撰文丨王聪 编辑丨王多鱼 排版丨水成文 迟发性阿尔茨海默病 （LOAD） ，通常在 65 岁以后发病，是阿尔茨海默病最常见的一种形式， 占所有阿 尔茨海默病病例的 90%以上。 与 早发性阿尔茨海默病 主要由特定基因突变引起不同， 迟发性阿尔茨海默 病 的 病因尚不完全明确，其 遗传风险因素更复杂， 被认为是遗传、环境和生活方式等多种因素共同作用 的结果。 全基因组关联研究 （GWAS） 强烈表明， 神经炎症 与 迟发性阿尔茨海默病 （LOAD） 相关。LOAD 的 遗传风险位点富含小胶质细胞中表达的基因，但小胶质细胞的 LOAD 风险基因之间的关系尚不清楚。 2026 年 2 月 2 日，中国科学院上海有机化学研究所 袁钧瑛 院士团队在 Cell 子刊 Immunity 上发表了题 为： Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors 的研究论文。 该研究表明， INPP5D ...

Core Viewpoint - Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid plaques and tau protein tangles, leading to progressive cognitive decline. Current disease-modifying therapies are limited, and chronic neuroinflammation is recognized as a significant component of AD, making the regulation of neuroinflammatory pathways a promising treatment strategy [1][2]. Group 1: Dietary Interventions - Diet is an easily implementable intervention to regulate neuroinflammation, with black rice diet (BRD) being rich in unsaturated fatty acids that may combat neurodegeneration associated with aging [2][5]. - Increased intake of ω-3 fatty acids and carotenoids from fish and plants is linked to improved brain function and delayed cognitive decline [2]. Group 2: Research Findings - A study published in Nature Aging revealed that α-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA) from black rice can inhibit amyloid pathology in AD mouse models through allosteric activation of cell-type-specific GPR120, improving cognitive function and extending lifespan [3][10]. - The research demonstrated that BRD significantly prevents cognitive decline in two common AD mouse models, APP/PS1 and 5×FAD [5]. Group 3: Mechanisms of Action - ALA and EDA are identified as key mediators that reduce amyloid pathology and restore cognitive performance to wild-type levels by activating GPR120 in plaque-associated macrophages and activated microglia [7][8]. - The study elucidated the structural binding patterns of ALA and EDA with GPR120, enhancing the understanding of their allosteric effects and downstream signaling pathways [8]. Group 4: Implications for Treatment - The findings suggest that GPR120 activation has cell-type-specific functions in the brain, providing insights for the development of targeted therapies for Alzheimer's disease [10]. - While the actual intake of black rice may be challenging to achieve therapeutic concentrations, this research lays the groundwork for developing standardized therapeutic agents [11].

Core Viewpoint - The article discusses the significant role of neuroinflammation in the development and progression of dementia, suggesting that neurotropic viruses, particularly herpes simplex virus, may contribute to or accelerate the course of dementia [1] Group 1: Research Findings - A recent study published in the journal Cell indicates that shingles vaccination can prevent or delay mild cognitive impairment and dementia in the elderly, as well as slow the progression of dementia in diagnosed patients, reducing the risk of dementia-related mortality [2] - The study utilized a natural experiment design based on the UK's vaccination policy, which created a unique opportunity to compare two groups with similar conditions but different vaccination eligibility based on birth dates [5] Group 2: Study Methodology - The research employed a rigorous regression discontinuity design, comparing over 300,000 participants, including more than 280,000 without cognitive impairment and over 14,000 diagnosed with dementia, tracked over nine years [7] - Results showed that vaccination reduced the risk of mild cognitive impairment by 3.1 percentage points in cognitively normal individuals, meaning that for every 100 vaccinated individuals, 3 avoided cognitive decline [7] Group 3: Gender Differences - The protective effect of the shingles vaccine was more pronounced in women, with a 5.1 percentage point reduction in mild cognitive impairment risk and a 52.3 percentage point reduction in dementia-related mortality risk, while the effects in men were not statistically significant [10] Group 4: Mechanisms of Action - The study proposes that the shingles vaccine may protect brain health by reducing the reactivation of the varicella-zoster virus, which can cause neuroinflammation, a key factor in the development of dementia [12] - Additionally, the vaccine may help combat immune aging, maintaining a more youthful immune response that better protects the nervous system [12] Group 5: Implications for Public Health - The study's methodology offers a strong basis for causal inference, suggesting that shingles vaccination could be a cost-effective strategy for preventing or delaying dementia, especially in the context of an aging population [16][18] - The findings highlight the potential for vaccines to provide multiple health benefits beyond immediate infection prevention, opening new perspectives on public health strategies [16]

