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. 2022 Jun 6:e221261. Online ahead of print. doi: 10.1001/jamaneurol.2022.1261

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

Leroy L Cooper 1,✉, Adrienne O’Donnell 2,3, Alexa S Beiser 2,3,4, Emma G Thibault 5, Justin S Sanchez 5, Emelia J Benjamin 3,6,7,8,9, Naomi M Hamburg 7,8, Ramachandran S Vasan 3,6,7,8,9, Martin G Larson 2,3, Keith A Johnson 5,10, Gary F Mitchell 11, Sudha Seshadri 3,12
PMCID: PMC9171656  PMID: 35666520

Key Points

Question

Are measures of aortic stiffness and pressure pulsatility associated with global amyloid-β plaques and regional tau burden in the brain among middle-aged and older adults without dementia?

Findings

In a cross-sectional study of 257 Framingham Third Generation participants, higher measures of aortic stiffness and pressure pulsatility were associated with higher rhinal and entorhinal tau burden but were not associated with global amyloid-β burden. Associations for tau outcomes were more prominent among older participants and were independent of amyloidosis.

Meaning

These findings suggest that abnormal central vascular hemodynamics may contribute to higher tau burden in brain regions that are vulnerable to early tau deposition.

This cross-sectional study evaluates the association of aortic stiffness and pressure pulsatility with global amyloid-β and regional tau burden among middle-aged and older Framingham Heart Study Third Generation 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.

Introduction

Aging is associated with progressive cognitive decline and alterations in the structure and function of blood vessels, including a pronounced increase in aortic stiffness. Vascular risk factors are associated with late-onset dementia, including Alzheimer disease (AD). In one Framingham Heart Study (FHS) analysis, incident mild cognitive impairment was associated with aortic stiffness and pressure pulsatility, which are potentially modifiable correlates of cognitive impairment. Community-based studies have revealed associations of aortic stiffness and flow pulsatility with alterations in brain structure and function; however, mechanisms that link aortic stiffness to cognitive function remain incompletely elucidated.

A hallmark of AD is the accumulation of amyloid-β (Aβ) plaques and tau protein tangles in the parenchyma, which often coincides with vascular dysfunction. Mawuenyega et al reported that AD is characterized by an overall impairment in Aβ clearance. Because vascular and paravascular glymphatic pathways enable the removal of Aβ from the brain, aortic stiffening may contribute to cerebrovascular dysfunction and impaired Aβ and tau clearance. Studies have shown significant associations of elevated pulse pressure with higher cerebral spinal fluid AD biomarkers. In addition, using positron emission tomography (PET), small studies revealed that brain Aβ plaques are associated with blood pressure measures and vascular stiffness. Moreover, a large population-based study suggested that higher levels of cerebral microvascular remodeling and microvascular parenchymal damage partially mediated the observed associations of elevated aortic stiffness with poorer memory function. The foregoing observations suggest that excessive pressure and flow pulsatility may contribute to impaired clearance of Aβ and tau protein from the brain. We hypothesized that measures of aortic stiffness and pressure pulsatility are associated with Aβ plaques and tau burden among individuals without dementia.

Methods

Procedures for requesting data can be found through the FHS website. This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Sample

The sample comprised participants from the FHS Third Generation Cohort, which is a community-based cohort representing children of FHS Offspring Study (second-generation) participants. We acquired comprehensive hemodynamic evaluations during examination 3 (2016-2019) in 3092 participants. The FHS conducts ongoing surveillance for dementia and cognitive impairment on the basis of all available data, including neurology and cognitive assessments and external medical record review. In a supplemental visit (2015-2021), we acquired PET images of brain Aβ plaques and tau protein deposition in a subset of participants without dementia. Participants who underwent both comprehensive hemodynamic evaluations and PET assessment (n = 270) were eligible for this investigation. From the eligible participants, we excluded 13 who had missing laboratory or covariate data for a final sample size of 257. All participants provided written informed consent, and protocols were approved by the institutional review boards of Boston University Medical Center and Massachusetts General Hospital.

