Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease, and the development of effective therapies remains a critical global priority. Japan currently has the highest number of approved ALS drugs, including riluzole, edaravone, methylcobalamin, and tofersen. Despite this progress, participation in multinational clinical trials has been limited, raising concerns about potential drug lag and restricted patient access to emerging treatments. Worldwide, approximately 50 ALS trials are ongoing, with innovative designs such as platform and adaptive trials improving efficiency and accelerating therapeutic development.

Several barriers hinder Japan's involvement in global studies, including differences in healthcare systems, regulatory frameworks, and clinical infrastructure. Efforts are underway to establish national clinical trial guidelines aligned with international standards and to strengthen genetic testing networks for familial ALS, thereby improving patient identification and recruitment.

Japan also possesses notable strengths. ALS trials conducted in Japan demonstrate exceptionally low dropout rates, resulting in minimal missing data and high statistical reliability. In addition, the country's compact geography and advanced transportation systems facilitate patient access to trial sites and support adherence. By leveraging these advantages while enhancing patient centralization and promoting earlier engagement in global trial design, Japan can assume a more prominent role in international ALS drug development and help ensure timely access to innovative therapies for patients.

Neurodegenerative disorders including Parkinson disease (PD) and Alzheimer disease (AD) are increasingly recognized to share a fundamental pathophysiological substrate involving disruption of cerebral energy metabolism. Despite traditionally being defined by the accumulation of pathogenic proteins such as α–synuclein, amyloid–β, and tau, accumulating evidence indicates that impairment of mitochondrial function and cellular bioenergetics precedes and facilitates these pathological cascades.

The brain depends on sustained ATP production through tightly mitochondrial oxidative phosphorylation (OXPHOS) and regulated glucose metabolism. Failure of these mechanisms results in compromised synaptic function, impaired protein clearance, and increased neuronal vulnerability. In PD, early mitochondrial dysfunction leads to ATP depletion, attenuated glycolysis, enhanced fatty acid β–oxidation, and a substrate shift from glucose to lipids. While these changes initially serve as compensatory non–OXPHOS metabolic adaptations to sustain neuronal survival, chronic imbalance promotes oxidative stress, proteostatic failure, and neurotoxicity. Moreover, decreased hypoxanthine levels in cerebrospinal fluid and serum further highlight impaired purine–mediated ATP regeneration as a contributory factor.

Similarly, AD is characterized by early cerebral glucose hypometabolism, insulin signaling impairment, mitochondrial dysfunction, and excessive oxidative stress. APOE4 further contributes to these metabolic disturbances by disrupting glucose handling and impairing mitochondrial function, which may potentiate energy vulnerability and accelerate neurodegenerative processes.

Based on this evolving pathophysiological framework, therapeutic approaches targeting energy metabolism have emerged as promising disease–modifying strategies. These include GLP–1 receptor agonists, glycolysis enhancers, NAD⁺–boosting compounds, ketogenic interventions, and agents modulating purine metabolism in PD, as well as insulin–based therapies, mitochondrial stabilizers, and metabolic modulators in AD. Although definitive clinical validation remains incomplete, these strategies represent a conceptual shift away from purely symptomatic treatment toward precision metabolic intervention.

Together, these insights position energy metabolism as a unifying and central therapeutic target across neurodegenerative diseases.

Many neurodegenerative disorders are characterized by the presence of abnormal protein aggregates within neurons. It has become increasingly evident that the aggregated proteins themselves, or molecular modifiers and degradation factors that are closely involved in their metabolism, correspond to the causative gene products or disease–susceptibility gene products in various hereditary neurodegenerative diseases. Through experimental validation using model cell systems and animal models based on this concept, it has now been concluded with a high degree of certainty that abnormal protein aggregation plays a critical role in disease pathogenesis (Nat Rev Mol Cell Biol 25:926, 2024).

Despite the widespread view that “abnormal protein aggregation” is directly linked to the etiology of neurodegenerative diseases, pharmacological agents that promote or facilitate human protein degradation systems―namely the autophagy–lysosome pathway (ALP) and the ubiquitin–proteasome system (UPS)―have not yet been translated into clinical practice. Clearance of this hurdle is expected to establish definitive evidence for the true contribution of protein aggregation to disease pathophysiology in humans.

In this review, owing to space limitations, we focus on Alzheimer disease (AD) and Parkinson disease (PD), which are highly prevalent neurodegenerative disorders, and provide a concise overview of their relationship with intracellular protein degradation systems. Based on this overview, we summarize the current landscape of ALP–related and UPS–related therapeutic agents. In particular, we highlight the remarkable recent advances in our understanding of the molecular mechanisms underlying selective ALP, and briefly discuss emerging drug discovery strategies targeting this pathway.

Neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) have long been viewed primarily as disorders with neuronal loss and pathogenic protein aggregation. Over the past two decades, however, glial cells–especially microglia and astrocytes–have emerged as active drivers and modulators of disease progression. In parallel, advances in single–cell and single–nucleus transcriptomics have revealed remarkable heterogeneity of neuroinflammatory states, reshaping our understanding of disease mechanisms. In this review, we first summarize the current concepts of neuroinflammation and microglial activation, including the limitations of the classical M1/M2 framework and the concept of non–cell autonomous neurodegeneration driven by neuron–glia–immune cell interactions. We then focus on disease–associated microglia, highlighting shared “neurodegeneration-associated” gene programs across AD and ALS, as well as the loss of homeostatic microglial signatures in human postmortem brains. We further discuss astrocyte pathology including disease–associated astrocytes and dysregulation of astrocyte morphological complexity and homeostatic functions, which interact with microglial responses to shape synaptic integrity and neuronal survival. Next, we review the bidirectional crosstalk between microglia and peripheral immune cells. In AD and tauopathies, infiltrating T cells–particularly cytotoxic T cells–can exacerbate neurodegeneration, whereas in ALS certain CD4+ T cell subsets and regulatory T cells appear to promote neuroprotective microglial phenotypes. Finally, we discuss therapeutic strategies targeting microglia and the broader neuroimmune network, including approaches to enhance beneficial DAM/MGnD–like responses or dampen maladaptive inflammatory signaling, as well as ongoing clinical trials of glia–modulating agents and T cell–directed therapies. Future disease–modifying therapies will need to precisely reprogram glial and immune states within spatially and temporally dynamic neuroinflammatory networks in AD, ALS, and related disorders.

In recent years, rapid developments in omic technologies have enabled the quantitative measurement of multimodal data such as the genome, transcriptome, proteome, and metabolome. In the field of neurodegenerative diseases, several large–scale longitudinal cohort studies have collected not only clinical and pathological information but also multimodal omic data from serum, cerebrospinal fluid, and postmortem brain tissues. These datasets are publicly available to researchers worldwide through platforms such as the AMP–AD Knowledge Portal, allowing for a wide range of integrative analyses. However, the integration of multimodal data remains challenging due to differences in data types, measurement scales, and noise structures. Thus, many multi–omic integrative analytical techniques have been proposed for biomarker discovery, prognosis prediction, and elucidation of molecular disease mechanisms. Integrative approaches can be broadly categorized into “knowledge-based approach” and “data-driven approach”. The former integrates different types of omic data by referencing prior knowledge accumulated in databases. On the other hand, the latter method employs statistical and machine–learning algorithms to extract latent structures or cross–modal relationships directly from data. In our recent study, we constructed a “metabolic trans-omic network” for Alzheimer disease by integrating transcriptomic, proteomic, and metabolomic data from the ROS/MAP study. This network analysis provided a systems–wide view on dysregulated energy metabolism in Alzheimer disease. Overall, integrative multi–omic analysis represents a powerful framework for investigating neurodegenerative diseases. Nonetheless, current approaches still face several limitations, including insufficient model interpretability and challenges in ensuring reproducibility and robustness. Thus, further improvements in integration techniques are anticipated.

Digital twins are a technology that uses data collected from real–world objects and systems to recreate identical conditions in a virtual space. In the medical field, digital twins, also known as “human digital twins,” digitize and recreate individual patients' physiological conditions, lifestyle, and medical information in a virtual space. These digital twins are expected to realize the ultimate in personalized medicine, including ultra–personalized/precision medicine, disease onset prediction, and optimal drug and treatment recommendations, with high effectiveness and minimal side effects. Digital twins are also being explored in the field of neuroscience, including the treatment of Alzheimer disease (AD) and Parkinson disease (PD). Building digital twins that reflect a patient's lifestyle and physiological status makes it possible to observe and predict how specific lifestyle habits (e.g., exercise, diet) and behavioral patterns affect a patient's cognitive function and condition. Furthermore, using digital twins to model the progression of brain atrophy and changes in functional connectivity over time can help predict future cognitive decline and the risk of worsening disease. Digital twins utilizing digital devices and AI will not only enable objective evaluation, but will also enable quantitative evaluation of gait patterns specific to PD (such as shuffling gait) and distinguish PD from other diseases. These advances are based on the technology of real–time, data–driven simulation of individual brain function, which is the core value of digital twins, and are expected to contribute to the elucidation, prediction, and development of personalized treatments for diseases such as AD and PD. This chapter will consider the possibilities and challenges of digital twins through recent project examples from Japan and abroad in the field of neurological disorders.

