Systolic blood pressure variability in late-life predicts cognitive trajectory and risk of Alzheimer's disease

Abstract

Background: The relationship of systolic blood pressure variability (SBPV) with Alzheimer's disease (AD) remains controversial. We aimed to explore the roles of SBPV in predicting AD incidence and to test the pathways that mediated the relationship of SBPV with cognitive functions.

Methods: Longitudinal data across 96 months (T₀ to T₄) were derived from the Alzheimer's disease Neuroimaging Initiative cohort. SBPV for each participant was calculated based on the four measurements of SBP across 24 months (T₀ to T₃). At T₃, logistic regression models were used to test the SBPV difference between 86 new-onset AD and 743 controls. Linear regression models were used to test the associations of SBPV with cognition and AD imaging endophenotypes for 743 non-demented participants (median age = 77.0, female = 42%). Causal mediation analyses were conducted to explore the effects of imaging endophenotypes in mediating the relationships of SBPV with cognitive function. Finally, Cox proportional hazard model was utilized to explore the association of SBPV with incident risk of AD (T₃ to T₄, mean follow-up = 3.5 years).

Results: Participants with new-onset AD at T₃ had significantly higher SBPV compared to their controls (p = 0.018). Higher SBPV was associated with lower scores of cognitive function (p = 0.005 for general cognition, p = 0.029 for memory, and p = 0.016 for executive function), higher cerebral burden of amyloid deposition by AV45 PET (p = 0.044), lower brain metabolism by FDG PET (p = 0.052), and higher burden of white matter hyperintensities (WMH) (p = 0.012). Amyloid pathology, brain metabolism, and WMH partially (ranging from 17.44% to 36.10%) mediated the associations of SBPV with cognition. Higher SBPV was significantly associated with elevated risk of developing AD (hazard ratio = 1.29, 95% confidence interval = 1.07 to 1.57, p = 0.008).

Conclusion: These findings supported that maintaining stable SBP in late life helped lower the risk of AD, partially by modulating amyloid pathology, cerebral metabolism, and cerebrovascular health.

Keywords: Alzheimer’s disease; amyloid; brain metabolism; systolic blood pressure variability; white matter hyperintensities.

FIGURE 1

Timeline of study design and flowchart for the overall selection process. SBPV was defined as the standard deviation of systolic blood pressure at T₀, T₁, T₂, and T₃ and divided into quartiles. SBP trajectory was based on 96-month follow-up. Cross-sectional studies were conducted at T₃. Longitudinal studies were conducted from T₃ onwards. Participants who were diagnosed with AD and aged <65 years old at baseline (T₀) were excluded from 2084 ADNI participants. A total of 1550 non-demented and elderly participants were followed up for 96 months (T₀ to T₄) to depict the SBP trajectory. A total of 899 non-demented and elderly participants with records of SBP, PP, and MMSE were selected. After excluding incident AD before T₃, 829 were included for logistic regression models. A total of 743 non-demented participants were included for multiple linear regression models and mediation analyses. For the longitudinal study, Cox proportional hazards models were applied to 658 participants.

FIGURE 2

(A) SBP trajectories between those with incident AD vs those who remain non-demented for 8 years. The SBP trajectory for participants with incident AD was plotted using SBP data from the year of AD onset and from 1 to 8 years before AD onset. The trajectory of SBP for those who remained non-demented was plotted using 8-year follow-up (T₀ to T₄) data. Participants with incident AD have greater SBP fluctuations than those who remain non-demented; (B) Association of SBPV with AD patients and those who remain free of AD. Participants who incident AD at T₃ were associated with greater SBPV compared to non-AD participants; (C) Association of SBPV with AD risk from T₃ to T₄. Participants with higher SBPV demonstrated a heightened risk of incident AD.

FIGURE 3

Associations of SBPV with cognition and AD imaging endophenotypes at T₃. Participants with higher SBPV were associated with poorer global cognition (A), memory (B), executive function (C), as well as higher amyloid load (D), lower cerebral FluoroDeoxyGlucose (FDG) metabolism (E) and higher white matter hyperintensities (WMH) (F) compared to those with lower SBPV.

FIGURE 4

Mediation analyses with ADAS and cognitive domains as cognitive outcomes. The relationship of SBPV with cognitive measures, including (A, D, G) global cognition measured by ADAS as well as cognitive domain of (B, E, H) memory (MEM) and (C, F, I) executive function (EF) was mediated by (A–C) amyloid load, (D–F) FluoroDeoxyGlucose (FDG) metabolism, and (G–I) white matter hyperintensities (WMH). IE, indirect effect. SBPV, systolic blood pressure variability; AD, Alzheimer’s disease; SD, standard deviation; IQR, interquartile range; APOE, apolipoprotein E gene; MCI, mild cognitive impairment; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; ADAS-13, Alzheimer’s Disease Assessment Scale 13; ADNI, Alzheimer’s Disease Neuroimaging Initiative; EF, executive function; MEM, memory; PET, positron emission tomography; AV45, 18F florbetapir; FDG, Fluorodeoxyglucose; WMH, white matter hyperintensities; MRI, magnetic resonance imaging; ICV, intracranial volume; Aβ,amyloid-beta; Q1-4, quartiles 1-4; T₀, baseline; T₁, month 6; T₂, month 12; T₃, month 24; T₄, month 96.