Noninvasive Hemodynamics

We acquired hemodynamic data as previously described. Arterial tonometry was obtained with simultaneous electrocardiography from brachial, radial, femoral, and carotid arteries using a custom tonometer. We digitized and transferred tonometric data to a core laboratory (Cardiovascular Engineering Inc) for blinded analyses. Tonometry waveforms were signal averaged using the electrocardiographic R wave as a fiducial point. We used cuff systolic and diastolic blood pressures to calibrate the peak and trough of the signal-averaged brachial pressure waveform. Diastolic blood pressure and integrated brachial mean arterial pressure were used to calibrate carotid pressure tracings, which represented central aortic pressure. We calculated central pulse pressure (CPP) as the difference between carotid systolic and diastolic blood pressures. Using measured central pressure and flow, we separated forward and backward pressure waves. We defined forward wave amplitude (FWA) as the difference between pressure at the foot and peak of the forward pressure waveform. We calculated carotid-femoral pulse wave velocity (CFPWV), accounting for parallel transmission in the carotid artery and aortic arch.

Brain PET Imaging

Before PET imaging, participants underwent computerized tomography scans for attenuation correction and structural brain magnetic resonance imaging for coregistration. Structural T1-weighted data were acquired using a Philips Achieva 3T (6800 milliseconds; echo time, 3.1 milliseconds; flip angle, 9°; voxel size, 0.98 × 0.98 × 1.2 mm). Images were processed with FreeSurfer, version 6.0 software to identify white matter and pial surface as well as standard cortical regions of interest for PET sampling, using manual correction of automated segmentation where required. 11C-Pittsburgh compound B (PiB) and 18F-flortaucipir (FTP) were prepared according to previously published protocols. 11C-Pittsburgh compound B and FTP were used to assess the burden of Aβ plaques and tau protein deposition in the brain, respectively. Positron emission tomography data were acquired using either a Siemens ECAT HR+ (3-dimensional mode; image planes, 63; axial field of view, 15.2 cm; transaxial resolution, 5.6 mm; slice interval, 2.4 mm) or a Discovery MI (GE Healthcare) camera. 11C-Pittsburgh compound B PET images were acquired with a bolus injection of 10 to 15 mCi followed by a 60-minute dynamic acquisition, and PiB retention was expressed as the distribution volume ratio compared with a cerebellar cortex reference region. 18F-flortaucipir PET was acquired from 80 to 100 minutes in 4 × 5-minute frames, and FTP retention was expressed as the standardized uptake value ratio with cerebellar gray matter reference. Positron emission tomography images were coregistered to the corresponding baseline T1 image for each participant using SPM8 software (Wellcome Centre for Human Neuroimaging), and FreeSurfer-derived regions of interest were sampled for all PET data sets. Positron emission tomography data were reconstructed, attenuation corrected, scatter corrected, and evaluated frame by frame for excessive head motion. Global Aβ burden was represented using the PiB distribution volume ratio in a large neocortical target region that included superior frontal, rostral middle frontal, rostral anterior cingulate, medial orbitofrontal, inferior and middle temporal, inferior parietal, and precuneus regions (FreeSurfer-defined frontal, lateral, and retrosplenial region) compared with a cerebellar cortical reference region. Participants in the highest Aβ quintile (≥1.09 PiB distribution volume ratio) were classified as positive for elevated Aβ burden. 18F-flortaucipir retention was assessed in the rhinal cortex using vertex-wise surface mapping of the cortical ribbon at the midpoint of the gray matter (surface smoothing kernel, 8 mm). Other region-of-interest standardized uptake value ratios were calculated using FreeSurfer-defined regions mapped to PET native space and averaged across voxels within each region of interest. We evaluated specific brain regions on the basis of previous knowledge regarding cortical regions that are vulnerable to early tau protein deposition.

