Paulsen Adam J, Driscoll Ira, Breidenbach Brianne M, Glittenberg Matthew, Lose Sarah R, Ma Yue, Sager Mark A, Carlsson Cynthia M, Gallagher Catherine L, Hermann Bruce P, Blennow Kaj, Zetterberg Henrik, Asthana Sanjay, Johnson Sterling C, Betthauser Tobey J, Christian Bradley T, Cook Dane B, Okonkwo Ozioma C
Wisconsin Alzheimer's Disease Research Center Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.
Wisconsin Alzheimer's Institute Madison Wisconsin USA.
Alzheimers Dement (N Y). 2025 Jun 24;11(2):e70122. doi: 10.1002/trc2.70122. eCollection 2025 Apr-Jun.
The accumulation of core Alzheimer's disease (AD) pathology contributes to cognitive decline. Cardiorespiratory fitness (CRF) influences AD pathological progression resulting in improvement or maintenance of cognitive function with age. CRF-related differences in accumulation rates or risk of reaching clinically relevant AD biomarker levels, and potentially interactive effects of core AD pathology and CRF on cognitive decline, remain largely unknown.
Participants ( = 533; Mean = 65, 70% female) from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention underwent serial blood draws, and cognitive and imaging assessments (Mean = 6.0 years). Positron emission tomography (PET) imaging of amyloid beta (Aβ) and tau (T) and plasma phosphorylated tau-217 (p-tau217) were used to determine biomarker status (±). Sex-specific estimated CRF (eCRF) tertiles were created using a validated equation. Kaplan-Meier survival curves and Cox proportional hazards examined the risk of becoming biomarker-positive. Linear mixed-effects models, stratified by biomarker status, estimated associations between baseline eCRF and core AD biomarker accumulation, and whether eCRF modified relationships between biomarker accumulation and cognitive decline.
There were no significant relationships between eCRF and biomarker trajectories. However, those in high eCRF group who were Aβ- at baseline had a significantly lower risk of becoming biomarker-positive (Aβ-PET: HR, 95% confidence interval [CI] = 0.42, 0.20-0.88; p-tau-217: 0.45, 0.21-0.97) compared to the low eCRF group. The detrimental relationship between Aβ accumulation and cognitive decline was significantly attenuated for Aβ+/T+ with high eCRF.
Although eCRF did not influence core AD biomarker accumulation trajectories, high eCRF seems protective against becoming biomarker-positive and attenuates the known deleterious relationship between biomarker accumulation and cognitive decline in Aβ+/T+.
High estimated cardiorespiratory fitness (eCRF) is associated with a lesser likelihood of becoming AD biomarker positive.High eCRF did not alter biomarker accumulation in those positive for Alzheimer's disease (AD) pathology.High eCRF attenuated the relationship between AD biomarkers and cognitive decline.Innovative methods: Stratifying analyses by amyloid beta and tau status.
阿尔茨海默病（AD）核心病理的积累会导致认知能力下降。心肺适能（CRF）会影响AD病理进展，从而随着年龄增长改善或维持认知功能。CRF在AD生物标志物临床相关水平的积累速率或风险方面的差异，以及AD核心病理与CRF对认知下降的潜在交互作用，在很大程度上仍然未知。
来自威斯康星州阿尔茨海默病研究中心和威斯康星州阿尔茨海默病预防登记处的参与者（n = 533；平均年龄 = 65岁，70%为女性）接受了系列血液采集、认知和影像学评估（平均随访6.0年）。使用淀粉样蛋白β（Aβ）和tau蛋白（T）的正电子发射断层扫描（PET）成像以及血浆磷酸化tau-217（p-tau217）来确定生物标志物状态（阳性/阴性）。使用经过验证的公式创建了按性别分层的估计CRF（eCRF）三分位数。采用Kaplan-Meier生存曲线和Cox比例风险模型来检验成为生物标志物阳性的风险。线性混合效应模型按生物标志物状态分层，估计基线eCRF与AD核心生物标志物积累之间的关联，以及eCRF是否改变生物标志物积累与认知下降之间的关系。
eCRF与生物标志物轨迹之间没有显著关系。然而，与低eCRF组相比，基线时Aβ阴性的高eCRF组参与者成为生物标志物阳性的风险显著更低（Aβ-PET：风险比[HR]，95%置信区间[CI]=0.42，0.20 - 0.88；p-tau-217：0.45，0.21 - 0.97）。对于Aβ阳性/T阳性且eCRF高的参与者，Aβ积累与认知下降之间的有害关系显著减弱。
尽管eCRF不影响AD核心生物标志物的积累轨迹，但高eCRF似乎对成为生物标志物阳性具有保护作用，并减弱了Aβ阳性/T阳性参与者中生物标志物积累与认知下降之间已知的有害关系。
高估计心肺适能（eCRF）与成为AD生物标志物阳性的可能性较小相关。高eCRF并未改变AD病理阳性者的生物标志物积累情况。高eCRF减弱了AD生物标志物与认知下降之间的关系。创新方法：按淀粉样蛋白β和tau蛋白状态进行分层分析。
