Association of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β and Regional Tau Burden Among Framingham Heart Study Participants Without Dementia

Abstract

Importance: Aortic stiffness is associated with clinical hallmarks of Alzheimer disease and related dementias and could be a modifiable target for disease prevention.

Objective: To assess associations of aortic stiffness and pressure pulsatility with global amyloid-β plaques and regional tau burden in the brain of middle-aged and older adults without dementia.

Design, setting, and participants: The sample for this cross-sectional study was drawn from the Framingham Heart Study Third Generation Cohort at examination 3 (N = 3171; 2016-2019), of whom 3092 successfully underwent comprehensive hemodynamic evaluations. In a supplemental visit (2015-2021), a subset of 270 participants without dementia who represented the spectrum of vascular risk also underwent positron emission tomography. Thirteen participants were excluded for missing covariate data. The final sample size was 257 participants.

Exposures: Three measures of aortic stiffness and pressure pulsatility (carotid-femoral pulse wave velocity, central pulse pressure [CPP], and forward wave amplitude [FWA]) were evaluated using arterial tonometry.

Main outcomes and measures: Global amyloid-β plaques and regional tau were assessed using 11C-Pittsburgh compound B and 18F-flortaucipir positron emission tomography tracers, respectively.

Results: The mean (SD) age of the 257 participants was 54 (8) years, and 126 were women (49%). All participants were White Western European race. In multivariable models, higher CPP (β per SD = 0.17; 95% CI, 0.00-0.35; P = .045) and FWA (β per SD = 0.16; 95% CI, 0.00-0.31; P = .04) were associated with greater entorhinal tau burden. In similar models, higher CPP (β per SD = 0.19; 95% CI, 0.02-0.36; P = .03) and FWA (β per SD = 0.17; 95% CI, 0.01-0.32; P = .03) were associated with greater rhinal tau burden. Aortic stiffness and pressure pulsatility measures were not associated with amygdala, inferior temporal, precuneus tau burden, or global amyloid-β plaques. Associations for entorhinal and rhinal tau outcomes were more prominent in older participants (≥60 years). For example, higher levels of all aortic stiffness and pressure pulsatility measures (β per SD = 0.40-0.92; P = .001-.02) were associated with higher entorhinal tau burden among older but not younger participants in stratified analyses.

Conclusions and relevance: In this cross-sectional study, abnormal central vascular hemodynamics were associated with higher tau burden in specific brain regions. Findings suggest that aortic stiffness, which is potentially modifiable, may be a probable independent target for prevention of tau-related pathologies.

Figure 1.. Flow Diagram of the Framingham Heart Study Third Generation Analysis Sample Selection

Aβ indicates amyloid-β; PET, positron emission tomography.

Figure 2.. Effect Modification by Age on Associations of Aortic Stiffness and Pressure Pulsatility Measures With Entorhinal, Rhinal, and Amygdala Tau Deposition

Effect sizes (βs) and 95% CIs from linear regression models that assessed associations of tonometry measures with entorhinal (A), rhinal (B), and amygdala regional tau (C) retention stratified by younger and older age (<60 and ≥60 years, respectively). The βs are expressed as SD change in ¹⁸F-flortaucipir retention standardized uptake value ratio for each SD change in continuous tonometric measure. All models were adjusted for continuous age, sex, apolipoprotein E ε4 status, camera, body mass index, mean arterial pressure, heart rate, hypertension treatment, prevalent nonstroke cardiovascular disease, ratio of total to high-density lipoprotein cholesterol, active smoking, prevalent diabetes, and time between tonometry and positron emission tomography assessment. For entorhinal and amygdala tau retention, 172 younger and 51 older participants were evaluated; for rhinal tau retention, 172 younger and 50 older participants were evaluated. We did not observe significant central pulse pressure (CPP)-age group and forward wave amplitude (FWA)-age group interactions for amygdala tau retention. CFPWV indicates carotid-femoral pulse wave velocity.

Figure 3.. Scatterplots Depicting the Correlation of Hemodynamic Variables With Rhinal and Entorhinal Tau Outcomes in Participants Stratified by Age Group

Correlations of tonometry measures with entorhinal (A) and rhinal regional tau (B) retention stratified by younger and older age (<60 and ≥60 years, respectively). CFPWV indicates carotid-femoral pulse wave velocity; CPP, central pulse pressure; FTP SUVR, ¹⁸F-flortaucipir standardized uptake value ratio; FWA, forward wave amplitude.