Core Insights - The study highlights the role of lipid metabolism dysregulation in promoting chronic microglial activation and neuroinflammation in Alzheimer's disease (AD) [2][6] - MFE-2 is identified as a potential drug target, with the small molecule CKBA showing promise in restoring MFE-2 expression and treating AD [6] Group 1: Research Findings - The expression level of MFE-2, a key enzyme regulating fatty acid β-oxidation, is found to be decreased in microglia from both human AD patients and AD model mice [3] - Specific knockout of MFE-2 in microglia of AD model mice leads to microglial abnormalities, neuroinflammation, and β-amyloid (Aβ) deposition [3] - The absence of MFE-2 promotes lipid accumulation, resulting in excessive arachidonic acid, increased mitochondrial reactive oxygen species (ROS), and production of pro-inflammatory cytokines [3] Group 2: Therapeutic Potential - The natural triterpenoid compound AKBA's derivative CKBA can bind with high affinity to MFE-2, stabilizing its levels and inhibiting excessive microglial activation [3] - CKBA improves neuroinflammation and pathological damage associated with Alzheimer's disease [3][6]

Core Insights - Stroke is the second leading cause of death globally and a major factor in long-term disability, with its rising incidence closely linked to population aging [3] - Post-Stroke Emotional Disorder (PSED) significantly impacts patient recovery and quality of life, increasing the risk of stroke recurrence and mortality [3] Research Findings - A study published in the journal Neuron identified the role of Lcn2 from neutrophil extracellular traps (NETs) in the development of PSED, highlighting the interaction between the peripheral immune system and the central nervous system [4] - The research indicates that NETs in serum are a significant feature of PSED, controlled by the permeability of the blood-brain barrier (BBB) [6][7] - The study suggests that the release of Lcn2 protein from NETs promotes the proliferation of astrocytes, which is a core mechanism of PSED [6][7] - Transcranial direct current stimulation (tDCS) can alleviate PSED by reducing the release of Lcn2 [6][7] Implications - The findings illustrate a unique peripheral-central immune interaction pattern following BBB damage, emphasizing the potential of non-invasive stimulation in reshaping the neuroimmune environment [9]

Core Viewpoint - Sleep deprivation activates the body's inflammatory response, leading to cognitive impairment and increased risk of various diseases [2][3][6]. Group 1: Impact of Sleep Deprivation - A study involving 2,641 participants found that sleeping less than 6 hours triggers systemic inflammation and increases the risk of cognitive impairment [3]. - Sleep deprivation causes a series of inflammatory responses in the brain, releasing pro-inflammatory factors that adversely affect neurons and cognitive functions [3]. - Chronic sleep deprivation leads to oxidative stress and cellular damage, further exacerbating cognitive decline [3][6]. Group 2: Health Risks Associated with Sleep Deprivation - Insufficient sleep and chronic inflammation are linked to various diseases, including metabolic disorders, cancer, and mental health issues [6]. - Research indicates that sleeping less than 6 hours per night for a week can negatively impact metabolism, inflammation, immunity, and stress response [6]. - Prolonged sleep deprivation keeps the body in a state of stress, lowering immune function and increasing disease risk [6]. Group 3: Recommendations for Mitigating Damage - Adults typically need 7-8 hours of sleep per night, while older adults may require 5-7 hours [11]. - To combat sleep deprivation, lifestyle adjustments and medical interventions are recommended, such as increasing sunlight exposure and regular exercise [13]. - A balanced diet rich in anti-inflammatory foods, such as whole grains, deep-sea fish, cruciferous vegetables, and berries, can help reduce inflammation [14][15].