Clinical Evaluation and Covariates

Medical history and physical examination were performed routinely at each research examination. Age, sex, hypertension treatment, cardiovascular history, and smoking status were assessed through questionnaires. Race and ethnicity were not used as a biologic variable in this study. Cardiovascular diseases were adjudicated by end point panels from standardized criteria used in reviewing all available records. Active smoking was defined as self-reported regular use of cigarettes in the year preceding examination. Height (meters) and weight (kilograms) were assessed during examination. Body mass index was calculated as weight in kilograms divided by height in meters squared. Heart rate and mean arterial pressure were assessed during tonometry. Serum cholesterol levels were measured from a fasting blood test. Criteria for diabetes were a fasting glucose level of ≥126 mg/dL (7.0 mmol/L) or treatment with insulin or an oral hypoglycemic agent. Participants were classified as apolipoprotein E (APOE) ε4 positive if they carried at least 1 ε4 allele.

Statistical Analysis

We tabulated characteristics for the study sample. We used multivariable linear regression models to relate measures of aortic stiffness and pressure pulsatility (CFPWV, CPP, and FWA) with PET markers of global Aβ plaques and regional tau burden. We entered continuous exposure and outcome variables as standardized z scores in all models. CFPWV was inverted to limit heteroscedasticity, then multiplied by −1000 to convert units to millisecond per meter and rectify directionality of associations with aortic stiffness. We selected covariates a priori. Multivariable models were adjusted for age, sex, APOE ε4 status, camera type, 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 PET assessment. We assessed presence of effect modification (interaction) by age (<60 vs ≥60 years), sex, or APOE ε4 status by incorporating corresponding interaction terms into the analyses. For significant interactions, we performed stratified analyses and generated scatterplots to help visualize correlations.

All analyses were performed with SAS for Windows, version 9.4 (SAS Institute Inc). Two-tailed P < .05 was considered significant, except for tests of interaction, where P < .1 was considered significant.

Results

A flow diagram for the analysis sample is presented in Figure 1. The sample included 257 participants (126 women [49%] and 131 men [51%]). The mean (SD) age was 54 (8) years. All participants were White Western European race. Characteristics of the sample are presented in Table 1. The sample comprised relatively healthy middle-aged and older adults with a low prevalence of diabetes, smoking, and hypertension treatment. A comparison of these characteristics between included and excluded participants is presented in eTable 1 in the Supplement. Included and excluded participants had similar risk factor and vascular hemodynamic measures.

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

Figure 1.

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

Table 1. Sample Demographic and Clinical Characteristicsa.

Variable Value b
Clinical characteristics and medical history
Age at examination 3, y 54 (8)
Sex, No. (%)
Women 126 (49)
Men 131 (51)
Race
White Western European 257 (100)
Body mass index 28.6 (5.5)
Mean arterial pressure, mm Hg 92 (11)
Heart rate, beats/min 59 (9)
Total/high-density lipoprotein cholesterol ratio 3.4 (1.1)
Prevalent nonstroke cardiovascular disease, No. (%) 10 (4)
Prevalent diabetes, No. (%) 23 (9)
Active smoking, No. (%) 16 (6)
Antihypertension treatment, No. (%) 59 (23)
APOE ε4 allele carrier status, No. (%)c 61 (24)
Aortic stiffness and pulsatility variables
Central pulse pressure, mm Hg 59 (17)
Carotid-femoral pulse wave velocity, m/s 8 (2)
Forward wave amplitude, mm Hg 48 (13)
Brain positron emission tomography variables
Global Aβ burden, PiB DVR (n = 253) 1.06 (0.08)
Amygdala tau retention, FTP SUVR (n = 223) 1.14 (0.11)
Entorhinal tau retention, FTP SUVR (n = 223) 1.04 (0.08)
Rhinal tau retention, FTP SUVR (n = 222) 1.08 (0.09)
Inferior temporal tau retention, FTP SUVR (n = 223) 1.13 (0.07)
Precuneus tau retention, FTP SUVR (n = 223) 1.07 (0.07)
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Abbreviations: Aβ, amyloid-β; APOE, apolipoprotein E; FTP SUVR, 18F-flortaucipir standardized uptake value ratio; PiB DVR, 11C-Pittsburgh compound B distribution volume ratio.

a

n = 257.

b

All values are mean (SD) except as noted.

c

Positive for at least 1 APOE ε4 allele.

