阿尔茨海默病中 tau 病理学的弹性的生物学机制。

Biological mechanisms of resilience to tau pathology in Alzheimer's disease.

机构信息

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, 211 46, Lund, Sweden.

Memory Clinic, Skåne University Hospital, 214 28, Malmö, Sweden.

出版信息

Alzheimers Res Ther. 2024 Oct 12;16(1):221. doi: 10.1186/s13195-024-01591-9.

DOI:10.1186/s13195-024-01591-9

PMID:39396028

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11470552/

Abstract

BACKGROUND

In Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).

METHODS

We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.

RESULTS

Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (β = -0.009, p = 0.047) and VEGF-B (β = -0.010, p = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, p = 0.033) and lower baseline cortical thickness (β = -0.708, p = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; β -0.073--0.069, p 0.001-0.045), vascular (VEGF-A, VEGF-D, PGF; β -0.099--0.063, p < 0.001-0.046), synaptic (14-3-3ζ/δ; β = -0.092, p = 0.041), axonal (NfL; β = -0.079, p < 0.001), and neurotrophic (NGF; β = 0.091, p < 0.001) biomarkers. In MCI higher NfL levels (β = -0.690, p = 0.025) were associated with faster cognitive decline independent of tau-PET signal.

CONCLUSIONS

Biomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.

摘要

背景

在阿尔茨海默病（AD）中，tau 病理学与脑萎缩和认知能力下降之间的关联已得到充分证实，但并不完善。我们研究了脑脊液（CSF）生物标志物（血管、突触和轴突完整性、神经炎症、神经营养因子）是否可以解释 tau 病理学与脑萎缩（脑弹性）以及 tau 病理学与认知能力下降（认知弹性）之间的脱节。

方法

我们纳入了来自 BioFINDER-2 研究的 428 名淀粉样蛋白阳性参与者（134 名认知正常（CU）、128 名轻度认知障碍（MCI）、166 名 AD 痴呆）。在基线时，参与者接受了 tau 正电子发射断层扫描（tau-PET）、磁共振成像（MRI）、认知测试和腰椎穿刺。MRI 有纵向数据（平均（标准差）随访 26.4（10.7）个月）和认知（25.2（11.4）个月）。我们分析了 18 种预先选择的 CSF 蛋白，反映了血管、突触和轴突完整性、神经炎症和神经营养因子。根据认知状态分层，我们使用皮质厚度（脑弹性）和整体认知（认知弹性）作为因变量进行线性混合效应模型分析，以评估 CSF 生物标志物与 tau-PET 水平在皮质萎缩和认知下降方面的相互作用。

结果

关于脑弹性，在 AD 痴呆中观察到了交互作用，血管完整性生物标志物（VEGF-A（β=−0.009，p=0.047）和 VEGF-B（β=−0.010，p=0.037））负调节了 tau-PET 信号与萎缩之间的关系。在 MCI 中，较高的 NfL 水平与更多的纵向皮质萎缩（β=−0.109，p=0.033）和基线皮质厚度降低（β=−0.708，p=0.033）有关，控制了 tau-PET 信号。在 CU 中，认知弹性分析显示，tau-PET 信号与炎症（GFAP、IL-15；β=−0.073--0.069，p 0.001-0.045）、血管（VEGF-A、VEGF-D、PGF；β=−0.099--0.063，p<0.001-0.046）、突触（14-3-3ζ/δ；β=−0.092，p=0.041）、轴突（NfL；β=−0.079，p<0.001）和神经营养因子（NGF；β=0.091，p<0.001）生物标志物之间存在相互作用。在 MCI 中，较高的 NfL 水平（β=−0.690，p=0.025）与 tau-PET 信号无关，与认知能力下降较快有关。