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Elevated Blood Pressure Variability Shows Relationship With Alzheimer-Related Biomarkers

The combination of APOE ε4 carrier status with elevated blood pressure variability represented the fastest increase in phosphorylated tau levels over time.

Findings from a prospective cohort study of cognitively unimpaired or mildly impaired older adults suggested that elevated visit-to-visit blood pressure variability (BPV) was associated with increased cerebrospinal fluid (CSF) phosphorylated tau, increased total tau, and decreased CSF amyloid-ß levels over time.1

To understand more about the associations between BPV and Alzheimer disease (AD)-related biomarkers, senior author Daniel A. Nation, PhD, assistant professor of psychology, University of Southern California, and colleagues conducted a retrospective analysis. A total of 466 participants from the Alzheimer’s Disease Neuroimaging Initiative underwent 3 to 4 blood pressure measurements over a 12-month period with at least 1 lumbar puncture.

Using CSF samples collected after the final blood pressure measurement (n = 757 samples), elevated BPV was found to be associated with increased phosphorylated tau levels (systolic: ß: 0.81 [95% CI, 0.74-0.97]; diastolic: ß: 3.79 [95% CI, 2.14-5.41]), increased tau levels (systolic: ß: .98 [95% CI, 0.71-1.31]; diastolic: ß: 2.01 [95% CI, 1.10-2.90]) and decreased amyloid-ß levels (systolic: ß: –1.52 [95% CI, –3.55 to –0.34]; diastolic: ß: –3.46 [95% CI, –7.02 to –0.26]).

Each of these associations were analyzed in separate models, which Nation et al noted "allowed us to appreciate individual contributions from these hallmark AD biomarkers." Additionally, BPV was calculated from blood pressure measurements collected in a way that is similar to routine clinical visits, "further highlighting the utility of BPV as a marker related to AD pathophysiology in clinical practice," they added.1

READ MORE:Amyloid-ß and Vascular Burden Show Independent Additive Effects on Neurodegeneration Rates in the Cognitively Normal

A separate aim of the study was to determine whether associations between BPV and AD-related biomarkers differed by apolipoprotein (APOE) ε4 carrier status. APOE ε4 carriers were defined as having at least 1 ε4 allele. All told, the combination of elevated BPV with APOE ε4 status had the fastest increase in phosphorylated tau levels (systolic: ß: 9.03 [95% CI, 1.67-16.36]; diastolic: ß: 22.28 [95% CI, 13.90-30.52]).

These findings were aligned with other research published by Nation et al in 2021. In that study, a Bayesian growth model revealed a significant interaction of BPV and ε4 status by time on hippocampal (ß: –2.61; 95% CI, –3.02 to –2.12) and entorhinal cortex (ß: –1.47; 95% CI, –1.71 to –1.17) volume decline. A similar pattern emerged in subsets with AD pathophysiology, including abnormal levels of both amyloid-ß and phosphorylated tau.2

While APOE ε4 carriers had the fastest increase in phosphorylated tau levels, there was no significant interaction related to total tau levels (systolic: ß: –0.33 [95% CI, –1.21 to 0.57]; diastolic: ß: –0.24 [95% CI, –1.18 to 0.73]) or amyloid-ß levels (systolic: ß: –1.07 [95% CI, –2.31 to 0.07]; diastolic: ß: 1.95 [95% CI, –1.11 to 3.81]) over time.1

Nation et al noted that it was interesting to see APOE ε4 modify the relationship between BPV and CSF phosphorylated tau, but not CSF total tau or CSF amyloid-ß. “Growing evidence suggests CSF phosphorylated tau is associated with neurofibrillary tangles, a neuropathological marker of tau associated with AD, whereas CSF total tau may represent a less specific marker of neurodegeneration," they wrote.1

On sensitivity analyses, the associations between CSF change and BPV remained statistically significant after controlling for history of smoking, history of dyslipidemia, use of antidementia agents, clinical diagnosis of either cognitively unimpaired or mild cognitive impairment (MCI), body mass index, and history of alcohol abuse. Additionally, findings based on APOE ε4 carrier status remained statistically significant for CSF phosphorylated tau. When examining cognitive unimpaired and MCI groups, investigators found similar associations using both clinical diagnostic criteria.

1. Sible IJ, Nation DA. Visit-to-visit blood pressure variability and CSF Alzheimer disease biomarkers in cognitively unimpaired and mildly impaired older adults. Neurology. Published online April 13, 2022. doi:10.1212/WNL.0000000000200302
2. Sible IJ, Nation DA. Blood pressure variability and medial temporal atrophy in apolipoprotein ε4 carriers. Brain Imaging and Behav. 2022;16:792-801. doi:10.1007/s11682-021-00553-1