Core Viewpoint - The research on Alzheimer's disease (AD) has shifted focus from the traditional view of amyloid-beta (Aβ) accumulation and tau protein tangles as the primary causes of dementia, highlighting the role of dysfunctional microglia and chronic neuroinflammation in disease progression [2][3]. Group 1: Research Findings - Recent studies indicate that abnormal protein deposition is a pathological feature of AD rather than its causative mechanism, emphasizing the harmful effects of these proteins on disease progression [2]. - The study published by Xu Peisheng's team at the University of South Carolina introduces a ceria nanocluster-based therapy that targets activated microglia and reduces Aβ deposition [3][4]. Group 2: Innovative Treatment Approach - The developed brain-targeted ceria nanoparticles (T-CeNP) effectively penetrate the blood-brain barrier (BBB) and alleviate neuroinflammation while reducing Aβ accumulation [4][6]. - T-CeNP operates through a triple-function mechanism: it crosses the BBB via RAGE-targeting peptides, regulates pathological processes by enhancing microglial phagocytosis of Aβ, and exhibits multi-pathway synergistic effects in AD mouse models [6][7]. Group 3: Implications for Future Research - The study's findings suggest that T-CeNP can effectively block the pathological cascade of Alzheimer's disease by modulating the neuroinflammatory microenvironment and amyloid metabolism, providing a new paradigm for multi-target therapies in neurodegenerative diseases [9].

Financial Data and Key Metrics Changes - The net loss attributable to common stockholders for Q1 2025 was approximately $9.7 million, compared to approximately $11 million for the same period in 2024, indicating an improvement [26] - Research and development expenses totaled approximately $7.6 million for Q1 2025, down from approximately $8.7 million in Q1 2024 [26] - General and administrative expenses remained stable at approximately $2.3 million for both Q1 2025 and Q1 2024 [26] - As of March 31, 2025, the company had cash and cash equivalents of approximately $19.3 million, which is expected to fund operations through Q3 2025 [27] Business Line Data and Key Metrics Changes - The company is preparing to report top-line results from the MINDFUL phase two trial in early Alzheimer's disease, expected in mid to late June 2025 [6][27] - The market opportunity for EXPAREL in early Alzheimer's disease has increased to nearly 70% of early AD patients, up from the previously estimated 40% [7][8] - The safety profile of EXPAREL remains excellent, with no reports of adverse events in the ongoing trial [9] Market Data and Key Metrics Changes - The approval of mecanumab in the EU and UK excludes patients with two copies of the APOE4 gene, creating an unmet need for EXPAREL therapy in this subgroup [10][11] - The evolving biomarker landscape in Alzheimer's disease, particularly the significance of p-tau217, is expected to enhance the company's market position [12] Company Strategy and Development Direction - The company is focused on targeting neuroinflammation in Alzheimer's disease, positioning itself as a leader in this area [81][82] - Plans for the Kordstrom program include filing a Biologics License Application (BLA) in 2026 for the treatment of recessive dystrophic epidermolysis bullosa (RDEB) [17][24] - The company aims to transition manufacturing processes to optimize production for both Kordstrom and Inkmune, ensuring cost-effectiveness and regulatory compliance [24] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the upcoming MINDFUL trial results, believing they will significantly impact the treatment landscape for early Alzheimer's disease [16][81] - The company is optimistic about the regulatory environment for rare disease treatments, particularly following recent FDA comments [18][24] Other Important Information - The company has successfully transitioned its drug supply logistics for Inkmune to a US-based contractor, Cryoport, to ensure trial completion [21] - The company is also preparing for an IND submission for Kordstrom in the US, with manufacturing of a new batch of products using US-approved cord donors starting soon [73] Q&A Session Summary Question: Can you walk us through the next steps for the program assuming a positive readout in June? - Management indicated that they would defer specific timelines until after the FDA meeting, aiming to move quickly to open sites and enroll patients [32][33] Question: Can you comment on the FDA review team for your program? - Management believes that the FDA has remained on track and that the review team is stable, although they cannot predict future outcomes [36] Question: How do you think investors will react if EMAC hits but CDR is equivocal? - Management emphasized that EMAC is the primary driver for cognitive changes, and they expect correlations with CDR, which is a more blunt instrument [46][49] Question: Are APOE4 patients inherently inflammatory? - Management confirmed that APOE4 carriers tend to have earlier onset and faster progression of Alzheimer's disease, indicating a link to inflammation [62] Question: Are you still on track to initiate the twelve-month open-label trial for Cordstrom mid this year? - Management confirmed they are following FDA guidance and expect to submit an IND late this year, with plans for a follow-on trial in the US [73][74]

