-based treatments have become a revolutionary solution. Both functionalized and non-functionalized protein and peptide-loaded nanoparticles provide protection against degradation, cross the BBB, and allow sustained and targeted delivery of neuronal tissues. The ligand-functionalized nanoparticle systems increase the accumulation of therapeutics in the brain as they cross the blood-brain barrier more efficiently. These are also able to protect the circulatory proteins and peptides, and eventually lead to improved therapeutic results in preclinical models. The present review highlights the therapeutic and delivery potential of protein- and peptide-based nanocarriers as dual therapeutic and delivery vectors with disease-modifying capability and precision targeting. Together, these advances have placed nanotechnology-based protein and peptide therapeutics for better management of AD.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 103000"},"PeriodicalIF":12.4,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.arr.2025.102997
E. Garcia-Cabello , A. Habich , Y. Molina , L. Perestelo-Pérez , J. Barroso , D. Ferreira
Despite ample research on cognitive aging, it is still largely unknown whether cognition is organized in a distinct manner, with different cognitive domains and subcomponents interrelating with each other. It is also unknown whether this cognitive organization is stable or changes with increasing age. Following the PRISMA guidelines statement, we conducted a systematic review of multivariate studies of cognitive aging with the aim to identify a potential cognitive organization in healthy aging. We consulted Embase, PsycInfo and Medline electronic databases from 2000 to October 2025. The methodological quality of the included studies was analysed using CASP tools and a narrative synthesis of the selected articles was performed. We screened 1518 references and a total of 14 research articles met selection criteria and were included. We found convergent findings across studies suggesting a cognitive organization of four factors: memory, language, executive functions, and processing speed. This cognitive organization was rather consistent across studies, cohorts, and methodologies. A fifth factor for visuospatial abilities was identified in several studies. Some studies reported that processing speed may influence age-related changes in the direct performance of other cognitive domains. However, the current evidence did not allow concluding on the effect of age in this cognitive organization. Therefore, it is yet to be clarified whether this cognitive organization remains invariant throughout age. Advancing in our understanding of cognitive aging can result in a more accurate and personalized clinical assessment and intervention in people at risk of cognitive impairment.
{"title":"A systematic review of multivariate studies in cognitive aging: Introducing the concept of cognitive organization","authors":"E. Garcia-Cabello , A. Habich , Y. Molina , L. Perestelo-Pérez , J. Barroso , D. Ferreira","doi":"10.1016/j.arr.2025.102997","DOIUrl":"10.1016/j.arr.2025.102997","url":null,"abstract":"<div><div>Despite ample research on cognitive aging, it is still largely unknown whether cognition is organized in a distinct manner, with different cognitive domains and subcomponents interrelating with each other. It is also unknown whether this cognitive organization is stable or changes with increasing age. Following the PRISMA guidelines statement, we conducted a systematic review of multivariate studies of cognitive aging with the aim to identify a potential cognitive organization in healthy aging. We consulted Embase, PsycInfo and Medline electronic databases from 2000 to October 2025. The methodological quality of the included studies was analysed using CASP tools and a narrative synthesis of the selected articles was performed. We screened 1518 references and a total of 14 research articles met selection criteria and were included. We found convergent findings across studies suggesting a cognitive organization of four factors: memory, language, executive functions, and processing speed. This cognitive organization was rather consistent across studies, cohorts, and methodologies. A fifth factor for visuospatial abilities was identified in several studies. Some studies reported that processing speed may influence age-related changes in the direct performance of other cognitive domains. However, the current evidence did not allow concluding on the effect of age in this cognitive organization. Therefore, it is yet to be clarified whether this cognitive organization remains invariant throughout age. Advancing in our understanding of cognitive aging can result in a more accurate and personalized clinical assessment and intervention in people at risk of cognitive impairment.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102997"},"PeriodicalIF":12.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.arr.2025.102996
Liren Duan , Shenli Li , Qi Yan , Yaodong Sun , Shiyue Wang , Lin Zhao , Mark G. Davies , Jian Zhang
Background
Recent research indicates a potential correlation between white matter microstructure (WMM) and abdominal aortic aneurysm (AAA). This research employed a bidirectional Mendelian randomization (MR) framework to elucidate exposure-outcome causality. The research design prioritized estimation of exposure effect on outcomes.
