Abstract Background and aims Hemodynamic instability characterized by high systolic blood pressure variability (SBPV) may disrupt constant cerebral perfusion, thereby exacerbating ischemic injury to white matter tracts and promoting neurodegenerative processes in aging populations. To investigate the impact of SBPV on brain structure and cognitive function in non-frail and pre-frail individuals, and to provide theoretical evidence for cognitive preservation in frail populations. Methods Based on the UK Biobank cohort, 59,087 individuals without baseline frailty were included. Systolic blood pressure standard deviation was calculated from three follow-up visits. Multimodal magnetic resonance imaging was used to quantify brain structural indices, and standardized cognitive tests were applied to assess cognitive function. Multivariable-adjusted models were constructed to evaluate the associations between SBPV and brain structure/cognition, with restricted cubic spline (RCS) analysis to explore non-linear relationships. Results In the high-SBPV group, total brain volume decreased (β = -25,550.15, 95 % CI: -27,748.01 to -23,352.28), while white-matter hyperintensity volume increased (β = 1,471.48, 95 % CI: 1,329.99 to 1,612.98). RCS showed an inverted U-shaped relationship between brain volume indices and SBPV, and a J-shaped increase in white-matter hyperintensities. Cognitive analyses revealed complex non-linear effects of SBPV on prospective memory and processing speed. Conclusions SBPV was identified as an independent predictor of brain atrophy and cognitive decline in non-frail and pre-frail adults. These findings underscore that SBPV represents a distinct vascular burden beyond traditional mean blood pressure metrics. Consequently, targeting SBPV offers a critical therapeutic window to preserve brain health prior to the onset of overt frailty. Conflict of interest Junqi Yang,Jianwen Liang:nothing to disclose Figure 1 - belongs to Background and aims Table 1 - belongs to Methods Table 2 - belongs to Results Figure 2 - belongs to Conclusions
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