Financial Data and Key Metrics Changes - The net loss attributable to common stockholders for Q1 2025 was approximately $9.7 million, compared to approximately $11 million for the same period in 2024, indicating an improvement [27] - Research and development expenses totaled approximately $7.6 million for Q1 2025, down from approximately $8.7 million in Q1 2024 [27] - General and administrative expenses remained stable at approximately $2.3 million for both Q1 2025 and Q1 2024 [27] - As of March 31, 2025, the company had cash and cash equivalents of approximately $19.3 million, sufficient to fund operations through Q3 2025 [28] Business Line Data and Key Metrics Changes - The company is preparing to report top-line results from the MINDFUL trial, a Phase 2 trial in early Alzheimer's disease, expected in mid to late June 2025 [5][16] - The market opportunity for EXPAREL in early Alzheimer's disease patients has increased to nearly 70%, up from the previously estimated 40% [6][8] - The safety profile of EXPAREL remains strong, with no reports of adverse events in the MINDFUL trial [9] Market Data and Key Metrics Changes - The approval of mecanumab in the EU and UK excludes patients with two copies of the APOE4 gene, creating an unmet need for EXPAREL therapy in this subgroup [10][11] - The evolving biomarker landscape in Alzheimer's disease, particularly the significance of p-tau217, is expected to enhance the company's market position [12] Company Strategy and Development Direction - The company aims to position itself as a leader in targeting immune dysfunction that drives neuroinflammation in Alzheimer's disease [81][82] - Plans to file a Biologics License Application (BLA) for Cordstrom in 2026, with ongoing development for Inkmune in prostate cancer [17][29] - The company is focused on transitioning manufacturing processes to meet regulatory requirements and maximize production efficiency [25] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in reporting results that could change the care of patients with early Alzheimer's disease, highlighting substantial share ownership by management as alignment with investor interests [16][80] - The company anticipates an end-of-Phase 2 meeting with the FDA in Q4 2026 to discuss the design of a Phase 3 trial [29] Other Important Information - The company has successfully transitioned its drug supply logistics for Inkmune to a US contractor, ensuring readiness for trial completion [21] - The FDA has indicated a willingness to expedite the approval process for rare disease treatments, which bodes well for Cordstrom [18] Q&A Session Summary Question: What are the next steps for the program assuming a positive readout in June? - Management indicated that they would defer specific timelines until after the results and discussions with the FDA [35] Question: Can you comment on the turnover at the FDA and the receptivity at the ADPD conference? - Management believes the FDA remains on track and noted positive feedback from the ADPD conference regarding their approach to measuring cognition [39][44] Question: How many APOE homozygous patients are in the trial? - The trial includes approximately 9% of APOE homozygous patients, which is consistent with other studies [53] Question: What is the expected reduction in CDR for the trial? - Management expressed confidence in their power calculations based on previous studies, suggesting they are well-positioned to achieve statistically significant results [62] Question: Are you still on track to initiate the open-label trial for Cordstrom? - The company is following FDA guidance and expects to submit an IND later this year, with plans for a follow-on trial in the US [73]