Auditory Dysfunction Might Sound an Early Alarm for Alzheimer’s Disease

Alzheimer’s disease and related dementias are best known for progressive cognitive decline, but growing evidence suggests that sensory systems might also be affected early in disease. This presents a new opportunity for diagnosis before irreversible brain damage or mental decline occurs.

A recent experimental study exploring this opportunity, led by UC Irvine researchers, looked at Alzheimer’s disease and related dementias, with a particular focus on tauopathy — neurodegenerative diseases in which abnormal tau protein accumulates in the brain.

“The findings suggest that hearing-related tests might one day detect early evidence of Alzheimer’s disease,” says Xiangmin Xu, UC Irvine Chancellor’s Professor of anatomy and neurobiology and director of the Center for Neural Circuit Mapping.

The study illustrates what becomes possible when different areas of expertise and research infrastructure come together. “We combined expertise in neurodegeneration and neural circuit analysis with UC Irvine’s major strengths in auditory neuroscience and hearing research,” says Xu, “to ask whether changes in sensory circuits might reveal disease at an earlier stage.”

Xu, along with School of Medicine colleagues from the Department of Otolaryngology — Wei Dong, PhD, and Fan-Gang Zeng, PhD, director of the Center for Hearing Research — partnered with Karina S. Cramer, PhD, a professor of neurobiology and behavior in the Charlie Dunlop School of Biological Sciences. The team also included staff researchers Ann M. Nguyen and Helen Lo, and an undergraduate researcher, James Fields.

They present their findings in a paper, “Temporal Progression of Auditory Brainstem Dysfunction and Behavioral Phenotypes in Mouse Models of Tauopathy,” published in The Journal of Neuroscience.

Listening for Early Changes in the Brain

The researchers asked whether dysfunction in the auditory system could be detected before more apparent behavioral changes.

To test this, they studied PS19 mice — those carrying the human P301S tau mutation, which causes frontotemporal dementia and related neurodegenerative tauopathies. They also studied mice in which the tau mutation was combined with the human apolipoprotein E (APOE) gene — specifically, APOE4, the strongest genetic risk factor for Alzheimer’s. Auditory function was measured using auditory brainstem response (ABR) testing, while anxiety-related and motor behaviors were assessed at different stages of disease progression.

ABR testing records the electrical responses generated as sound information travels from the auditory nerve through successive neural structures in the brainstem. The measurements provide information not only about hearing sensitivity, but also about the strength and timing of neural activity along the auditory pathway. “ABR gives us a way to listen to how the nervous system itself is processing sound,” says Xu. “Instead of waiting for an animal to develop a major behavioral deficit, we can ask whether the underlying neural circuit is already beginning to function abnormally.” The answer was yes.

At only three months of age, PS19 mice already showed reduced neural response amplitudes and delayed transmission across multiple portions of the auditory pathway. Importantly, these abnormalities occurred when the animals did not yet show detectable differences in the anxiety-like or motor behaviors examined in the study. This suggests that ABRs may provide an early, objective and noninvasive readout of tau-related brain dysfunction.

The researchers also examined how APOE4 influences auditory dysfunction associated with tau pathology. The results showed that genetic background mattered substantially. PS19 mice and APOE4/PS19 mice did not follow the same physiological trajectory. APOE4/PS19 mice exhibited distinct changes in auditory response amplitudes and timing that persisted with age and were accompanied by changes in behavioral measures.

The finding may have implications for future biomarker development, because physiological indicators of disease may need to be interpreted in the context of a person’s genetic background.

Toward a Noninvasive Biomarker

ABR testing is already widely used in clinical settings to evaluate auditory pathway function, making its potential application to neurodegenerative disease particularly intriguing. However, the researchers emphasized that the current study was performed in mouse models and does not establish ABR as a diagnostic test for Alzheimer’s disease in people.

The researchers plan to determine how closely ABR abnormalities correspond to the progression and distribution of tau pathology, identify the cellular and circuit mechanisms responsible for the physiological changes, and test whether similar auditory signatures occur in additional disease models and, ultimately, in people at risk for Alzheimer’s disease and related dementias.

The research team is particularly interested in whether longitudinal ABR measurements could eventually be used not only for early detection but also to monitor disease progression or responses to therapy.

This work was supported by grant funding from the National Institutes of Health (R01AG065675; R01DC021209).

— Shani Murray