Alanko Vilma, Mravinacová Sára, Hall Anette, Hagman Göran, Mohanty Rosaleena, Westman Eric, Nilsson Peter, Kivipelto Miia, Månberg Anna, Matton Anna
Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Brain Commun. 2025 Feb 21;7(2):fcaf078. doi: 10.1093/braincomms/fcaf078. eCollection 2025.
Alzheimer's disease and related dementias have a multifactorial aetiology and heterogeneous biology. The current study aims to identify different biological signatures in a deeply phenotyped memory clinic patient population. In this cross-sectional study, we analysed 49 pre-specified proteins using a multiplex antibody-based suspension bead array in 278 CSF samples from the real-world research database and biobank at the Karolinska University Hospital Memory Clinic, Solna, Sweden. Patients with a clinical diagnosis of subjective cognitive decline ( = 151), mild cognitive impairment ( = 61), Alzheimer's disease ( = 47), or other diagnoses ( = 19; vascular dementias, alcohol-related dementia, unspecified dementias, or other amnesias) were included. Principal component analyses were performed, and resulting principal components (PCs) were tested for associations with clinical variables and Alzheimer's disease biomarkers (CSF biomarkers beta-amyloid 42, beta-amyloid 42/40, phosphorylated tau 181, phosphorylated tau 181/beta-amyloid 42). PC 1 (explaining 52% of the variance between patients) was associated with the clinical Alzheimer's disease CSF biomarkers beta-amyloid 42, phosphorylated tau 181, and total tau but not with Alzheimer's disease-related neurodegeneration imaging markers, cognitive performance, or clinical diagnosis. PC 2 (explaining 9% of the variance) displayed an inflammatory profile with high contributions of chitinase 3 like 1 (CHI3L1) and triggering receptor expressed on myeloid cells 2 (TREM2) and significant correlation to CSF free light chain kappa. In contrast to PC 1, PC 3 (explaining 5% of the variance) showed associations with all the clinical Alzheimer's disease CSF biomarkers, the imaging markers, cognitive impairment and clinical diagnosis. Serpin family A member 3 (SERPINA3), chitinase 1 (CHIT1), and neuronal pentraxin 2 (NPTX2) contributed most to PC 3. PC 4 (explaining 4% of the variance) exhibited an inflammatory profile distinct from PC 2, with the largest contributions from TREM2, leucine-rich alpha-2-glycoprotein 1 (LRG1) and complement C9. The component was associated with peripheral inflammation. We found that CSF protein profiles in a memory clinic cohort reflect molecular differences across diagnostic groups. Our results emphasize that real-world memory clinic patients can have different ongoing biological processes despite receiving the same diagnosis. In the future, this information could be utilized to identify patient endotypes and uncover precision biomarkers and novel therapeutic targets.
阿尔茨海默病及相关痴呆症具有多因素病因和异质性生物学特性。本研究旨在确定深度表型化记忆门诊患者群体中的不同生物学特征。在这项横断面研究中，我们使用基于多重抗体的悬浮微珠阵列，对瑞典斯德哥尔摩卡罗林斯卡大学医院记忆门诊真实世界研究数据库和生物样本库中的278份脑脊液样本中的49种预先指定的蛋白质进行了分析。纳入了临床诊断为主观认知下降（n = 151）、轻度认知障碍（n = 61）、阿尔茨海默病（n = 47）或其他诊断（n = 19；血管性痴呆、酒精相关痴呆、未特定的痴呆症或其他遗忘症）的患者。进行了主成分分析，并对所得主成分（PCs）与临床变量和阿尔茨海默病生物标志物（脑脊液生物标志物β-淀粉样蛋白42、β-淀粉样蛋白42/40、磷酸化tau 181、磷酸化tau 181/β-淀粉样蛋白42）的相关性进行了测试。主成分1（解释患者间52%的方差）与临床阿尔茨海默病脑脊液生物标志物β-淀粉样蛋白42、磷酸化tau 181和总tau相关，但与阿尔茨海默病相关神经退行性变成像标志物、认知表现或临床诊断无关。主成分2（解释9%的方差）呈现出一种炎症特征，几丁质酶3样蛋白1（CHI3L1）和髓样细胞表达的触发受体2（TREM2）贡献较大，且与脑脊液游离轻链κ显著相关。与主成分1不同，主成分3（解释5%的方差）与所有临床阿尔茨海默病脑脊液生物标志物、成像标志物、认知障碍和临床诊断均相关。丝氨酸蛋白酶抑制剂家族A成员3（SERPINA3）、几丁质酶1（CHIT1）和神经元五聚体蛋白2（NPTX2）对主成分3的贡献最大。主成分4（解释4%的方差）呈现出一种与主成分2不同的炎症特征，TREM2、富含亮氨酸的α-2-糖蛋白1（LRG1）和补体C9的贡献最大。该成分与外周炎症相关。我们发现记忆门诊队列中的脑脊液蛋白质谱反映了不同诊断组之间的分子差异。我们的结果强调，尽管接受相同诊断，但真实世界记忆门诊患者可能存在不同的正在进行的生物学过程。未来，这些信息可用于识别患者内型，发现精准生物标志物和新的治疗靶点。
