Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer's disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear. To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships. Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized clinical trial SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan. This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks. Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC). Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = -0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = -0.068; 95 % CI -0.126, -0.011). Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.
Jung et al. (Mon,) studied this question.
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