Methods
Published genome-wide association studies (GWAS) datasets encompassing 39,221 AAA cases and 1086,107 controls were analyzed alongside diffusion tensor imaging metrics from 43,802 European participants. The analytical framework adopted a bidirectional MR design, incorporating sensitivity analyses through five robust methods: random-effects IVW regression, MR-Egger regression, weighted median estimator, and simple/weighted mode approaches. Genetic and neuroimaging resources were systematically curated from two publicly accessible repositories: (1) the AAAgen Consortium providing aneurysm susceptibility loci, and (2) the Brain Imaging Genetics Knowledge Portal (BIG-KP) portal housing population-level brain imaging genomics data.
Results
Our findings revealed that lower mean fractional anisotropy (FA) in cingulum (hippocampus) significantly elevated AAA risk (OR 1.266; 95 % CI 1.126–1.424; P = 8.28 × 10⁻⁵). Similarly, reduced third FA principal component (PC) in retrolenticular part of internal capsule significantly elevated AAA risk (OR 1.196; 95 % CI 1.089–1.316; P = 1.82 × 10⁻⁴). The reverse causality analysis within our MR framework demonstrated null associations between AAA and WMM (all P > 2.326 × 10−4). Based on the study, we observed white matter integrity influences the chances of developing AAA.
Conclusion
Our bidirectional MR analysis revealed the causal influence of WMM alterations on AAA.
背景：最近的研究表明白质微结构（WMM）与腹主动脉瘤（AAA）之间存在潜在的相关性。本研究采用双向孟德尔随机化（MR）框架来阐明暴露-结果因果关系。研究设计优先评估暴露对结果的影响。方法：已发表的全基因组关联研究（GWAS）数据集包括39,221例AAA病例和1,086,107例对照，以及来自43,802名欧洲参与者的弥散张量成像指标。分析框架采用双向MR设计，通过随机效应IVW回归、MR- egger回归、加权中位数估计和简单/加权模式五种稳健方法进行敏感性分析。遗传和神经影像学资源系统地从两个可公开访问的存储库中进行整理：(1)AAAgen联盟提供动脉瘤易感性位点，(2)脑成像遗传学知识门户（BIG-KP）门户存储人群水平的脑成像基因组学数据。结果：我们的研究结果显示，扣带（海马体）中较低的平均分数各向异性（FA）显著增加AAA风险（OR 1.266; 95% CI 1.126-1.424; P = 8.28 × 10⁻- 5）。同样，内囊透镜后部分第三FA主成分（PC）的减少显著增加AAA风险（OR 1.196; 95% CI 1.089-1.316; P = 1.82 × 10⁻⁴）。在我们的MR框架内的反向因果关系分析表明，AAA和WMM之间没有关联（所有P为2.326 × 10-4）。结论：我们的双向MR分析揭示了WMM改变对AAA的因果影响。
{"title":"Mendelian randomization analyses reveal relationships between white matter microstructure and risk of abdominal aortic aneurysm","authors":"Liren Duan , Shenli Li , Qi Yan , Yaodong Sun , Shiyue Wang , Lin Zhao , Mark G. Davies , Jian Zhang","doi":"10.1016/j.arr.2025.102996","DOIUrl":"10.1016/j.arr.2025.102996","url":null,"abstract":"<div><h3>Background</h3><div>Recent research indicates a potential correlation between white matter microstructure (WMM) and abdominal aortic aneurysm (AAA). This research employed a bidirectional Mendelian randomization (MR) framework to elucidate exposure-outcome causality. The research design prioritized estimation of exposure effect on outcomes.</div></div><div><h3>Methods</h3><div>Published genome-wide association studies (GWAS) datasets encompassing 39,221 AAA cases and 1086,107 controls were analyzed alongside diffusion tensor imaging metrics from 43,802 European participants. The analytical framework adopted a bidirectional MR design, incorporating sensitivity analyses through five robust methods: random-effects IVW regression, MR-Egger regression, weighted median estimator, and simple/weighted mode approaches. Genetic and neuroimaging resources were systematically curated from two publicly accessible repositories: (1) the AAAgen Consortium providing aneurysm susceptibility loci, and (2) the Brain Imaging Genetics Knowledge Portal (BIG-KP) portal housing population-level brain imaging genomics data.</div></div><div><h3>Results</h3><div>Our findings revealed that lower mean fractional anisotropy (FA) in cingulum (hippocampus) significantly elevated AAA risk (OR 1.266; 95 % CI 1.126–1.424; <em>P</em> = 8.28 × 10⁻⁵). Similarly, reduced third FA principal component (PC) in retrolenticular part of internal capsule significantly elevated AAA risk (OR 1.196; 95 % CI 1.089–1.316; <em>P</em> = 1.82 × 10⁻⁴). The reverse causality analysis within our MR framework demonstrated null associations between AAA and WMM (all P > 2.326 × 10<sup>−4</sup>). Based on the study, we observed white matter integrity influences the chances of developing AAA.</div></div><div><h3>Conclusion</h3><div>Our bidirectional MR analysis revealed the causal influence of WMM alterations on AAA.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102996"},"PeriodicalIF":12.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.arr.2025.102994
Madhuri Gawai , Neha Nistane , Amol A. Tatode , Mohammad Qutub , Milind J. Umekar , Tanvi Premchandani , Jayshree B. Taksande
Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disorder, contributing to the majority of dementia cases in the elderly globally. Characterized by progressive cognitive decline, AD is associated with complex neuropathological changes, including the accumulation of amyloid-beta (Aβ) plaques and tau tangles, synaptic loss, and neuroinflammation. One of the significant challenges in treating AD is the blood-brain barrier (BBB), which prevents many therapeutic agents from reaching the brain. Despite advancements in understanding AD's pathology, limited treatment options are available, largely due to the inability of conventional drugs to effectively target the brain. Ligand-conjugated nanoparticles (NPs) are promising for targeted drug delivery to the brain. These NPs, engineered with ligands that can bind to specific receptors or transporters on the BBB, facilitate the crossing of the barrier via receptor-mediated endocytosis or adsorptive-mediated transcytosis. This strategy enhances therapeutic agents' bioavailability and cellular uptake, offering a potential solution to overcome current limitations in AD treatment. Using nanotechnology to design ligand-conjugated NPs for targeted and sustained drug delivery could significantly improve therapeutic outcomes for AD patients by addressing key pathological processes in the brain.
{"title":"Transforming anti-Alzheimer’s therapy by targeting endogenous receptorrial system through ligand-conjugated nanoformulations","authors":"Madhuri Gawai , Neha Nistane , Amol A. Tatode , Mohammad Qutub , Milind J. Umekar , Tanvi Premchandani , Jayshree B. Taksande","doi":"10.1016/j.arr.2025.102994","DOIUrl":"10.1016/j.arr.2025.102994","url":null,"abstract":"<div><div>Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disorder, contributing to the majority of dementia cases in the elderly globally. Characterized by progressive cognitive decline, AD is associated with complex neuropathological changes, including the accumulation of amyloid-beta (Aβ) plaques and tau tangles, synaptic loss, and neuroinflammation. One of the significant challenges in treating AD is the blood-brain barrier (BBB), which prevents many therapeutic agents from reaching the brain. Despite advancements in understanding AD's pathology, limited treatment options are available, largely due to the inability of conventional drugs to effectively target the brain. Ligand-conjugated nanoparticles (NPs) are promising for targeted drug delivery to the brain. These NPs, engineered with ligands that can bind to specific receptors or transporters on the BBB, facilitate the crossing of the barrier via receptor-mediated endocytosis or adsorptive-mediated transcytosis. This strategy enhances therapeutic agents' bioavailability and cellular uptake, offering a potential solution to overcome current limitations in AD treatment. Using nanotechnology to design ligand-conjugated NPs for targeted and sustained drug delivery could significantly improve therapeutic outcomes for AD patients by addressing key pathological processes in the brain.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102994"},"PeriodicalIF":12.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.arr.2025.102995
Yan Lv , Xv-Shen Ding , Li Gao , Zheng Han , Chen-Xi Feng , Yang-Ni Li , Yu-Fei Wang , Qian Yang , David K. Simon , Xue-lian Wang , Yan Qu , Bao Wang
The accumulation of α-synuclein (α-syn) is a key pathophysiological feature of Parkinson’s disease (PD), and one contributing factor to this aggregation is impaired clearance mechanisms. Recent research has identified the glymphatic system as the brain’s intrinsic waste clearance pathway. This review examines glymphatic dysfunction in PD, with a focus on its impact on α-syn clearance and neurodegeneration. We summarize current evidence showing that disrupted aquaporin-4 (AQP4) polarization, reduced meningeal lymphatic drainage, and sleep disturbances collectively impair glymphatic flow, thereby promoting α-syn aggregation and dopaminergic neuronal loss. We also review emerging neuroimaging approaches, including the Diffusion Tensor Imaging Analysis Along the Perivascular Space (DTI-ALPS) index, enlarged perivascular spaces (EPVSs) and choroid plexus volume (CPV), which increasingly enable in vivo evaluation of glymphatic dysfunction and show correlations with motor severity and cognitive decline. In addition, we discuss potential therapeutic approaches aimed at restoring glymphatic function, including photobiomodulation, pharmacological AQP4 modulation, sleep based interventions, and surgical interventions like deep cervical lymphaticovenular anastomosis (dcLVA). Although these strategies show promise in preclinical studies, their clinical translation remains limited. By integrating insights from glymphatic biology, neuroimaging, and therapeutic development, this review highlights new avenues for PD management and underscores the glymphatic system as a promising therapeutic target for modifying disease progression.
