Yu Lei, Du Lianlian, Wang Tianhao, Barnes Lisa L, Dage Jeffrey L, Russ Kristen A, Foroud Tatiana, Bennett David A, Schneider Julie A, Boyle Patricia A
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Brain. 2025 Sep 3;148(9):3340-3349. doi: 10.1093/brain/awaf211.
There has been a rapid growth in research on peripheral fluid biomarkers for Alzheimer's disease (AD) and AD-related dementias, because they are non-invasive, relatively inexpensive and easily accessible. The most commonly used plasma biomarkers include amyloid-β (Aβ), phosphorylated tau (p-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). The extent to which distinct profiles of multiple plasma biomarkers correlate with common neuropathologies is unclear. Using clinicopathologic data from 405 community-dwelling older adults, we applied latent profile analysis to four plasma biomarkers, i.e. Aβ42/40 ratio, p-tau217, NfL and GFAP, and examined the correlates of the latent profiles with four degeneration measures: AD, Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis; and five vascular measures: chronic macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriosclerosis. On average, participants died at the age of 89, and blood samples for plasma biomarkers were measured 3.9 years before death. Over 75% were female, and 24% were non-Latino Black. We observed three distinct biomarker profiles. Profile 1, characterized by low p-tau217, low GFAP, low NfL and high Aβ42/40, represented most participants (55.6%), with better than average biomarker levels. Both Profile 2 and Profile 3 showed worse than average biomarker levels. Profile 2, representing 34.8% of the participants, was high in p-tau217 and GFAP. In contrast, Profile 3, representing 9.6% of the participants, was high in NfL and GFAP. Examination of neuropathologic correlates of these plasma biomarker profiles revealed that Profile 2 exemplifies older adults with a high burden of neurodegeneration; almost all participants (92.9%) in Profile 2 had a diagnosis of pathologic AD, and the group also had the highest percentage of participants with Lewy bodies (41.1%). In comparison, Profile 3 exemplifies older adults with more severe vascular conditions; participants in this group had the highest percentage of macroscopic infarcts (31.6%) and moderate or severe atherosclerosis (42.1%). Together, these findings suggest that common plasma biomarkers may exhibit profiles reflective of distinct pathophysiologic processes.
阿尔茨海默病（AD）及AD相关痴呆外周血生物标志物的研究迅速增长，因为它们具有非侵入性、相对廉价且易于获取的特点。最常用的血浆生物标志物包括淀粉样β蛋白（Aβ）、磷酸化tau蛋白（p-tau）、神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP）。多种血浆生物标志物的不同特征与常见神经病理学的关联程度尚不清楚。我们利用405名社区居住老年人的临床病理数据，对四种血浆生物标志物，即Aβ42/40比值、p-tau217、NfL和GFAP进行潜在特征分析，并研究潜在特征与四种神经退行性变指标（AD、路易小体、边缘叶为主的年龄相关性TDP-43脑病（LATE）和海马硬化）以及五种血管指标（慢性宏观梗死、微梗死、脑淀粉样血管病、动脉粥样硬化和动脉硬化）之间的相关性。参与者平均死亡年龄为89岁，血浆生物标志物的血样在死亡前3.9年采集。超过75%为女性，24%为非西班牙裔黑人。我们观察到三种不同的生物标志物特征。特征1以低p-tau217、低GFAP、低NfL和高Aβ42/40为特征，代表了大多数参与者（55.6%），其生物标志物水平高于平均水平。特征2和特征3的生物标志物水平均低于平均水平。特征2占参与者的34.8%，p-tau217和GFAP水平较高。相比之下，特征3占参与者的9.6%，NfL和GFAP水平较高。对这些血浆生物标志物特征的神经病理学相关性检查发现，特征2代表神经退行性变负担高的老年人；特征2中几乎所有参与者（92.9%）都被诊断为病理性AD，该组中患有路易小体的参与者比例也最高（41.1%）。相比之下，特征3代表血管状况更严重的老年人；该组参与者中宏观梗死的比例最高（31.6%），中度或重度动脉粥样硬化的比例为42.1%。总之，这些发现表明常见的血浆生物标志物可能呈现出反映不同病理生理过程的特征。
