Pub Date : 2025-08-15DOI: 10.1038/s41582-025-01127-1
Matthew Alsaloum, Dmytro Vasylyev, Stephen G. Waxman
Treatment of pain is a challenge for almost all clinicians, ranging from general practitioners to subspecialists such as pain medicine physicians, surgeons, neurologists and physiatrists. Over the past few years, clinical studies in people with acute postoperative pain have demonstrated that pain in humans can be reduced by inhibiting Nav1.8, a sodium channel that is essential for repetitive firing of peripheral pain-signalling neurons and has no essential function in the CNS. This discovery is an important step forward, but pain reduction in these studies was partial, not complete. Moreover, success via this approach thus far has been limited to people with acute pain, and translation to chronic pain must still be confronted. In this Perspective, we discuss the key questions of whether more effective Nav1.8 blockers can be built and whether neural mechanisms impose a ceiling on the pain relief that can be achieved by Nav1.8 inhibition. We then explore the challenge of developing therapeutics for chronic pain and ask whether compensatory changes or development of pain generators within the CNS might limit pain relief. Finally, we discuss the clinical complexity of pain and its implications for therapy and pose questions and suggest opportunities for the future. Earlier this year, the Nav1.8 channel inhibitor suzetrigine became the first new pain therapeutic to be approved in 20 years. Here, Waxman et al. discuss the challenges of improving Nav1.8-targeted relief for acute pain and the translation to chronic pain.
{"title":"Targeting sodium channels — challenges for acute pain and the leap to chronic pain","authors":"Matthew Alsaloum, Dmytro Vasylyev, Stephen G. Waxman","doi":"10.1038/s41582-025-01127-1","DOIUrl":"10.1038/s41582-025-01127-1","url":null,"abstract":"Treatment of pain is a challenge for almost all clinicians, ranging from general practitioners to subspecialists such as pain medicine physicians, surgeons, neurologists and physiatrists. Over the past few years, clinical studies in people with acute postoperative pain have demonstrated that pain in humans can be reduced by inhibiting Nav1.8, a sodium channel that is essential for repetitive firing of peripheral pain-signalling neurons and has no essential function in the CNS. This discovery is an important step forward, but pain reduction in these studies was partial, not complete. Moreover, success via this approach thus far has been limited to people with acute pain, and translation to chronic pain must still be confronted. In this Perspective, we discuss the key questions of whether more effective Nav1.8 blockers can be built and whether neural mechanisms impose a ceiling on the pain relief that can be achieved by Nav1.8 inhibition. We then explore the challenge of developing therapeutics for chronic pain and ask whether compensatory changes or development of pain generators within the CNS might limit pain relief. Finally, we discuss the clinical complexity of pain and its implications for therapy and pose questions and suggest opportunities for the future. Earlier this year, the Nav1.8 channel inhibitor suzetrigine became the first new pain therapeutic to be approved in 20 years. Here, Waxman et al. discuss the challenges of improving Nav1.8-targeted relief for acute pain and the translation to chronic pain.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 10","pages":"567-576"},"PeriodicalIF":33.1,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851390","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 : 2025-08-14DOI: 10.1038/s41582-025-01128-0
Andrea M. Harriott, Cenk Ayata
Migraine with aura is characterized by recurrent attacks of visual and, occasionally, sensory, language and/or motor disturbances, typically followed by headache. Migraine with aura can be associated with allodynia and vascular and psychiatric comorbidities. The electrophysiological cause of the aura is cortical spreading depolarization, a wave of depolarization that propagates slowly across the cortical surface, producing reversible metabolic and electrochemical perturbations. In this Review, we focus on the relationship of spreading depolarization with migraine aura and migraine headache. Abundant evidence causally links spreading depolarization to the headache phase of migraine with aura, as it can activate trigeminal nociceptors, produce dural and cortical inflammation, and induce trigeminal pain behaviour in rodents. In experimental models, migraine prophylaxis reduces susceptibility to spreading depolarization, and abortive treatments abrogate trigeminal pain behaviour that is induced by spreading depolarization. Although questions remain about the role of spreading depolarization in migraine with aura and models of spreading depolarization need to be refined, the cumulative evidence suggests that spreading depolarization is a putative target for therapeutic intervention in migraine. Elucidating the mechanisms by which spreading depolarization can induce trigeminal pain could facilitate drug discovery, and models of spreading depolarization could be effective screening platforms for migraine therapies. Spreading depolarization is widely accepted as the cause of migraine aura, but its relationship with migraine headache is less clear. In this Review, Harriott and Ayata review the evidence that links spreading depolarization with the headache phase of migraine with aura, and consider the potential of therapeutic targeting of spreading depolarization in migraine.