{"title":"Glymphatic dysfunction in Parkinson's disease: Aging-associated impairments, imaging biomarkers, and therapeutic strategies","authors":"Yan Lv , Xv-Shen Ding , Li Gao , Zheng Han , Chen-Xi Feng , Yang-Ni Li , Yu-Fei Wang , Qian Yang , David K. Simon , Xue-lian Wang , Yan Qu , Bao Wang","doi":"10.1016/j.arr.2025.102995","DOIUrl":"10.1016/j.arr.2025.102995","url":null,"abstract":"<div><div>The accumulation of α-synuclein (α-syn) is a key pathophysiological feature of Parkinson’s disease (PD), and one contributing factor to this aggregation is impaired clearance mechanisms. Recent research has identified the glymphatic system as the brain’s intrinsic waste clearance pathway. This review examines glymphatic dysfunction in PD, with a focus on its impact on α-syn clearance and neurodegeneration. We summarize current evidence showing that disrupted aquaporin-4 (AQP4) polarization, reduced meningeal lymphatic drainage, and sleep disturbances collectively impair glymphatic flow, thereby promoting α-syn aggregation and dopaminergic neuronal loss. We also review emerging neuroimaging approaches, including the Diffusion Tensor Imaging Analysis Along the Perivascular Space (DTI-ALPS) index, enlarged perivascular spaces (EPVSs) and choroid plexus volume (CPV), which increasingly enable in vivo evaluation of glymphatic dysfunction and show correlations with motor severity and cognitive decline. In addition, we discuss potential therapeutic approaches aimed at restoring glymphatic function, including photobiomodulation, pharmacological AQP4 modulation, sleep based interventions, and surgical interventions like deep cervical lymphaticovenular anastomosis (dcLVA). Although these strategies show promise in preclinical studies, their clinical translation remains limited. By integrating insights from glymphatic biology, neuroimaging, and therapeutic development, this review highlights new avenues for PD management and underscores the glymphatic system as a promising therapeutic target for modifying disease progression.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102995"},"PeriodicalIF":12.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.arr.2025.102993
Vanessa Kristina Wazny , Jozo Grgic , Pedro L. Valenzuela , Lei Feng , Andrea B. Maier
Cognitive decline is one of the key challenges with aging, with significant implications for independence, quality of life, and healthcare burden. As pharmacological treatments remain limited in efficacy and often carry adverse effects, there is growing interest in safe, accessible, non-pharmacological strategies to preserve cognitive function. This Short Review explores the potential of combining two approaches that, individually, have shown beneficial effects on cognitive function: ergothioneine, a naturally occurring amino acid with antioxidant and anti-inflammatory properties, and physical exercise. Ergothioneine accumulates in the brain and other high-stress organs, where it modulates the redox balance, dampens chronic inflammation and supports mitochondrial function. Meanwhile, physical exercise has well-documented benefits for neuroplasticity, cerebral perfusion, and cognitive performance. Preclinical studies suggest ergothioneine supports exercise performance and muscle recovery without attenuating adaptive responses. Despite their distinct and complementary mechanisms, currently there are no available studies exploring the combined effects of ergothioneine and exercise on cognition. We propose a future research agenda that includes mechanistic animal studies, dose-response trials, and clinical interventions in at-risk populations. Together, the combination of ergothioneine and exercise may offer a low-risk, multifaceted approach to enhancing cognitive resilience in aging.