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of amyloid β (Aβ) and tau protein aggregation followed by neuronal loss. Emerging evidence suggests that abnormal brain network activity precedes overt neurodegeneration and accelerates disease progression. Disruption of the excitation/inhibition (E/I) balance, particularly due to dysfunction of inhibitory interneurons such as parvalbumin–positive interneurons, may contribute to epileptiform activity and cognitive decline. Neuroinflammation further exacerbates this imbalance through astrocytic and microglial mechanisms, including altered GABA signaling and synaptic pruning. These findings highlight circuit–level dysfunction of GABAergic system as an early biomarker and therapeutic target. Recent approaches, such as antiepileptic drugs, PV neuron modulation, and non–invasive stimulation, offer promise in restoring network stability and mitigating pathology. Understanding the interplay between neuronal and glial components in E/I regulation will be critical for developing innovative strategies to attenuate AD progression.

Therapeutic strategies for neurodegenerative diseases, such as Alzheimer disease (AD) and Parkinson disease (PD), have historically relied on symptomatic treatments that compensate for lost neuronal function but fail to halt irreversible degeneration. However, the elucidation of “proteinopathies”, which involve the aggregation of abnormal proteins like amyloid β and α–synuclein, has paved the way for disease–modifying therapies. The recent clinical implementation of anti–amyloid antibodies in AD marks a historic turning point, demonstrating that altering the disease trajectory is achievable. Given that intervention after the onset of clinical symptoms is often too late to prevent neuronal loss, research is rapidly shifting toward preemptive treatments during the preclinical or prodromal stages. AD research leads this change in paradigm with biological definitions based on biomarkers and novel prevention trials such as the AHEAD 3–45 study. In parallel with pharmacological approaches, multidomain lifestyle interventions are also gaining attention for their potential to enhance cognitive reserve. Following the progress in AD, PD research is evolving through large–scale observational cohorts and the introduction of the biological definition of Neuronal Synuclein Disease. In Japan, the authors are conducting the NaT–PROBE study to identify subjects at high risk for Lewy body disease using prodromal symptoms within a health checkup system. We also discuss the NaT–PROBEi study, a phase 2 pilot trial of zonisamide for prodromal subjects. Although the trial did not meet its primary endpoint, it provided critical insights into the need for subject stratification and long–term follow–up. This review outlines current prevention strategies in AD and their application to PD. We conclude that preventing neurodegenerative diseases is no longer a fantasy but a scientifically testable goal. Future success will depend on establishing personalized prevention strategies that optimize interventions based on individual genetic, pathological, and environmental risks.

好酸球性多発血管炎性肉芽腫症（Eosinophilic Granulomatosis with Polyangiitis：EGPA）は高率に神経病変を合併し，症状の改善と再発予防には寛解導入・維持治療が必要であり，脳神経内科医にとって重要な疾患である．厚生労働省のEGPAの診断基準を満たし多発性単神経炎を呈した10例の臨床症状，多発性単神経炎の症状，検査所見，治療，予後について検討した．性別は男性4例，女性6例．神経症状の平均発症年齢は60.5歳（44–79歳）であり，多発性単神経炎の平均罹病期間は6.2年（1年8ヵ月–13年8ヵ月）であった．全例が感覚障害と痺れ感を呈し，運動障害のみを呈する患者はおらず，6例が下肢のみに症状を認めた．下垂足を5例に疼痛を7例に認めた．寛解導入治療は全例でグルココルチコイド：GC（ステロイドパルス9例，ステロイド内服1例）が使用され，免疫抑制剤を4例に併用した．GC単独例はprednisolone 5mg/day以上で再発を認める症例が存在した．Mepolizumabを6例に併用し，4例は再発時に導入し症状は改善し，2例はGC減量中に導入しGCの速やかな減量が可能であった．7例で免疫グロブリン大量静注療法（intravenous immunoglobulin：IVIg）を使用し，そのうち6例で残存する神経症状に対し，複数回投与（2, 3, 4, 9, 15回）を行ない有効であった．Mepolizumab使用例5例とazathioprine併用例の1例はprednisolone 5mg/day未満に減量可能であった．治療前平均mRS（modified Rankin Scale）3.8（2–4）は9例が1へ，1例は2に改善を認め良好な治療効果を認めた．