Sharma Niti, Kim Danyeong, Sharma Himadri, Kim Moon Il, Lee Hyon, Kim Minju, Ryoo Nayoung, Kang Min Ju, Pyun Jung-Min, Park Young Ho, Ryu Jisun, Oh Hyun Jung, Yang Hyun-Sik, Kim Hang-Rai, Kim Geon Ha, Han Sangwon, Yang YoungSoon, Youn Young Chul, Teunissen Charlotte, Zetterberg Henrik, Scheltens Philip, An Seong Soo A, Kim Young-Bum, Kim SangYun
Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Seongnam, Republic of Korea.
Department of Neurology, Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea.
Alzheimers Dement. 2025 Jul;21(7):e70475. doi: 10.1002/alz.70475.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, predominantly affecting the aging population. Early detection through biomarkers is essential for early intervention. Recent sub-classification of AD through extensive cerebrospinal fluid (CSF) proteomic analyses revealed distinct characteristics of each subtype, necessitating tailored therapeutic strategies. While CSF proteomics has identified potential biomarkers, the need for non-invasive and cost-effective substitutions highlights the importance of blood-based biomarkers (BBMs). This review is a comprehensive review that categorizes potential BBMs based on neuronal hyperplasticity (subtype 1), underlining their role in refining subtype classification and enabling precision medicine. Early AD is often marked by cortical and hippocampal hyperactivity, followed by hypoactivity during later stages of neurodegeneration. While the exact mechanisms remain unclear, factors like Ca, glutamate, amyloid beta, tau, genetic factors, and impaired glial function play a role. Advancements in blood-based diagnostics would improve detection, individual treatment strategies, and evaluation of therapeutic response, eventually reducing the burden of AD on health-care systems. HIGHLIGHTS: Alzheimer's disease (AD; subtype 1) exhibits neuronal hyperplasticity, mild cortical atrophy, and moderate microglial activation. The neuronal hyperplasticity subtype of AD is characterized by an upregulation of synaptic and plasticity-related proteins, distinguishing it from other AD subtypes. Identifying biomarkers specific to neuronal hyperplasticity would enable real-time monitoring of therapeutic responses, allowing for individualized therapy as opposed to a "one-size-fits-all" strategy. The treatments based on neuronal hyperactivity reduction, restoration of synaptic plasticity, and anti-inflammation/metabolic dysfunction would be useful in this AD subtype. Blood-based biomarkers offer a cost-effective and accessible alternative to cerebrospinal fluid and neuroimaging methods.
阿尔茨海默病（AD）是最常见的神经退行性疾病，主要影响老年人群。通过生物标志物进行早期检测对于早期干预至关重要。最近通过广泛的脑脊液（CSF）蛋白质组学分析对AD进行的亚分类揭示了每种亚型的独特特征，因此需要量身定制的治疗策略。虽然CSF蛋白质组学已经确定了潜在的生物标志物，但对非侵入性和经济有效的替代方法的需求凸显了基于血液的生物标志物（BBM）的重要性。本综述是一项全面的综述，根据神经元增生（亚型1）对潜在的BBM进行分类，强调它们在完善亚型分类和实现精准医学方面的作用。早期AD通常以皮质和海马体的过度活跃为特征，随后在神经退行性变的后期出现活动减退。虽然确切机制尚不清楚，但钙、谷氨酸、淀粉样β蛋白、tau蛋白、遗传因素和神经胶质功能受损等因素都起到了一定作用。基于血液的诊断方法的进步将改善检测、个性化治疗策略以及对治疗反应的评估，最终减轻AD对医疗保健系统的负担。要点：阿尔茨海默病（AD；亚型1）表现出神经元增生、轻度皮质萎缩和中度小胶质细胞激活。AD的神经元增生亚型的特征是突触和可塑性相关蛋白上调，这使其与其他AD亚型区分开来。识别特定于神经元增生的生物标志物将能够实时监测治疗反应，从而实现个性化治疗，而不是“一刀切”的策略。基于减少神经元过度活跃、恢复突触可塑性以及抗炎/代谢功能障碍的治疗方法对这种AD亚型将是有用的。基于血液的生物标志物为脑脊液和神经成像方法提供了一种经济有效且易于获得的替代方案。
