The right temperature at the right time: A framework for understanding thermoregulatory pathophysiology in Alzheimer's disease.

The neuromodulatory subcortical system (NSS) includes thermoregulatory neurons that maintain core body temperature (Tb) and brain temperature within a narrow, diurnally varying range. Cellular pathways in NSS neurons implicated in Alzheimer's disease (AD) may be vulnerable to Tb rhythm disturbance because of their sensitivity to temperature and their thermoregulatory function. This review evaluates a framework for pathophysiological interactions between thermoregulation and AD anchored in the functional anatomy of thermoregulatory neurons. Findings in humans show that thermoregulatory neurons exhibit tau pathology in early AD, and abnormal Tb rhythm is seen in advanced AD. In rodents, cellular risk pathways for tau aggregation are both modulated by diurnal range temperature change and involved in thermoregulation. Further research is needed to bridge human and rodent findings, to understand how sex differences in Tb impact AD risk, and to identify modifiable causal links between Tb disturbance and pathophysiology toward improving clinical outcomes in early AD.