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. 2025 Apr 21;17(1):85.
doi: 10.1186/s13195-025-01731-9.

Relationships between blood pressure indicators and fluid biomarkers of brain aging in functionally intact older adults

Anna M VandeBunte #  1   2 , Bailey L Ortiz #  1   2 , Emily W Paolillo  1 , Rowan Saloner  1 , Valentina Diaz  1 , Shubir Dutt  1 , Claire J Cadwallader  1 , Coty Chen  1 , Argentina Lario Lago  1 , Julio C Rojas  1 , Brandon Chan  1 , Isabel Sible  1 , Joel H Kramer  1 , Kaitlin B Casaletto  3
Affiliations

Relationships between blood pressure indicators and fluid biomarkers of brain aging in functionally intact older adults

Anna M VandeBunte et al. Alzheimers Res Ther. .

Abstract

Background: Dementia risk is significantly shaped by cardiovascular health, with elevated blood pressure emerging as a key risk factor for adverse brain aging. Blood biomarkers such as pTau181, Aβ42/40, NfL, and GFAP have improved our understanding of dementia pathophysiology, however, few studies have explored how specific blood pressure metrics relate to biomarker levels, which could inform personalized dementia prevention strategies as these biomarkers move into clinic. We examined how different blood pressure metrics associated with molecular markers of astrocytic activation (GFAP), neuronal axon breakdown (NfL), and Alzheimer's disease pathobiology (pTau181, Aβ42/40) in plasma.

Methods: 109 functionally intact (Clinical Dementia Rating Scale = 0) older adults completed blood draws with plasma assayed for Aβ42/40, GFAP, NfL, and pTau181 (Quanterix Simoa) and in-lab blood pressure quantification. Blood pressure metrics included diastolic blood pressure, systolic blood pressure, and pulse pressure (systolic minus diastolic). Separate regression models evaluated plasma biomarkers as a function of each blood pressure metric, adjusting for age and biological sex. Interaction models tested whether relationships between blood pressure metrics and plasma biomarkers differed by sex, age, or APOE-ε4 status.

Results: With the exception of Aβ42/40, higher pulse pressure related to higher levels of all plasma biomarkers examined (pTau181, NfL, GFAP). Additionally, higher systolic blood pressure related to higher pTau181, while diastolic blood pressure did not meaningfully associate with any biomarker. Interaction models revealed a significantly stronger relationship between elevated pulse pressure and higher GFAP concentrations in females compared to males, as well as a significantly stronger association between elevated pulse pressure and lower Aβ42/40 plasma concentrations in APOE-ε4 carriers compared to non-carriers.

Conclusions: Our findings suggest that elevated pulse pressure, and to a lesser extent systolic blood pressure, are associated with increased Alzheimer's disease and neurodegenerative (axonal and astrocytic health) biology among typically aging adults. These associations underscore the importance of blood pressure management, particularly pulse pressure, for reducing dementia risk. Cardiovascular health may be incorporated with biomarkers to further personalize dementia prevention and management strategies.

Keywords: Astrocytic activation; Axonal breakdown; Blood pressure; Cardiovascular health; Pulse pressure.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by the institutional review board of the University of California, San Francisco and is conducted in accordance with the latest Declaration of Helsinki Manuscripts, including written informed consent from all participants. Consent for publication: Not applicable. Competing interests: JHK receives royalties from Pearson’s Inc. JCR is a site principal investigator for clinical trials sponsored by Eli-Lilly, Eisai and Amylyx. The authors report no other conflict of interest.

Figures

Fig. 1
Fig. 1
a-c. Multivariable linear regression models examining associations among blood pressure indicators and plasma markers, covarying for age and sex
Fig. 2
Fig. 2
a-d. Interaction models examining whether associations between pulse pressure and plasma markers of interest differ by biological sex (male/female), covarying for age and sex
Fig. 3
Fig. 3
a-c. Interaction models examining whether associations among blood pressure indicators and plasma concentrations of Aβ42/40 differ based on APOE-ε4 status (ε4 carriers versus non-carriers), covarying for age and sex
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