Associations of measures of aortic stiffness and pressure pulsatility with regional tau burden in the whole sample are presented in Table 2. In multivariable models, higher CPP (β per SD = 0.17; SE, 0.09; 95% CI, 0.00-0.35; P = .045) and FWA (β per SD = 0.16; SE, 0.08; 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; SE, 0.09; 95% CI, 0.02-0.36; P = .03) and FWA (β per SD = 0.17; SE, 0.08; 95% CI, 0.01-0.32; P = .03) were associated with greater rhinal tau burden. CFPWV was not associated with entorhinal and rhinal tau burden in the full sample. In addition, measures of aortic stiffness and pressure pulsatility were not associated with amygdala, inferior temporal, and precuneus tau burden. We did not observe significant associations of measures of aortic stiffness and pressure pulsatility with Aβ burden (eTable 2 in the Supplement).

Table 2. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Regional Tau Burdena.

Tonometry measure FTP SUVR
Amygdala Entorhinal Rhinalb Inferior temporal Precuneus
β (SE) P value β (SE) P value β (SE) P value β (SE) P value β (SE) P value
CFPWV –0.09 (0.09) .28 0.07 (0.10) .45 0.09 (0.10) .36 –0.07 (0.09) .44 0.00 (0.09) .98
95% CI –0.27 to 0.08 –0.12 to 0.27 –0.10 to 0.28 –0.25 to 0.11 –0.18 to 0.17
CPP 0.03 (0.08) .73 0.17 (0.09) .045 0.19 (0.09) .03 0.07 (0.08) .41 –0.03 (0.08) .72
95% CI –0.13 to 0.18 0.00 to 0.35 0.02 to 0.36 –0.09 to 0.23 –0.20 to 0.14
FWA 0.03 (0.07) .63 0.16 (0.08) .04 0.17 (0.08) .03 0.07 (0.07) .34 0.00 (0.08) .99
95% CI –0.10 to 0.17 0.00 to 0.31 0.01 to 0.32 –0.07 to 0.22 –0.15 to 0.15
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Abbreviations: CFPWV, carotid-femoral pulse wave velocity; CPP, central pulse pressure; FTP SUVR, 18F-flortaucipir standardized uptake value ratio; FWA, forward wave amplitude.

a

n = 223. Derived from linear regression models. Effect size (β) estimates are expressed as SD change in FTP SUVR for each SD change in continuous tonometric measure. Models are adjusted for age, sex, apolipoprotein E ε4 status, 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, camera type, and time between tonometry and positron emission tomography assessment.

b

n = 222 for rhinal tau analyses.

