By Dennis Drayna, Ph.D.

Recent studies of Alzheimer’s Disease have produced results that could someday impact new treatments for stuttering. A research group led by Drs. Xunde Xian and Joachim Herz at the University of Texas (UT) Southwestern Medical Center studied how a molecule known as APOE4 moves through nerve cells. ApoE4 is the largest known risk factor for Alzheimer’s disease, and humans who carry a particular variant in ApoE4, for reasons that are not yet fully understood, have an increased chance of developing brain cell abnormalities that lead to the loss of memory and other brain functions in this disease. 

The UT Southwestern group investigated the failure of ApoE4 to properly move within cells, a process known as intracellular trafficking. They identified a likely cause of this failure of intracellular trafficking, and they went on to find pharmacological agents that could correct it. These agents not only restored proper trafficking of ApoE4, but also the proper trafficking of other important molecules in the brain known as neurotransmitter receptors, which are trafficked along with ApoE4. This represents an important new approach to treating Alzheimer’s Disease. 

The main hallmarks of Alzheimer’s Disease damage in the brain are called amyloid plaques and tangles. These features are prominent in the brains of individuals who have died of Alzheimer Disease, and many of the drugs being developed for this disease currently take the approach of either preventing the formation of these plaques and tangles, or helping the body to get rid of them. 

It is now becoming clear that intracellular trafficking defects can precede the appearance of amyloid plaques and tangles in individuals who will develop Alzheimer Disease. This has led researchers to speculate that a better approach to Alzheimer’s Disease treatment might be to correct trafficking defects, rather than focus on amyloid plaques and tangles. However, research approaches that seek to correct intracellular trafficking defects have not been available. The work of Drs. Xian, Herz, and colleagues now shows that such approaches exist, and that they can be used to identify exciting new drug-based approaches for this disease.

What is the relevance of these research findings to stuttering? Research studies over the past few years have begun to identify genetic factors in stuttering, and although the genes involved have diverse functions, all are involved in intracellular trafficking. Because research approaches aimed at correcting intracellular trafficking deficits were largely non-existent, the translation of these basic research findings into improved therapies for stuttering faced a large hurdle. The findings of Xian, Herz, and colleagues now substantially reduce the height of that hurdle.

While the first disorders to be associated with trafficking deficits were all rare inherited disorders, recent finds such as those in Alzheimer’s Disease suggest that such deficits also likely underlie many more common disorders. As demonstrated by the work of Xian, Herz, and colleagues, fundamental laboratory research on these common, severe neurological disorders may have an added dividend, producing findings that may be highly relevant to stuttering.

Dr. Drayna serves as a Section and Laboratory Chief at the National Institute on Deafness and Other Communication Disorders.

Reference: Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease.  Xian et al.  eLife 2018;7:e40048. DOI:
From the Winter 2019 Magazine