Probing the Links Between Tauopathies and Body Temperature 

Body temperature generally follows a natural 24-hour rhythm: low in the morning, rising throughout the day, then dropping in the evening and remaining low during sleep. In a study recently published in The Journal of Clinical Investigation, a team led by researchers at NYU Langone Health and Université Laval in Quebec found new evidence that these sleep-wake variations in core body and brain temperature play a crucial role in regulating levels of total and hyperphosphorylated tau—a marker of Alzheimer’s disease and other neurodegenerative conditions.

“Combining in vitro, in vivo, and clinical models, we revealed a pathway by which changes in body temperature over the sleep-wake cycle modulate both extracellular tau levels and phosphorylation,” says co-lead author Esther M. Blessing, MD, PhD, an assistant professor of psychiatry at NYU Langone.

The findings support the idea that sleep disturbances and age-related changes in body temperature may disrupt proper tau processes, thereby fueling the accumulation of tau aggregates in the brain.

Building on a Growing Body of Evidence 

The paper builds on a first-in-human study published in 2022, in which researchers led by Dr. Blessing and Ricardo S. Osorio Suarez, MD, director of NYU Langone’s Brain Aging and Sleep Center, found an association between lower body temperature during waking and increased tau pathology—including levels of phosphorylated tau in plasma and cerebrospinal fluid (CSF), as well as neurofibrillary tangle burden—in cognitively normal older adults.

The new study investigates the relationship between dynamic changes in temperature and tau across the sleep-wake cycle in humans by correlating these patterns with similar processes in a mouse model. It grew out of a collaboration between Dr. Blessing and Université Laval neuroscientist Emmanuel Planel, PhD, a longtime pioneer in studying the relationship between temperature and tau in preclinical settings.  

“Humans have very different body temperature regulation from mice,” Dr. Blessing explains. “To better understand the links between sleep-wake temperature rhythms and tauopathies, Dr. Planel and I have created an approach where we can ask questions using a combination of preclinical and clinical models.” 

Drawing a Detailed Picture  

The researchers began by testing whether temperatures mimicking body temperature variations during the sleep-wake cycle regulate neuronal tau secretion in human SH-SYSY cells stably expressing tau 3-repeat isoform and in primary mouse cortical cells. Using ELISA and dot blotting, the team found an approximately twofold increase in tau secretion at 38°C compared with 35°C in both human and mouse neuron-like cells, with the secreted tau species being dephosphorylated. The inverse relationship between temperature and tau phosphorylation matches that reported by others.

“Higher wake-like temperatures promote the secretion of truncated and dephosphorylated tau species, which are less prone to aggregation,” Dr. Blessing notes. “At the same time, cooling during sleep is important for reducing extracellular tau levels.” 

In investigating how messages about body temperature are communicated to influence tau processing, the team discovered a role for the UPS-1 pathway—a temperature-dependent protein secretion pathway.  

To get a more detailed picture of how temperature and tau interact in older adults, the researchers analyzed two datasets from subjects in whom body temperature and tau levels (CSF or plasma) were measured simultaneously throughout the sleep-wake cycle. They found that both metrics fluctuated in tandem, with average tau levels approximately 15 percent higher in the evening than in the morning.  

“To our knowledge, this study is the first to compare morning versus evening plasma tau levels in older adults,” says Dr. Blessing. “Participants exhibiting a large increase in tau in the evening compared with morning also showed a large increase in temperature, and those with negligible or negative changes in tau also showed minimal or negative changes in temperature.” 

Future Applications 

Although the precise mechanisms behind the process have yet to be determined, these findings support the hypothesis that body temperature is a key regulator of extracellular tau levels and tau secretion.  

One potential clinical implication, the researchers suggest, is that body temperature disruption caused by sleep disturbance may contribute to Alzheimer’s pathogenesis and related tauopathies. Another is that sleep-wake body temperature variations may be informative for understanding variability in plasma tau levels, which could be relevant to their utility as a biomarker. In addition, therapies aimed at correcting dysrhythmias in body temperature could prove useful in preventing or treating tau-related disorders.

“Interestingly, saunas and physical exercise have been shown to be beneficial in reducing Alzheimer’s risk,” Dr. Blessing observes. “Future studies may examine whether such thermogenic interventions can be used in a targeted way to delay tau-mediated neurodegeneration.”