We summarize interactions for associations of measures of aortic stiffness and pressure pulsatility with Aβ and tau protein deposition in eTable 3 in the Supplement. Associations for rhinal and entorhinal tau outcomes were most prominent among participants 60 years or older. Among these older participants, higher CPP (β per SD = 0.45; 95% CI, 0.07-0.82; P = .02), FWA (β per SD = 0.40; 95% CI, 0.06-0.74; P = .02), and CFPWV (β per SD = 0.92; 95% CI, 0.40-1.44; P = .001) were associated with higher entorhinal tau burden, whereas higher CPP (β per SD = 0.36; 95% CI, 0.01-0.72; P = .046), FWA (β per SD = 0.33; 95% CI, 0.002-0.65; P = .049), and CFPWV (β per SD = 0.86; 95% CI, 0.38-1.35; P < .001) were associated with higher rhinal tau burden (Figure 2). Associations for rhinal and entorhinal tau outcomes were not significant among younger participants. Scatterplots stratified by age group depicting the associations and dynamic range of hemodynamic variables with rhinal and entorhinal tau outcomes are presented in Figure 3. Measures of aortic stiffness and pressure pulsatility were correlated with entorhinal (CFPWV: r = 0.41, P = .003; CPP: r = 0.33, P = .02; FWA: r = 0.31; P = .03) and rhinal tau burden (CFPWV: r = 0.43, P = .002; CPP: r = 0.30, P = .04; FWA: r = 0.31; P = .03) among the older participants. We further adjusted age-stratified rhinal and entorhinal tau outcomes for Aβ burden; the results were similar (eFigure 1 in the Supplement). Scatterplots depicting the associations of hemodynamic variables with rhinal and entorhinal tau outcomes stratified by Aβ positivity are presented in eFigure 2 in the Supplement. Stratified analyses did not suggest a significant effect modification by Aβ positivity status (eFigure 3 in the Supplement). In addition, age stratum–specific associations for inferior temporal tau outcomes were not significant. However, we observed that higher CFPWV was associated with lower amygdala tau burden among younger (β per SD = –0.22; 95% CI, –0.41 to –0.03; P = .02) but not older participants (Figure 2). We also observed that higher CPP was associated with higher inferior temporal tau burden among participants classified as APOE ε4 positive (β per SD = 0.39; 95% CI, 0.02-0.76; P = .04). We present stratum-specific analyses for all other significant interactions in eTables 4 and 5 in the Supplement.

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

Figure 2.

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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.

Figure 3.

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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.

Discussion

In this cross-sectional study of FHS middle-aged and older adult participants without dementia, higher measures of aortic stiffness and pressure pulsatility were associated with greater rhinal and entorhinal tau burden, particularly among participants 60 years or older. Furthermore, associations for tau outcomes among older participants remained significant after adjustment for Aβ burden. We did not observe significant associations of measures of aortic stiffness and pressure pulsatility with global Aβ burden. Our data reveal that abnormal central vascular hemodynamics are associated with higher regional tau burden in brain regions that are vulnerable to early tau protein deposition, independent of brain amyloidosis.

Abnormal Vascular Hemodynamics and Tau Burden

Our findings provide further evidence that upstream arterial dysfunction and elevated pressure pulsatility may contribute to nascent neuronal toxicity associated with greater tau protein deposition. In the whole sample, we observed that participants with higher CPP and FWA exhibited greater entorhinal and rhinal tau burden but not amygdala, precuneus, and inferior temporal tau burden. Rhinal, entorhinal, and amygdala regions are perfused primarily by arterial branches near the circle of Willis that arise from the internal carotid arteries, which more directly expose these regions to higher pulsatile energy. However, the precuneus and inferior temporal brain regions are supplied by distal branches of the posterior and middle cerebral arteries, respectively, which may provide additional impedance that attenuates pressure and flow pulsatility.

