Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular–tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ–tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF–tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF–tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF–tau and sPDGFRβ–tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF–tau relationships in individuals with lower MoCA scores were driven by amyloid⁺ participants. Tau PET was a significant mediator CBF/sPDGFRβ–MoCA relationships in numerous regions. Our results demonstrate vascular–tau associations across the AD spectrum and suggest that early vascular–tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.

SIGNIFICANCE STATEMENT Emerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novel in vivo evidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF–tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor β, an independent CSF vascular biomarker, confirmed vascular–tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-β, and tau levels may more effectively preserve cognitive function than single-target therapies.

Tau 蛋白病理学和血管功能障碍是阿尔茨海默病 (AD) 的重要诱因，但人们对血管-tau 蛋白关联及其对认知的影响知之甚少。我们通过独立发现中的脑血流 (CBF) 和 tau 正电子发射断层扫描 (PET) 图像之间的体素比较来研究男性和女性人类中的这些关联[认知正常 (CN), 19;轻度认知障碍 (MCI) 风险，43； MCI，6] 和复制（CN，73；MCI，45；AD，20）队列。在一个亚组中，我们评估了 tau 与可溶性血小板衍生生长因子 β (sPDGFRβ)（周细胞损伤的脑脊液标志物）之间的关系。我们根据蒙特利尔认知评估 (MoCA) 整体认知表现或淀粉样蛋白负荷测试了 CBF/sPDGFRβ-tau 关系是否存在差异。中介分析评估了 CBF/sPDGFRβ、tau 蛋白和认知之间的关系。 CBF-tau 负相关主要在颞顶叶区域观察到。在复制队列中，随着疾病严重程度的增加，早期的 CBF-tau 负相关性在空间范围和相关强度上都增加了。在淀粉样蛋白负荷较大和 MoCA 评分较低的参与者中观察到更强的 CBF-tau 和 sPDGFRβ-tau 相关性。重要的是，当按淀粉样蛋白状态分层时，MoCA 评分较低的个体中更强的 CBF-tau 关系是由淀粉样蛋白⁺参与者驱动的。 Tau PET 是许多区域 CBF/sPDGFRβ-MoCA 关系的重要调节者。我们的结果证明了整个 AD 谱系中的血管-tau 相关性，并表明早期血管-tau 相关性在淀粉样蛋白存在的情况下会加剧，这与 AD 认知的二次打击模型一致。 针对血管健康、β-淀粉样蛋白和 tau 蛋白水平的联合治疗可能比单靶点治疗更有效地保护认知功能。

意义声明新出现的证据表明，血管功能障碍是阿尔茨海默病病理生理学的一个重要因素。然而，血管功能障碍与 tau 蛋白病理学之间的关联及其对认知的影响仍然知之甚少。对来自两个独立队列的多模态神经影像数据进行分析，以提供脑血流量 (CBF)、血管健康的 MRI 测量值和使用 PET 的 tau 病理学之间关联的新的体内证据。 CBF-tau 关联与认知相关，部分由淀粉样蛋白负担驱动。可溶性血小板衍生生长因子 β（一种独立的脑脊液血管生物标志物）在亚组分析中证实了血管与 tau 蛋白的关联。这些结果表明，针对血管健康、β-淀粉样蛋白和 tau 蛋白水平的联合治疗可能比单靶点治疗更有效地保护认知功能。