{"title":"Ergothioneine and exercise: A match made in (cognitive) heaven?","authors":"Vanessa Kristina Wazny , Jozo Grgic , Pedro L. Valenzuela , Lei Feng , Andrea B. Maier","doi":"10.1016/j.arr.2025.102993","DOIUrl":"10.1016/j.arr.2025.102993","url":null,"abstract":"<div><div>Cognitive decline is one of the key challenges with aging, with significant implications for independence, quality of life, and healthcare burden. As pharmacological treatments remain limited in efficacy and often carry adverse effects, there is growing interest in safe, accessible, non-pharmacological strategies to preserve cognitive function. This <em>Short Review</em> explores the potential of combining two approaches that, individually, have shown beneficial effects on cognitive function: ergothioneine, a naturally occurring amino acid with antioxidant and anti-inflammatory properties, and physical exercise. Ergothioneine accumulates in the brain and other high-stress organs, where it modulates the redox balance, dampens chronic inflammation and supports mitochondrial function. Meanwhile, physical exercise has well-documented benefits for neuroplasticity, cerebral perfusion, and cognitive performance. Preclinical studies suggest ergothioneine supports exercise performance and muscle recovery without attenuating adaptive responses. Despite their distinct and complementary mechanisms, currently there are no available studies exploring the combined effects of ergothioneine and exercise on cognition. We propose a future research agenda that includes mechanistic animal studies, dose-response trials, and clinical interventions in at-risk populations. Together, the combination of ergothioneine and exercise may offer a low-risk, multifaceted approach to enhancing cognitive resilience in aging.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102993"},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.arr.2025.102991
Lin Yang , Zirui Zhang , Jie Zhang , Jingyou Miao , Hui Zhang , Yihui Du , Lilu Ding
Background
Cardiometabolic multimorbidity (CMM)—the co-occurrence of diabetes, cardiovascular disease, and related conditions—is a growing global health burden. Identifying risk factors across its developmental trajectory is critical for targeted prevention.
Methods
We conducted a systematic review and meta-analysis to quantify risk factors for the incidence and progression of CMM across five transitions: health → first cardiometabolic disease (FCMD), FCMD→CMM, CMM→death, FCMD→death, and health→death. For incidence, we used conventional random-effects meta-analysis to estimate pooled odds ratios (ORs). For disease progression, we applied Bayesian multi-state meta-analysis to estimate pooled hazard ratios (HRs). Subgroup analyses were performed to assess heterogeneity.
Results
Nine modifiable risk factors were identified for CMM incidence. Metabolic factors (overweight: OR=1.82, obesity: OR=3.13, hypertension: OR=2.05) and socioeconomic determinants (low income: OR=1.24, living alone: OR=1.58) showed the strongest associations. Depression (OR=1.70) and behavioral factors (smoking, physical inactivity, alcohol use) further increased risk. Trajectory analyses revealed stage-specific drivers: overweight/obesity drove transitions from healthy to FCMD (OR=1.69) and FCMD to CMM (OR=1.36), while smoking showed escalating effects across stages (health→FCMD: OR=1.22; FCMD→CMM: OR=1.37; CMM→death: OR=1.83). Alcohol use and physical inactivity increased mortality risk (13–28 %). Heterogeneity primarily stemmed from outcome measurement methods (i.e., objective vs. self-reported) and CMM composition.
Conclusion
CMM prevention requires stage-specific prioritization: early weight management, hypertension control and depression intervention to mitigate incidence; smoking cessation to curb progression; and intensified lifestyle interventions targeting smoking and alcohol cessation in established CMM. This evidence underscores the need for dynamic, trajectory-informed interventions to reduce the CMM burden.