Elevated aortic stiffness and pressure pulsatility may contribute to higher tau protein levels through mechanisms that involve elevated cerebrovascular resistance (CVR) and chronic hypoperfusion of gray matter in specific brain regions. Previous work in older adults revealed that associations of higher aortic stiffness and pressure pulsatility with worse memory were partially mediated by higher CVR. Persistent transmission of excessive pulsatile energy into the cerebral microcirculation may contribute to pericyte dysfunction or promote cerebral arteriole constriction (increasing CVR) as a protective mechanism. At midlife, aortic stiffness increases dramatically, leading to higher CVR, which may contribute to an initial maladaptive phase of cerebrovascular dysfunction. For example, a recent Vanderbilt Memory and Aging Project study indicated that higher aortic pulse wave velocity was marginally to significantly associated with lower cerebrospinal fluid–derived total and phosphorylated tau among younger participants (≤73 vs >73 years). Consistent with the foregoing study and the maladaptive hypothesis, higher CFPWV was associated with lower amygdala tau burden among younger participants in the current study. Therefore, younger and older individuals may have discordant associations of vascular hemodynamics measures with tau burden, which may have contributed to the lack of significant association of CFPWV with entorhinal and rhinal tau burden in the full sample. Over time, elevated CVR can interfere with autoregulation and lead to chronic hypoperfusion of downstream tissues. In animal models, chronic cerebral hypoperfusion led to greater tau expression and hyperphosphorylation, which gives rise to toxic neurofibrillary tangles. Sugawara et al showed that older age was associated with higher cerebrovascular impedance. Therefore, age-related increases in brain hypoperfusion may explain why we observed associations of abnormal vascular hemodynamics and greater entorhinal and rhinal tau burden primarily among older individuals. These data suggest that effects of abnormal hemodynamics on brain PET markers are detectable after the period of marked increase in aortic stiffness and pressure pulsatility (ie, age ≥50 years). Yet, the relation of hypoperfusion with tau burden remains debatable in light of a small PET imaging study. Thus, additional studies that address the hypoperfusion hypothesis are needed.

Among participants classified as APOE ε4 positive, higher CPP was associated with greater inferior temporal tau burden. These data are consistent with a study by Baek et al, who recently showed that progressive tau accumulation was more pronounced among APOE ε4 carriers, particularly within the temporal cortex. However, APOE ε4 carriers may have different patterns of neuropathology location and density. Additional investigations should evaluate the role of APOE ε4 status in associations of vascular hemodynamics with tau-related pathologies.

Vascular Hemodynamics, Amyloidosis, and Tau Burden

Aortic stiffening and subsequent remodeling of downstream arterioles and cerebrovascular damage has been hypothesized to disrupt lymphatic and intramural clearance of Aβ from the brain. Although previous work revealed that Aβ clearance is impaired among patients with AD, a recent in vitro study suggested that pressure pulsatility may enhance Aβ production. Consistent with these observations, we hypothesized that higher levels of aortic stiffness and pressure pulsatility are associated with higher Aβ burden in the brain parenchyma. However, we did not observe significant associations of measures of aortic stiffness and pressure pulsatility with global Aβ burden in our sample. Our observations are similar to a Ginkgo Evaluation of Memory imaging substudy and a recent Atherosclerosis Risk in Communities study among elderly individuals. However, in the latter study, in brain areas with subclinical vascular disease (ie, white matter hyperintensities), CFPWV was associated with higher odds of Aβ positivity. In addition, studies by Nation and colleagues revealed that increasing pulse pressure is associated with higher preclinical phosphorylated tau and lower Aβ1-42 levels in cerebrospinal fluids (Aβ1-42 levels in cerebrospinal fluid fall as AD progresses). The amyloid cascade hypothesis of AD suggests that Aβ pathology precedes and induces neurofibrillary tau tangles. Contrary to animal models, clinical studies suggest that tau tangles may precede Aβ plaques or may be independent of plaque formation. We observed that associations of abnormal vascular hemodynamics with higher entorhinal and rhinal tau burden among older persons are independent of Aβ burden (eFigure 1 in the Supplement). Among participants with elevated Aβ deposition, abnormal hemodynamics may contribute to AD pathology where abnormal Aβ facilitates tau proliferation to other regions of the brain. Otherwise, tau accumulates in the entorhinal cortex among persons with normal Aβ with normal aging. Higher aortic stiffness and pressure pulsatility may contribute to tau-related cognitive impairment associated with normal aging rather than an AD trajectory. For example, Maass et al observed that higher entorhinal tau accumulation contributes to episodic memory loss independent of Aβ among participants with normal cognition. Longitudinal investigations should examine the role of vascular hemodynamics on regional PET biomarkers of AD and related dementias.

