Delvenne Aurore, Gobom Johan, Reus Lianne M, Dobricic Valerija, Ten Kate Mara, Schindler Suzanne E, Ramakers Inez, Tijms Betty M, Vandenberghe Rik, Schaeverbeke Jolien, Martinez-Lage Pablo, Tainta Mikel, Teunissen Charlotte E, Popp Julius, Peyratout Gwendoline, Tsolaki Magda, Freund-Levi Yvonne, Lovestone Simon, Streffer Johannes, Barkhof Frederik, Bertram Lars, Blennow Kaj, Zetterberg Henrik, Visser Pieter Jelle, Vos Stephanie J B
Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229 ER, The Netherlands.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 80, Sweden.
Brain Commun. 2025 Jun 20;7(4):fcaf253. doi: 10.1093/braincomms/fcaf253. eCollection 2025.
Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing individuals with abnormal tau and/or neurodegeneration markers but normal amyloid levels. SNAP is common in individuals with normal cognition (NC), but its underlying pathophysiology is understudied, while being relevant for clinical trial design and treatment approaches. We aimed to investigate the pathophysiology of individuals with NC who are amyloid-negative and tau-positive (SNAP) through cerebrospinal fluid (CSF) proteomics. Two hundred and ninety-one individuals with NC were classified based on CSF amyloid β1-42 and phosphorylated tau 181, as amyloid-negative/tau-negative (controls), amyloid-negative/tau-positive (SNAP), amyloid-positive/tau-negative and amyloid-positive/tau-positive. We measured 3102 proteins in CSF using tandem mass tag proteomic analyses. We compared protein abundance between groups using analysis of covariance and identified enriched biological pathways using Gene Ontology. We also examined differences between groups in genetic risk for Alzheimer's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels ( = 360) compared with controls, mainly associated with neuroplasticity, angiogenesis, and protein modification and degradation. The proteomic profile of SNAP was similar to that of amyloid-positive/tau-positive individuals, while distinct from amyloid-positive/tau-negative individuals, who showed mainly decreased proteins associated with neuroplasticity. Higher levels of amyloid β1-40 and amyloid β1-42 were observed in SNAP compared with the three other groups. Polygenic risk scores analyses showed no significant differences between SNAP, amyloid-positive/tau-negative, and amyloid-positive/tau-positive individuals, while SNAP showed some genetic differences from controls, which were driven by . Individuals with NC and SNAP or amyloid-positive/tau-positive status showed similar CSF proteomic profiles, while amyloid-positive/tau-negative individuals showed a distinct CSF proteomic profile. This suggests that tau, rather than amyloid, might be the main driver of the proteomic profiles in SNAP and other amyloid/tau subgroups. This may have implications for future proteomic studies and clinical trial design, as these findings highlight the importance of considering tau status in future studies.
疑似非阿尔茨海默病病理生理学（SNAP）是一个基于生物标志物的概念，用于描述tau和/或神经退行性变标志物异常但淀粉样蛋白水平正常的个体。SNAP在认知正常（NC）的个体中很常见，但其潜在的病理生理学研究较少，而这与临床试验设计和治疗方法相关。我们旨在通过脑脊液（CSF）蛋白质组学研究淀粉样蛋白阴性且tau阳性（SNAP）的NC个体的病理生理学。根据脑脊液淀粉样β1-42和磷酸化tau 181，将291名NC个体分为淀粉样蛋白阴性/tau阴性（对照组）、淀粉样蛋白阴性/tau阳性（SNAP）、淀粉样蛋白阳性/tau阴性和淀粉样蛋白阳性/tau阳性。我们使用串联质谱标签蛋白质组学分析测量了脑脊液中的3102种蛋白质。我们使用协方差分析比较了各组之间的蛋白质丰度，并使用基因本体论确定了富集的生物学途径。我们还使用基于全基因组关联研究数据的多基因风险评分，检查了各组在阿尔茨海默病遗传风险方面的差异。与对照组相比，NC的SNAP个体大多蛋白质水平升高（=360），主要与神经可塑性、血管生成以及蛋白质修饰和降解有关。SNAP的蛋白质组学特征与淀粉样蛋白阳性/tau阳性个体相似，而与淀粉样蛋白阳性/tau阴性个体不同，后者主要表现为与神经可塑性相关的蛋白质减少。与其他三组相比，SNAP中淀粉样β1-40和淀粉样β1-42水平更高。多基因风险评分分析显示，SNAP、淀粉样蛋白阳性/tau阴性和淀粉样蛋白阳性/tau阳性个体之间无显著差异，而SNAP与对照组存在一些遗传差异，这些差异由......驱动。NC且处于SNAP或淀粉样蛋白阳性/tau阳性状态的个体显示出相似的脑脊液蛋白质组学特征，而淀粉样蛋白阳性/tau阴性个体显示出独特的脑脊液蛋白质组学特征。这表明tau而非淀粉样蛋白可能是SNAP和其他淀粉样蛋白/tau亚组中蛋白质组学特征的主要驱动因素。这可能对未来的蛋白质组学研究和临床试验设计有影响，因为这些发现突出了在未来研究中考虑tau状态的重要性。