{"title":"Spreading depolarization as a therapeutic target in migraine","authors":"Andrea M. Harriott, Cenk Ayata","doi":"10.1038/s41582-025-01128-0","DOIUrl":"10.1038/s41582-025-01128-0","url":null,"abstract":"Migraine with aura is characterized by recurrent attacks of visual and, occasionally, sensory, language and/or motor disturbances, typically followed by headache. Migraine with aura can be associated with allodynia and vascular and psychiatric comorbidities. The electrophysiological cause of the aura is cortical spreading depolarization, a wave of depolarization that propagates slowly across the cortical surface, producing reversible metabolic and electrochemical perturbations. In this Review, we focus on the relationship of spreading depolarization with migraine aura and migraine headache. Abundant evidence causally links spreading depolarization to the headache phase of migraine with aura, as it can activate trigeminal nociceptors, produce dural and cortical inflammation, and induce trigeminal pain behaviour in rodents. In experimental models, migraine prophylaxis reduces susceptibility to spreading depolarization, and abortive treatments abrogate trigeminal pain behaviour that is induced by spreading depolarization. Although questions remain about the role of spreading depolarization in migraine with aura and models of spreading depolarization need to be refined, the cumulative evidence suggests that spreading depolarization is a putative target for therapeutic intervention in migraine. Elucidating the mechanisms by which spreading depolarization can induce trigeminal pain could facilitate drug discovery, and models of spreading depolarization could be effective screening platforms for migraine therapies. Spreading depolarization is widely accepted as the cause of migraine aura, but its relationship with migraine headache is less clear. In this Review, Harriott and Ayata review the evidence that links spreading depolarization with the headache phase of migraine with aura, and consider the potential of therapeutic targeting of spreading depolarization in migraine.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 10","pages":"529-543"},"PeriodicalIF":33.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850836","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}
Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins — amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) — are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public–private partnerships focused on biomarker development. Neurodegenerative diseases such as Alzheimer disease, Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy are characterized pathologically by deposition of specific proteins in the brain. This article reviews the latest advances in the development of PET radiotracers for neurodegenerative proteinopathies and highlights the diagnostic and therapeutic applications of this technology.
{"title":"Advances in PET imaging of protein aggregates associated with neurodegenerative disease","authors":"Makoto Higuchi, Kenji Tagai, Keisuke Takahata, Hironobu Endo","doi":"10.1038/s41582-025-01126-2","DOIUrl":"10.1038/s41582-025-01126-2","url":null,"abstract":"Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins — amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) — are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public–private partnerships focused on biomarker development. Neurodegenerative diseases such as Alzheimer disease, Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy are characterized pathologically by deposition of specific proteins in the brain. This article reviews the latest advances in the development of PET radiotracers for neurodegenerative proteinopathies and highlights the diagnostic and therapeutic applications of this technology.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 9","pages":"506-522"},"PeriodicalIF":33.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819489","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 : 2025-08-11DOI: 10.1038/s41582-025-01130-6
Robert A. Joyce
Robert Joyce has lived with multiple sclerosis for over 30 years. Here, he highlights the problems with using standard test scores to assess changes in physical and cognitive function and calls for testing to ensure that individual baselines are recorded.
{"title":"Why am I compared to an average?","authors":"Robert A. Joyce","doi":"10.1038/s41582-025-01130-6","DOIUrl":"10.1038/s41582-025-01130-6","url":null,"abstract":"Robert Joyce has lived with multiple sclerosis for over 30 years. Here, he highlights the problems with using standard test scores to assess changes in physical and cognitive function and calls for testing to ensure that individual baselines are recorded.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 10","pages":"523-523"},"PeriodicalIF":33.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819714","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 : 2025-08-05DOI: 10.1038/s41582-025-01129-z
Lisa Kiani
New evidence supports trans-synaptic propagation of tau pathology in the neurodegenerative disease progressive supranuclear palsy.
