Amyloid and tau aggregates are considered to cause neurodegeneration and consequently cognitive decline in individuals with Alzheimer’s disease (AD). Here, we explore the potential of cerebrospinal fluid (CSF) proteins to reflect AD pathology and cognitive decline, aiming to identify potential biomarkers for monitoring outcomes of disease-modifying therapies targeting these aggregates. We used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from the Swedish GEDOC memory clinic cohort at the Karolinska University Hospital. The cohort comprised 148 amyloid- and tau-negative individuals (A-T-) and 65 amyloid- and tau-positive individuals (A+T+). An independent sample set of 26 A-T- and 26 A+T+ individuals from the Amsterdam Dementia Cohort was used for validation. The measured proteins were clustered based on their correlation to CSF amyloid beta peptides, tau and NfL levels. Further, we used support vector machine modelling to identify protein pairs, matched based on their cluster origin, that reflect AD pathology and cognitive decline with improved performance compared to single proteins. The protein-clustering revealed 11 proteins strongly correlated to t-tau and p-tau (tau-associated group), including mainly synaptic proteins previously found elevated in AD such as NRGN, GAP43 and SNCB. Another 16 proteins showed predominant correlation with Aβ42 (amyloid-associated group), including PTPRN2, NCAN and CHL1. Support vector machine modelling revealed that proteins from the two groups combined in pairs discriminated A-T- from A+T+ individuals with higher accuracy compared to single proteins, as well as compared to protein pairs composed of proteins originating from the same group. Moreover, combining the proteins from different groups in ratios (tau-associated protein/amyloid-associated protein) significantly increased their correlation to cognitive decline measured with cognitive scores. The results were validated in an independent cohort. Combining brain-derived proteins in pairs largely enhanced their capacity to discriminate between AD pathology-affected and unaffected individuals and increased their correlation to cognitive decline, potentially due to adjustment of inter-individual variability. With these results, we highlight the potential of protein pairs to monitor neurodegeneration and thereby possibly the efficacy of AD disease-modifying therapies.

中文翻译：

---

脑脊液蛋白质比率更有可能反映阿尔茨海默病病理学和神经退行性变

淀粉样蛋白和 tau 蛋白聚集物被认为会导致阿尔茨海默病 (AD) 患者的神经退行性病变，从而导致认知能力下降。在这里，我们探索脑脊液 (CSF) 蛋白反映 AD 病理学和认知能力下降的潜力，旨在识别潜在的生物标志物，用于监测针对这些聚集体的疾病缓解疗法的结果。我们使用基于多重抗体的悬浮珠阵列来测量卡罗林斯卡大学医院瑞典 GEDOC 记忆诊所队列中脑脊液中 49 种蛋白质的水平。该队列由 148 名淀粉样蛋白和 tau 阴性个体 (AT-) 和 65 名淀粉样蛋白和 tau 阳性个体 (A+T+) 组成。使用来自阿姆斯特丹痴呆队列的 26 位 AT- 和 26 位 A+T+ 个体组成的独立样本集进行验证。测量的蛋白质根据其与 CSF 淀粉样蛋白 β 肽、tau 和 NfL 水平的相关性进行聚类。此外，我们使用支持向量机建模来识别蛋白质对，并根据其簇起源进行匹配，这些蛋白质对反映了 AD 病理学和认知能力下降，与单个蛋白质相比，性能有所改善。蛋白质聚类揭示了 11 种与 t-tau 和 p-tau（tau 相关组）密切相关的蛋白质，其中主要包括先前在 AD 中发现升高的突触蛋白，例如 NRGN、GAP43 和 SNCB。另外 16 个蛋白与 Aβ42（淀粉样蛋白相关组）显示出显着相关性，包括 PTPRN2、NCAN 和 CHL1。支持向量机模型显示，与单个蛋白质以及由来自同一组的蛋白质组成的蛋白质对相比，成对组合的两组蛋白质能够以更高的准确度区分 AT- 和 A+T+ 个体。此外，以比例（tau 相关蛋白/淀粉样蛋白相关蛋白）组合不同组的蛋白质显着增加了它们与认知评分测量的认知下降的相关性。结果在一个独立队列中得到了验证。将脑源性蛋白质成对组合在很大程度上增强了它们区分受 AD 病理影响和未受影响个体的能力，并增加了它们与认知能力下降的相关性，这可能是由于个体间差异的调整所致。通过这些结果，我们强调了蛋白质对监测神经退行性变的潜力，从而可能提高 AD 疾病缓解疗法的功效。