{"title":"Stage-specific risk factors of cardiometabolic multimorbidity: A systematic review and meta-analysis from incidence to mortality","authors":"Lin Yang , Zirui Zhang , Jie Zhang , Jingyou Miao , Hui Zhang , Yihui Du , Lilu Ding","doi":"10.1016/j.arr.2025.102991","DOIUrl":"10.1016/j.arr.2025.102991","url":null,"abstract":"<div><h3>Background</h3><div>Cardiometabolic multimorbidity (CMM)—the co-occurrence of diabetes, cardiovascular disease, and related conditions—is a growing global health burden. Identifying risk factors across its developmental trajectory is critical for targeted prevention.</div></div><div><h3>Methods</h3><div>We conducted a systematic review and meta-analysis to quantify risk factors for the incidence and progression of CMM across five transitions: health → first cardiometabolic disease (FCMD), FCMD→CMM, CMM→death, FCMD→death, and health→death. For incidence, we used conventional random-effects meta-analysis to estimate pooled odds ratios (ORs). For disease progression, we applied Bayesian multi-state meta-analysis to estimate pooled hazard ratios (HRs). Subgroup analyses were performed to assess heterogeneity.</div></div><div><h3>Results</h3><div>Nine modifiable risk factors were identified for CMM incidence. Metabolic factors (overweight: OR=1.82, obesity: OR=3.13, hypertension: OR=2.05) and socioeconomic determinants (low income: OR=1.24, living alone: OR=1.58) showed the strongest associations. Depression (OR=1.70) and behavioral factors (smoking, physical inactivity, alcohol use) further increased risk. Trajectory analyses revealed stage-specific drivers: overweight/obesity drove transitions from healthy to FCMD (OR=1.69) and FCMD to CMM (OR=1.36), while smoking showed escalating effects across stages (health→FCMD: OR=1.22; FCMD→CMM: OR=1.37; CMM→death: OR=1.83). Alcohol use and physical inactivity increased mortality risk (13–28 %). Heterogeneity primarily stemmed from outcome measurement methods (i.e., objective vs. self-reported) and CMM composition.</div></div><div><h3>Conclusion</h3><div>CMM prevention requires stage-specific prioritization: early weight management, hypertension control and depression intervention to mitigate incidence; smoking cessation to curb progression; and intensified lifestyle interventions targeting smoking and alcohol cessation in established CMM. This evidence underscores the need for dynamic, trajectory-informed interventions to reduce the CMM burden.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102991"},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.arr.2025.102992
Savani Ulpathakumbura , Sicong Kenric Lu , Rasika Gunarathne , John Zhiyong Yang , Johnson Liu , Xiaodong Jin , Qiang Zhou , Jun Lu
Aging is a complex biological process characterized by the gradual deterioration of cellular functions, leading to an increased susceptibility to chronic diseases. In the search for interventions to promote healthy aging and extend lifespan, Pyrroloquinoline Quinone (PQQ) and Nicotinamide Mononucleotide/Nicotinamide Riboside (NMN/NR) have emerged as promising anti-aging agents. PQQ exerts its anti-aging effect primarily through enhancing mitochondrial biogenesis, exerting antioxidant activity, and modulating inflammatory pathways. On the other hand, NMN/NR act as key precursors in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in energy metabolism, cellular homeostasis, and DNA repair, thereby promoting longevity. This review systematically compares the mechanisms of action and efficacy of those compounds in mitigating age-related complications. Furthermore, this emphasizes the potent synergistic effect when PQQ and NMN/NR are used in combined formulations, highlighting their complementary pathways to support healthy aging. Despite supporting preliminary data and patented formulations, strong scientific evidence encouraging the synergistic anti-aging potential of PQQ and NMN/NR remains limited, highlighting the need for robust studies. Collectively, PQQ and NMN/NR offer distinct complementary strategies to promote healthy aging and prevent age-related diseases; their combination could offer a more effective approach to enhance healthy aging and longevity.
{"title":"Comparison of anti-aging effect of PQQ (Pyrroloquinoline quinone) and NMN/NR (Nicotinamide mononucleotide /Nicotinamide riboside) – possible combination use","authors":"Savani Ulpathakumbura , Sicong Kenric Lu , Rasika Gunarathne , John Zhiyong Yang , Johnson Liu , Xiaodong Jin , Qiang Zhou , Jun Lu","doi":"10.1016/j.arr.2025.102992","DOIUrl":"10.1016/j.arr.2025.102992","url":null,"abstract":"<div><div>Aging is a complex biological process characterized by the gradual deterioration of cellular functions, leading to an increased susceptibility to chronic diseases. In the search for interventions to promote healthy aging and extend lifespan, Pyrroloquinoline Quinone (PQQ) and Nicotinamide Mononucleotide/Nicotinamide Riboside (NMN/NR) have emerged as promising anti-aging agents. PQQ exerts its anti-aging effect primarily through enhancing mitochondrial biogenesis, exerting antioxidant activity, and modulating inflammatory pathways. On the other hand, NMN/NR act as key precursors in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in energy metabolism, cellular homeostasis, and DNA repair, thereby promoting longevity. This review systematically compares the mechanisms of action and efficacy of those compounds in mitigating age-related complications. Furthermore, this emphasizes the potent synergistic effect when PQQ and NMN/NR are used in combined formulations, highlighting their complementary pathways to support healthy aging. Despite supporting preliminary data and patented formulations, strong scientific evidence encouraging the synergistic anti-aging potential of PQQ and NMN/NR remains limited, highlighting the need for robust studies. Collectively, PQQ and NMN/NR offer distinct complementary strategies to promote healthy aging and prevent age-related diseases; their combination could offer a more effective approach to enhance healthy aging and longevity.