新的证据支持神经退行性疾病进行性核上性麻痹中tau病理的突触传播。
{"title":"Trans-synaptic tau propagation in progressive supranuclear palsy","authors":"Lisa Kiani","doi":"10.1038/s41582-025-01129-z","DOIUrl":"10.1038/s41582-025-01129-z","url":null,"abstract":"New evidence supports trans-synaptic propagation of tau pathology in the neurodegenerative disease progressive supranuclear palsy.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 9","pages":"467-467"},"PeriodicalIF":33.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786816","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 : 2025-07-29DOI: 10.1038/s41582-025-01125-3
Ricardo F. Allegri
Dementia research, and research in general, has historically been scarce in low-income and middle-income countries (LMICs). However, a high burden of dementia is faced by these regions, with a higher prevalence compared with high-income countries, worsened by low control of modifiable risk factors, poverty, low levels of education and limited access to care. Researchers in LMICs face many challenges owing to a lack of funding, scarce resources and equipment and brain drain. However, LMICs also offer opportunities because of their large urban populations and ethnic and cultural diversity. In recent years, interactions between researchers from high-income countries and LMICs have increased, but have largely followed a neocolonial model with little benefit for LMIC researchers. The time has come to address the north–south inequality with collaborative models that can help to reverse this reality. In this Review, we outline the challenges faced by dementia researchers in LMICs and propose a win–win model to improve and develop research in LMICs that includes regional and international collaborations, international fundraising and the democratization of science. This approach will enable LMIC researchers not only to obtain data and samples for research but also to build local capacity and ultimately improve dementia care for populations in LMICs. Low-income and middle-income countries bear a high burden from dementia that is not reflected in research. This Review outlines the reasons for this disparity and explores the challenges and opportunities of dementia research in low-income and middle-income countries.
{"title":"Dementia research in low-income and middle-income countries — a view from Latin America","authors":"Ricardo F. Allegri","doi":"10.1038/s41582-025-01125-3","DOIUrl":"10.1038/s41582-025-01125-3","url":null,"abstract":"Dementia research, and research in general, has historically been scarce in low-income and middle-income countries (LMICs). However, a high burden of dementia is faced by these regions, with a higher prevalence compared with high-income countries, worsened by low control of modifiable risk factors, poverty, low levels of education and limited access to care. Researchers in LMICs face many challenges owing to a lack of funding, scarce resources and equipment and brain drain. However, LMICs also offer opportunities because of their large urban populations and ethnic and cultural diversity. In recent years, interactions between researchers from high-income countries and LMICs have increased, but have largely followed a neocolonial model with little benefit for LMIC researchers. The time has come to address the north–south inequality with collaborative models that can help to reverse this reality. In this Review, we outline the challenges faced by dementia researchers in LMICs and propose a win–win model to improve and develop research in LMICs that includes regional and international collaborations, international fundraising and the democratization of science. This approach will enable LMIC researchers not only to obtain data and samples for research but also to build local capacity and ultimately improve dementia care for populations in LMICs. Low-income and middle-income countries bear a high burden from dementia that is not reflected in research. This Review outlines the reasons for this disparity and explores the challenges and opportunities of dementia research in low-income and middle-income countries.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 9","pages":"499-505"},"PeriodicalIF":33.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719386","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 : 2025-07-25DOI: 10.1038/s41582-025-01124-4
Muireann Irish
The modulating influence of biological sex on clinical variability, disease trajectories and treatment response represents a nascent topic in frontotemporal dementia (FTD) research. Recent empirical studies leveraging large-scale consortium data illuminate how biological sex impinges on — and potentially interacts with — variations in clinical symptomatology, pathophysiology and disease trajectory in FTD.
