Jacobs Tovia, Jacobson Sean R, Fortea Juan, Berger Jeffrey S, Vedvyas Alok, Marsh Karyn, He Tianshe, Gutierrez-Jimenez Eugenio, Fillmore Nathanael R, Bubu Omonigho M, Gonzalez Moses, Figueredo Luisa, Gaggi Naomi L, Plaska Chelsea Reichert, Pomara Nunzio, Blessing Esther, Betensky Rebecca, Rusinek Henry, Zetterberg Henrik, Blennow Kaj, Glodzik Lidia, Wisniewski Thomas M, Leon Mony J, Osorio Ricardo S, Ramos-Cejudo Jaime
New York University (NYU) Grossman School of Medicine.
Hospital de la Santa Creu y Sant Pau, Universitat Autònoma de Barcelona.
Res Sq. 2024 Mar 14:rs.3.rs-4076789. doi: 10.21203/rs.3.rs-4076789/v1.
An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau), as well as the trajectories of these CSF measures obtained longitudinally.
A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data.
We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.
血液中中性粒细胞与淋巴细胞比值（NLR）升高与阿尔茨海默病（AD）有关。然而，NLR升高也与许多其他作为AD危险因素的疾病有关，这促使人们研究NLR是与AD病理直接相关，还是潜在合并症的结果。在此，我们探讨了认知未受损（CU）受试者脑脊液（CSF）中NLR与AD生物标志物之间的关系。在调整社会人口统计学、APOE4和常见合并症后，我们在两个队列中研究了这些关联：阿尔茨海默病神经影像学倡议（ADNI）队列和纽约大学的M.J. 德莱昂脑脊液储存库队列。具体而言，我们研究了NLR与淀粉样β蛋白42（Aβ42）、总tau蛋白（t-tau）和磷酸化tau蛋白（p-tau）的横断面测量值之间的关联，以及纵向获得的这些脑脊液测量值的变化轨迹。
共有111名ADNI参与者和190名纽约大学参与者被归类为CU，并提供了可用的NLR、脑脊液和协变量数据。与纽约大学参与者相比，ADNI参与者年龄更大（73.79岁对61.53岁，p < 0.001），男性比例更高（49.5%对36.8%，p = 0.042），体重指数更高（27.94对25.79，p < 0.001），高血压病史患病率更高（47.7%对16.3%，p < 0.001），Aβ阳性比例更高（34.2%对20.0%，p = 0.009）。在ADNI队列中，我们发现NLR与脑脊液Aβ42之间存在横断面关联（β=-12.193，p = 0.021），但与t-tau或p-tau无关联。在纽约大学队列中，我们发现NLR与脑脊液t-tau（β = 26.812，p = 0.019）和p-tau（β = 3.441，p = 0.015）之间存在横断面关联，但与Aβ42无关联。仅在纽约大学队列中，与Aβ阴性受试者或未分层队列相比，被归类为Aβ阳性（n = 38）的受试者中NLR与t-tau之间的关联更强（β = 100.476，p = 0.037）。在两个队列中，纳入纵向脑脊液数据后，横断面分析中观察到的相同关联依然存在。
我们报告了老年ADNI队列中NLR与Aβ42之间的关联，以及年轻纽约大学队列中NLR与t-tau和p-tau之间的关联。在调整合并症后，这些关联仍然存在，表明NLR与AD之间存在直接联系。然而，NLR与特定AD生物标志物之间关联的变化可能是免疫衰老的一部分。