Limitations

This study has several limitations. Because of the cross-sectional design, additional work is required to ascertain whether the observed associations are observed prospectively and represent causal relationships. Although we adjusted for potential confounders, we can not exclude the possibility of residual confounding. We had limited statistical power to detect modest associations among older participants, given the sample size and the extent of multiple testing. Thus, our results are more susceptible to type I error. We used 2 different cameras to acquire PET images, and arterial tonometry and PET imaging did not occur on the same day. Thus, these circumstances may have increased the variability of our estimates; however, we adjusted for time between the 2 assessments as well as for camera type. We used nonpartial volume–corrected PET data, which may have led to some misclassification of elevated Aβ plaque status. However, our primary analyses were performed with Aβ burden as a continuous measure. We did not assess regional Aβ burden; however, additional studies that assess associations of vascular hemodynamics with regional Aβ burden are warranted. Furthermore, we acknowledge that although we observed significant associations that were limited to the medial temporal lobe, our observations may be due to limited tau spread outside these regions among the participants and not to vascular factors. Because aortic stiffness and PET biomarkers of AD and related dementias are markedly higher among older persons, observations in our relatively younger cohort may be limited in replicating previous studies assessing associations of aortic stiffness with PET or cerebrospinal fluid Aβ burden. The study findings may not be generalizable to other ethnic or racial groups because the sample comprised White participants of Western European descent.

Conclusions

In this cross-sectional study of middle-aged and older FHS Third Generation participants without dementia, higher aortic stiffness and pressure pulsatility were associated with greater rhinal and entorhinal tau burden. Associations were more prominent in adults 60 years or older and were independent of Aβ burden. Aortic stiffness and pressure pulsatility were not associated with global Aβ burden. These findings support the hypothesis that abnormal central vascular hemodynamics contribute to higher tau burden in specific brain regions susceptible to early tau protein deposition. Aortic stiffness is potentially modifiable and, therefore, represents a probable independent target for prevention of tau-related pathologies.

Supplement.

eTable 1. Comparison of Sample Characteristics of Excluded and Included Participants

eTable 2. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β Burden

eTable 3. Interactions for Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β and Regional Tau Deposition

eTable 4. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Regional Tau Deposition Stratified by Sex

eTable 5. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β and Inferior Temporal Tau Deposition Stratified by Apolipoprotein E (APOE) ε4 Status

eFigure 1. Assessment of Effect Modification by Age on Relations of Aortic Stiffness and Pressure Pulsatility Measures With Entorhinal and Rhinal Tau Deposition With Further Adjustment for Amyloid-β Deposition

eFigure 2. Scatterplots Depicting the Correlations of Hemodynamic Variables With Rhinal and Entorhinal Tau Outcomes in Participants Stratified by Amyloid-β Positivity Status

eFigure 3. Assessment of Effect Modification by Amyloid-β Positivity Status on Relations of Aortic Stiffness and Pressure Pulsatility Measures With Entorhinal and Rhinal Tau Deposition

Click here for additional data file. (675.8KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Comparison of Sample Characteristics of Excluded and Included Participants

eTable 2. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β Burden

eTable 3. Interactions for Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β and Regional Tau Deposition

eTable 4. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Regional Tau Deposition Stratified by Sex

eTable 5. Associations of Measures of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β and Inferior Temporal Tau Deposition Stratified by Apolipoprotein E (APOE) ε4 Status

eFigure 1. Assessment of Effect Modification by Age on Relations of Aortic Stiffness and Pressure Pulsatility Measures With Entorhinal and Rhinal Tau Deposition With Further Adjustment for Amyloid-β Deposition

eFigure 2. Scatterplots Depicting the Correlations of Hemodynamic Variables With Rhinal and Entorhinal Tau Outcomes in Participants Stratified by Amyloid-β Positivity Status

eFigure 3. Assessment of Effect Modification by Amyloid-β Positivity Status on Relations of Aortic Stiffness and Pressure Pulsatility Measures With Entorhinal and Rhinal Tau Deposition

Click here for additional data file. (675.8KB, pdf)

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