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102992"},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer’s disease (AD), first identified by Dr. Alois Alzheimer in 1906, has evolved from a rare presenile dementia to a global health crisis affecting over 58 million people as of 2020, with projections reaching 152 million by 2050. Manuscript offers a comprehensive overview of AD, tracing its historical origins, epidemiological trends, pathophysiological mechanisms, diagnostic advancements, and therapeutic strategies. The pathogenesis of AD is multifactorial, involving amyloid-β plaque accumulation, tau protein hyperphosphorylation, cholinergic deficits, oxidative stress, and metal ion dyshomeostasis. These mechanisms converge to cause progressive neurodegeneration, cognitive decline, and behavioral disturbances. Clinically, AD manifests through a spectrum of neuropsychiatric symptoms, progressing from mild cognitive impairment to severe dementia, with distinct phenotypes and overlapping features with other dementias like DLB and VaD. Diagnostic approaches have advanced from clinical observation to biomarker-based precision, incorporating CSF and plasma tau assays, neuroimaging modalities (MRI, PET, SPECT), and AI-driven models for early detection. Despite these innovations, definitive diagnosis remains challenging due to symptom heterogeneity and overlap with other conditions. Therapeutically, the landscape has shifted from symptomatic treatments (e.g., cholinesterase inhibitors, memantine) to disease-modifying agents. Recent FDA approvals of monoclonal antibodies like Aducanumab, Lecanemab, and Donanemab mark a new era in targeted immunotherapy. However, many candidates targeting amyloid and tau pathways have failed in trials, underscoring the complexity of AD. Emerging drug delivery systems, including nanocarriers and intranasal formulations, aim to overcome the BBB and enhance therapeutic efficacy. The manuscript emphasizes the urgent need for integrative, personalized, and scalable solutions to manage AD’s growing burden.
{"title":"Unveiling Alzheimer’s disease (1901–2025): Historical insights, global burden, biological mechanisms, diagnostics, and therapeutic strategies","authors":"Premkumar Shantilal Baviskar , Hitendra Shaligram Mahajan","doi":"10.1016/j.arr.2025.102990","DOIUrl":"10.1016/j.arr.2025.102990","url":null,"abstract":"<div><div>Alzheimer’s disease (AD), first identified by Dr. Alois Alzheimer in 1906, has evolved from a rare presenile dementia to a global health crisis affecting over 58 million people as of 2020, with projections reaching 152 million by 2050. Manuscript offers a comprehensive overview of AD, tracing its historical origins, epidemiological trends, pathophysiological mechanisms, diagnostic advancements, and therapeutic strategies. The pathogenesis of AD is multifactorial, involving amyloid-β plaque accumulation, tau protein hyperphosphorylation, cholinergic deficits, oxidative stress, and metal ion dyshomeostasis. These mechanisms converge to cause progressive neurodegeneration, cognitive decline, and behavioral disturbances. Clinically, AD manifests through a spectrum of neuropsychiatric symptoms, progressing from mild cognitive impairment to severe dementia, with distinct phenotypes and overlapping features with other dementias like DLB and VaD. Diagnostic approaches have advanced from clinical observation to biomarker-based precision, incorporating CSF and plasma tau assays, neuroimaging modalities (MRI, PET, SPECT), and AI-driven models for early detection. Despite these innovations, definitive diagnosis remains challenging due to symptom heterogeneity and overlap with other conditions. Therapeutically, the landscape has shifted from symptomatic treatments (e.g., cholinesterase inhibitors, memantine) to disease-modifying agents. Recent FDA approvals of monoclonal antibodies like Aducanumab, Lecanemab, and Donanemab mark a new era in targeted immunotherapy. However, many candidates targeting amyloid and tau pathways have failed in trials, underscoring the complexity of AD. Emerging drug delivery systems, including nanocarriers and intranasal formulations, aim to overcome the BBB and enhance therapeutic efficacy. The manuscript emphasizes the urgent need for integrative, personalized, and scalable solutions to manage AD’s growing burden.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"114 ","pages":"Article 102990"},"PeriodicalIF":12.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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