Dubbelman Mark A, Liu Andy, Donohue Michael C, Langford Oliver, Raman Rema, Rentz Dorene M, Amariglio Rebecca, Sperling Reisa Anne, Aisen Paul S, Marshall Gad A
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School; and.
Neurology. 2025 Jun 24;104(12):e213775. doi: 10.1212/WNL.0000000000213775. Epub 2025 May 29.
Everyday functioning declines gradually over time in Alzheimer disease (AD), with the earliest changes potentially occurring at the preclinical stage. We investigated how changes in everyday functioning relate to (changes in) amyloid and tau in a large sample of cognitively unimpaired older adults, most of whom had elevated amyloid levels at the start of the study.
This prospective study included participants from a 240-week randomized controlled trial of an anti-amyloid drug, solanezumab, and individuals who screen-failed because of a negative amyloid PET scan. A subset (n = 434) underwent repeated tau PET scans. Participants and their study partners completed the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument multiple times during the double-blind phase of the trial. Using generalized least-squares models, fit by restricted maximum likelihood, we analyzed how changes in everyday functioning related to amyloid and tau PET. We also correlated changes in amyloid and tau PET with changes in everyday functioning.
A total of 1,707 participants (71.5 ± 4.7 years, 60% female) showed a marginal decline in everyday functioning. Among individuals with elevated amyloid, those with the highest levels of neocortical and medial temporal tau showed the largest decline in everyday functioning, as reported by the participants and their study partners. Increases in neocortical and medial temporal tau correlated moderately (correlation coefficient ranging from -0.2 to -0.5) with a decline in ADCS ADL-PI scores. Functional changes were not evident with amyloid alone. At the item level, participants and their study partners were most likely to report increased difficulty at the last visit with completing complex activities and selecting and paying for items when shopping.
Higher tau levels are associated with the fastest decline in everyday functioning in the presence of elevated amyloid, and those accumulating more tau show a faster decline in everyday functioning. These findings demonstrate the utility of including sensitive measures of everyday functioning in clinical practice and clinical trials at the stage of preclinical AD.
The A4 study, ClinicalTrials.gov ID: NCT02008357; and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration, ClinicalTrials.gov ID: NCT02488720.
在阿尔茨海默病（AD）中，日常功能会随着时间逐渐衰退，最早的变化可能发生在临床前阶段。我们在大量认知未受损的老年人样本中研究了日常功能的变化与淀粉样蛋白和tau蛋白（的变化）之间的关系，这些老年人中的大多数在研究开始时淀粉样蛋白水平升高。
这项前瞻性研究纳入了一项抗淀粉样蛋白药物索拉珠单抗的240周随机对照试验的参与者，以及因淀粉样蛋白PET扫描呈阴性而筛查失败的个体。其中一个子集（n = 434）接受了重复的tau蛋白PET扫描。在试验的双盲阶段，参与者及其研究伙伴多次完成阿尔茨海默病协作研究日常生活预防工具。使用通过限制最大似然法拟合的广义最小二乘模型，我们分析了日常功能的变化与淀粉样蛋白和tau蛋白PET之间的关系。我们还将淀粉样蛋白和tau蛋白PET的变化与日常功能的变化进行了相关性分析。
共有1707名参与者（71.5±4.7岁，60%为女性）的日常功能出现了轻微下降。在淀粉样蛋白水平升高的个体中，新皮质和内侧颞叶tau蛋白水平最高的个体，其日常功能下降幅度最大，这是参与者及其研究伙伴报告的情况。新皮质和内侧颞叶tau蛋白的增加与阿尔茨海默病协作研究日常生活预防工具（ADCS ADL-PI）评分的下降呈中度相关（相关系数范围为-0.2至-0.5）。仅淀粉样蛋白水平变化时，功能变化并不明显。在项目层面，参与者及其研究伙伴最有可能报告在最后一次访视时，完成复杂活动以及购物时挑选和付款变得更加困难。
在淀粉样蛋白水平升高的情况下，较高的tau蛋白水平与日常功能下降最快相关，且积累更多tau蛋白的个体日常功能下降更快。这些发现证明了在临床前AD阶段的临床实践和临床试验中纳入日常功能敏感测量指标的实用性。
A4研究，ClinicalTrials.gov标识符：NCT02008357；淀粉样蛋白风险与神经退行性变纵向评估，ClinicalTrials.gov标识符：NCT02488720。
