Gunasekaran Tamil Iniyan, Sanchez Danurys, Reyes-Dumeyer Dolly, Ventura Rabel, Morales Clarissa, Alshikho Mohamad, Lee Annie J, Lantigua Rafael A, Gu Yian, Honig Lawrence S, Vardarajan Badri N, Brickman Adam M, Mayeux Richard
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Ann Neurol. 2025 Jul 30. doi: 10.1002/ana.70006.
Blood-based biomarkers for Alzheimer's disease (AD), representing antemortem indicators of AD pathophysiology, have greatly improved the accuracy of diagnosis. However, these biomarkers may not capture a frequent coincident pathology, such as cerebrovascular disease.
We measured plasma amyloid-β40, amyloid-β42, total tau, tau phosphorylated at threonine 181, tau phosphorylated at threonine 217, glial fibrillary acidic protein, and neurofilament light chain in 685 multiancestral individuals who had clinical assessments and brain magnetic resonance imaging. The cohort was represented by individuals of European, African American, and Caribbean Hispanic ancestry. Participants were then classified as biomarker-positive or -negative for AD based on previously established cutoffs: 2.65 pg/mL for, tau phosphorylated at threonine 181 and 0.39 pg/mL for tau phosphorylated at threonine 217. We used magnetic resonance images to compare white matter hyperintensity volume (WMH), silent brain infarcts, microhemorrhages, and hippocampus volume across groups by their clinical diagnosis and biomarker status.
In the P-tau181 group (n = 685), 70 individuals (10.2%) had dementia or amnestic mild cognitive impairment. A total of 40 (57%) were biomarker-positive for AD, and 30 were classified as other dementia. Among 615 without dementia, 265 (40.3%) were preclinical AD, and 348 (50.8%) were biomarker-negative controls. In the tau phosphorylated at threonine 217 group (n = 535), 54 (10.1%) had dementia or amnestic mild cognitive impairment, including 33 biomarker-positive for AD and 21 with other dementia, whereas 183 (38.0%) were preclinical AD and 298 (61.9%) were biomarker-negative controls. Across both classifications, biomarker-positive for AD and other dementia individuals showed greater WMH volumes, more infarcts, and smaller hippocampus. However, P-tau217 positivity was more sensitive to WMH volume differences, whereas tau phosphorylated at threonine 181 better captured hippocampal atrophy and silent brain infarcts. Interestingly, ethnic differences may also influence detection of changes in WMH volumes, hippocampal volume, and infarcts in relation to specific biomarkers.
The results indicate that cerebrovascular disease is consistently involved in dementia either directly or as a coincident pathology in AD. These results underscore the need to incorporate both blood-based biomarkers and structural imaging in the evaluation of patients with dementia. ANN NEUROL 2025.
用于阿尔茨海默病（AD）的血液生物标志物代表了AD病理生理学的生前指标，极大地提高了诊断的准确性。然而，这些生物标志物可能无法捕捉到常见的并发病理情况，如脑血管疾病。
我们测量了685名多祖先个体的血浆淀粉样蛋白-β40、淀粉样蛋白-β42、总tau蛋白、苏氨酸181位点磷酸化的tau蛋白、苏氨酸217位点磷酸化的tau蛋白、胶质纤维酸性蛋白和神经丝轻链，这些个体均进行了临床评估和脑磁共振成像。该队列由欧洲、非裔美国和加勒比西班牙裔血统的个体组成。然后根据先前确定的临界值将参与者分为AD生物标志物阳性或阴性：苏氨酸181位点磷酸化的tau蛋白为2.65 pg/mL，苏氨酸217位点磷酸化的tau蛋白为0.39 pg/mL。我们使用磁共振图像，根据临床诊断和生物标志物状态比较各组之间白质高信号体积（WMH）、无症状脑梗死、微出血和海马体积。
在P-tau181组（n = 685）中，70名个体（10.2%）患有痴呆或遗忘性轻度认知障碍。其中40名（57%）为AD生物标志物阳性，30名被归类为其他痴呆。在615名无痴呆的个体中，265名（40.3%）为临床前期AD，348名（50.8%）为生物标志物阴性对照。在苏氨酸217位点磷酸化的tau蛋白组（n = 535）中，54名（10.1%）患有痴呆或遗忘性轻度认知障碍，其中33名AD生物标志物阳性，21名患有其他痴呆，而183名（38.0%）为临床前期AD，298名（61.9%）为生物标志物阴性对照。在两种分类中，AD生物标志物阳性和其他痴呆个体的WMH体积更大、梗死灶更多、海马更小。然而，P-tau217阳性对WMH体积差异更敏感，而苏氨酸181位点磷酸化的tau蛋白更能捕捉海马萎缩和无症状脑梗死。有趣的是，种族差异也可能影响与特定生物标志物相关的WMH体积、海马体积和梗死灶变化的检测。
结果表明，脑血管疾病无论是直接还是作为AD的并发病理情况，都一直与痴呆有关。这些结果强调了在痴呆患者评估中同时纳入血液生物标志物和结构成像的必要性。《神经病学纪事》2025年。