{"title":"Sex differences in frontotemporal dementia","authors":"Muireann Irish","doi":"10.1038/s41582-025-01124-4","DOIUrl":"10.1038/s41582-025-01124-4","url":null,"abstract":"The modulating influence of biological sex on clinical variability, disease trajectories and treatment response represents a nascent topic in frontotemporal dementia (FTD) research. Recent empirical studies leveraging large-scale consortium data illuminate how biological sex impinges on — and potentially interacts with — variations in clinical symptomatology, pathophysiology and disease trajectory in FTD.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 9","pages":"471-472"},"PeriodicalIF":33.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701708","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 : 2025-07-23DOI: 10.1038/s41582-025-01115-5
Anneke van der Walt, Eva M. M. Strijbis, Francesca Bridge, Timothy Coetzee, Jennifer Graves, Wallace J. Brownlee, Helmut Butzkueven, Ruth Ann Marrie, Le H. Hua, Anna Lampe, Mar Tintore, Xavier Montalban, Peter A. Calabresi, Frederik Barkhof, on behalf of the International Advisory Committee Clinical Trials in MS Workshop on Ageing and MS members
Multiple sclerosis (MS) typically presents in early to middle adulthood, but owing to advancements in health care, many individuals with MS now live a normal lifespan, and approximately half of the people currently living with MS are ≥50 years of age. As people living with MS age, their diagnosis, treatment and disease management become more complex owing to the effects of ageing, immunosenescence and comorbidities. Furthermore, diagnosis of late-onset MS (onset above 50 years of age) often requires additional tests, such as spinal cord imaging and cerebrospinal fluid analysis, to differentiate the disease from age-associated conditions such as cerebrovascular disease. Monitoring disease progression also becomes more complicated with increasing age, as physiological age-related changes can confound MRI findings and measurements of disability and cognition. Treatment decisions in older people with MS are also challenging, as high-efficacy treatments carry increased risks with ageing and their benefits can be reduced, yet little evidence is available to guide treatment in older adults. In this Consensus statement, we present the outcomes of an International Advisory Committee on Clinical Trials (IACCT) in MS workshop on ageing and MS; we review the current status of the field and identify knowledge gaps, and provide recommendations to advance the areas of unmet need. Approximately half of the people currently with multiple sclerosis (MS) are ≥50 years of age, yet guidelines for management of MS in older age are lacking. This Consensus statement presents the outcomes of an International Advisory Committee on Clinical Trials (IACCT) in MS workshop on ageing and MS, including recommendations for advancing research, care and awareness.
{"title":"Advancing multiple sclerosis management in older adults","authors":"Anneke van der Walt, Eva M. M. Strijbis, Francesca Bridge, Timothy Coetzee, Jennifer Graves, Wallace J. Brownlee, Helmut Butzkueven, Ruth Ann Marrie, Le H. Hua, Anna Lampe, Mar Tintore, Xavier Montalban, Peter A. Calabresi, Frederik Barkhof, on behalf of the International Advisory Committee Clinical Trials in MS Workshop on Ageing and MS members","doi":"10.1038/s41582-025-01115-5","DOIUrl":"10.1038/s41582-025-01115-5","url":null,"abstract":"Multiple sclerosis (MS) typically presents in early to middle adulthood, but owing to advancements in health care, many individuals with MS now live a normal lifespan, and approximately half of the people currently living with MS are ≥50 years of age. As people living with MS age, their diagnosis, treatment and disease management become more complex owing to the effects of ageing, immunosenescence and comorbidities. Furthermore, diagnosis of late-onset MS (onset above 50 years of age) often requires additional tests, such as spinal cord imaging and cerebrospinal fluid analysis, to differentiate the disease from age-associated conditions such as cerebrovascular disease. Monitoring disease progression also becomes more complicated with increasing age, as physiological age-related changes can confound MRI findings and measurements of disability and cognition. Treatment decisions in older people with MS are also challenging, as high-efficacy treatments carry increased risks with ageing and their benefits can be reduced, yet little evidence is available to guide treatment in older adults. In this Consensus statement, we present the outcomes of an International Advisory Committee on Clinical Trials (IACCT) in MS workshop on ageing and MS; we review the current status of the field and identify knowledge gaps, and provide recommendations to advance the areas of unmet need. Approximately half of the people currently with multiple sclerosis (MS) are ≥50 years of age, yet guidelines for management of MS in older age are lacking. This Consensus statement presents the outcomes of an International Advisory Committee on Clinical Trials (IACCT) in MS workshop on ageing and MS, including recommendations for advancing research, care and awareness.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 8","pages":"432-448"},"PeriodicalIF":33.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41582-025-01115-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-21DOI: 10.1038/s41582-025-01123-5
Michael S. Rafii, Paul S. Aisen
The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice. Here, Rafii and Aisen review recent progress surrounding the approvals of amyloid-targeting monoclonal antibodies, the first disease-modifying therapies for Alzheimer disease. The Review highlights key factors that affect the integration of these treatments into clinical practice and explores future directions.
{"title":"Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions","authors":"Michael S. Rafii, Paul S. Aisen","doi":"10.1038/s41582-025-01123-5","DOIUrl":"10.1038/s41582-025-01123-5","url":null,"abstract":"The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice. Here, Rafii and Aisen review recent progress surrounding the approvals of amyloid-targeting monoclonal antibodies, the first disease-modifying therapies for Alzheimer disease. The Review highlights key factors that affect the integration of these treatments into clinical practice and explores future directions.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 9","pages":"490-498"},"PeriodicalIF":33.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677459","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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