O9 - Plasma Tau Biomarkers of Alzheimer's Disease Correlate with Stiffness Loss in Older Adults

Introduction: : Alzheimer’s Disease (AD) is the most common cause of dementia in older adults and is defined as the accumulation of amyloid beta and tau pathology. The accumulation of amyloid beta protein in the brain as extracellular plaques is the first discernible pathology of AD, followed by increased tau phosphorylation and secretion, increasing risk of neuronal degeneration (DeTure 2019, Palmqvist 2019). The current gold standard to identify AD pathology is amyloid positron emission tomography (PET imaging), which is costly and involves injection of a radioactive tracer (Cohen 2019). Blood-based tests have emerged that can detect concentrations of amyloid and tau proteins in the blood plasma in the picomolar range and may be a less invasive alternative. Blood biomarkers have been shown to correlate with more established biomarkers of amyloid and tau (cerebrospinal fluid and PET imaging) and are more cost-effective and accessible than their more established counterparts (Janelidze 2020, Gonzalez-Ortiz 2024), and can be used to assess disease course and relation to tissue integrity and cognitive function. MR elastography (MRE) is a technique for quantifying mechanical properties of tissues in vivo and reflects tissue microstructural integrity (Hiscox 2016). Hippocampal stiffness correlates with functional outcomes and distinguish early stages of dementia from normal aging (Delgorio 2023). As such, MRE may be a sensitive biomarker able to characterize tissue microstructure disruption caused by amyloid and tau accumulation in asymptomatic individuals (Hall 2020). Here, we examine the relationship between MRE measures of brain mechanics and blood-based biomarkers in individuals at risk of developing AD.

Materials and

Methods: : A cohort of 37 middle-aged and older adults (46-86 years old, 13M/24F) were enrolled in the Delaware Longitudinal Study for Alzheimer’s Prevention, which targets nonclinical and asymptomatic subjects who are at elevated risk of developing AD. Blood-based assays were performed in duplicate using EDTA-treated plasma and analyzed using the Single Molecule Array (Simoa) platform on a Quanterix SR-X biomarker analyzer as demonstrated in Figure 1. These assays were used to quantify concentrations of plasma biomarkers of AD pathology, specifically phosphorylated tau (pTau-181 and pTau-217), which has been shown to have a strong positive correlation with PET imaging amyloid and tau concentrations (Jonaitis 2023). During an imaging session, MRE data were collected with a 1.5 mm isotropic resolution spiral MRE sequence on a Siemens 3T Prisma scanner to capture displacements induced by 50 Hz vibrations from a pneumatic actuator (Resoundant) to obtain maps of brain mechanical properties, from which we quantified stiffness in the hippocampus and entorhinal cortex (ERC). These structures have been identified as the first locations of amyloid and tau accumulation in early stages of AD through the Braak staging method (Therriault 2022). We examined potential associations between stiffness of the hippocampus and ERC with pTau-181 and pTau-217, while controlling for age.

Results, Conclusions, and Discussions:: We found that hippocampal and ERC stiffness both have statistically significant inverse correlations with plasma phosphorylated tau protein concentrations. Plasma biomarkers pTau-181 and pTau-217 were found to correlate significantly with stiffness of the hippocampus (R=-0.53, p=0.0008, Figure 2A; R=-0.45, p=0.005, Figure 2B) such that greater biomarker concentration was associated with lower stiffness of the hippocampus. Stiffness of the ERC exhibited similar relationships with pTau-181 and pTau-217 (R=-0.45, p=0.006, Figure 2C; R=-0.37, p=0.03, Figure 2D), with ERC stiffness being lower with higher protein concentrations. A representative image of two age and sex matched subjects but with different biomarker burden illustrates the association stiffness in the hippocampus and entorhinal cortex (Figure 3).

This work is the first to examine the relationship between brain mechanical properties and blood-based amyloid and tau biomarkers. We believe the observed lower tissue stiffness in the hippocampus and ERC occurs due to disruption of the cellular structure caused by amyloid and tau accumulation in the brain. This is similar to previous work where an association between amyloid burden from PET and whole brain stiffness was reported (Gonzalez-Ortiz 2024). These the increasing concentration of these blood-based markers of amyloid and tau likely indicates increasing disease severity. Within our cohort of asymptomatic individuals, we find that individuals with greater disease severity indicated by increased blood biomarker concentration appear to have more significant disruption of the microstructural integrity in the hippocampus and ERC regions. It is likely that these blood-based biomarkers can act as a marker of developing disease severity prior to clinical presentation and occur simultaneous to early pathological remodeling of the hippocampus and ERC as an early stage of neurodegeneration. These preliminary results in asymptomatic older adults highlight the strong sensitivity of MRE-derived brain mechanical properties to early pathological changes associated with amyloid and tau protein aggregates—measured using cost-efficient and accessible blood-based biomarkers. This underscores MRE’s potential as a powerful tool for early detection of Alzheimer’s disease progression. Future longitudinal measurements in this cohort will further clarify how amyloid and tau accumulation rates influence brain mechanics and related cognitive performance.

Acknowledgements and/or References (Optional):: This research was supported in part by NIH grants R01-AG058853, R01-AG080052, and F31-AG086036 as well as the Delaware Community Foundation Boerger Fund. Recruitment of research subjects was supported by the Delaware Center for Cognitive Aging Research.

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