Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer’s disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, ¹¹C-Pittsburgh compound-B-PET, ¹⁸F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

早期神经元损伤的非侵入性生物标志物可能有助于识别认知正常的个体是否有患阿尔茨海默病 (AD) 的风险。最近的扩散加权成像 (DWI) 方法允许通过皮质平均扩散率 (cmD) 评估皮质微观结构，建议比宏观结构神经变性更敏感。在这里，我们旨在调查老年人中 cMD 与淀粉样蛋白-β 和 tau 病理学的关联，以及 cMD 是否预测纵向认知衰退、神经变性和临床进展。研究样本包括来自哈佛大脑老化研究的n  = 196 名认知正常的老年人（平均 [SD] 72.5 [9.4] 岁；114 名女性 [58.2%]）。在基线时，所有参与者都接受了结构 MRI、DWI、¹¹ C-匹兹堡化合物-B-PET、¹⁸ F-flortaucipir-PET 成像和认知评估。 在超过 3.72 (1.96) 年的随访中， n = 186 人获得了临床前阿尔茨海默认知组合 5 的纵向测量。前瞻性临床随访可用于n = 163 人超过 3.2 (1.7) 年。基于表面的图像分析评估了 cMD、全局淀粉样蛋白-β、内嗅和颞下 tau 之间的顶点关系。多变量回归、混合效应模型和 Cox 比例风险回归评估了纵向认知、大脑结构变化和临床进展。Tau 而不是淀粉样蛋白-β，与 AD 易感区域的 cMD 呈正相关。校正基线人口统计学和认知，增加的 cMD 预示着更严重的认知下降，这在校正淀粉样蛋白-β、厚度和内嗅 tau 后仍然显着；在认知斜率上，CMD 与淀粉样蛋白-β 和 tau 之间存在协同相互作用。区域 cMD 预测海马萎缩率，独立于淀粉样蛋白-β、tau 和厚度。升高的 cMD 预示着轻度认知障碍的进展。皮质微结构是一种非侵入性生物标志物，可独立预测随后的认知衰退、神经变性和临床进展，表明在临床试验中的实用性。