The present study aimed at investigating if the main biomarkers of Alzheimer’s disease (AD) neuropathology and their association with cognitive disturbances and dementia are modified by the individual’s frailty status. We performed a cross-sectional analysis of data from participants with normal cognition, mild cognitive impairment (MCI), and AD dementia enrolled in the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI2) study. Frailty was operationalized by computing a 40-item Frailty Index (FI). The following AD biomarkers were considered and analyzed according to the participants’ frailty status: CSF Aβ_1-42, ¹⁸¹P-tau, and T-tau; MRI-based hippocampus volume; cortical glucose metabolism at the FDG PET imaging; amyloid deposition at the ¹⁸F-AV-45 PET imaging. Logistic regression models, adjusted for age, sex, and education, were performed to explore the association of biomarkers with cognitive status at different FI levels. Subjects with higher FI scores had lower CSF levels of Aβ_1-42, hippocampus volumes at the MRI, and glucose metabolism at the FDG PET imaging, and a higher amyloid deposition at the ¹⁸F-AV-45 PET. No significant differences were observed among the two frailty groups concerning ApoE genotype, CSF T-tau, and P-tau. Increasing frailty levels were associated with a weakened relationship between dementia and ¹⁸F-AV-45 uptake and hippocampus volume and with a stronger relationship of dementia with FDG PET. Frailty contributes to the discrepancies between AD pathology and clinical manifestations and influences the association of AD pathological modifications with cognitive changes. AD and dementia should increasingly be conceived as “complex diseases of aging,” determined by multiple, simultaneous, and interacting pathophysiological processes.

本研究旨在调查阿尔茨海默病（AD）神经病理学的主要生物标志物及其与认知障碍和痴呆的关联是否会因个体的虚弱状态而改变。我们对参与阿尔茨海默病神经影像计划 2 (ADNI2) 研究的正常认知、轻度认知障碍 (MCI) 和 AD 痴呆参与者的数据进行了横断面分析。脆弱性通过计算 40 项脆弱指数 (FI) 来实施。根据参与者的虚弱状况考虑并分析了以下 AD 生物标志物：CSF Aβ ^1-42、181 _P - tau 和 T-tau；基于 MRI 的海马体体积；FDG PET 成像中的皮质葡萄糖代谢；¹⁸ F-AV-45 PET 成像中的淀粉样蛋白沉积。采用逻辑回归模型，根据年龄、性别和教育程度进行调整，以探索生物标志物与不同 FI 水平认知状态的关联。FI 评分较高的受试者的脑脊液 Aβ _1-42水平、MRI 中的海马体积和 FDG PET 成像中的葡萄糖代谢水平较低，而¹⁸ F-AV-45 PET 中的淀粉样蛋白沉积较高。两个虚弱组之间在 ApoE 基因型、CSF T-tau 和 P-tau 方面没有观察到显着差异。^{虚弱程度的增加与痴呆与18} F-AV-45 摄取和海马体积之间的关系减弱有关，并且与痴呆与 FDG PET 之间的关系更强相关。虚弱导致 AD 病理学与临床表现之间的差异，并影响 AD 病理改变与认知变化的关联。AD 和痴呆症应该越来越多地被视为“复杂的衰老疾病”，由多种、同时发生和相互作用的病理生理过程决定。