2024 Alzheimer's Association Clinician Scientist Fellowship (AACSF)

Characterizing the Cognitive and Neuroimaging Profile of LATE-NC

How does a little understood brain disorder linked to Alzheimer’s impact the brain and promote dementia progression?

Leslie Gaynor, Ph.D.
Vanderbilt University Medical Center
Nashville, TN - United States

Background

Alzheimer’s disease is associated with specific brain changes, including the accumulation of beta-amyloid and tau proteins into abnormal plaques and tangles, respectively. In addition to beta-amyloid plaques and tau tangles, some individuals with Alzheimer’s exhibit additional biological brain changes that also contribute to cognitive dysfunction and behavior changes; this is referred to as mixed dementia and involves brain changes associated with different brain diseases. According to the 2024 Alzheimer’s and Association Facts and Figures report, recent studies show that the majority of individuals who had Alzheimer's also had brain changes of one or more other causes of dementia. Such findings indicate the need to better understand the disorders that take place along Alzheimer’s, and the role they play in overall disease progression.

One little understood disorder in mixed dementia is called limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), and studies show it can occur in up to half of individuals with Alzheimer’s-related brain changes. Research also suggests that LATE-NC involves unusual brain cell loss (or loss of volume) in certain brain regions, and it may accelerate the progression of memory loss and other symptoms in Alzheimer’s. However, the exact details of what this disease does to the brain remain unknown.

Research Plan

Dr. Leslie Gaynor and colleagues will use their research grant to conduct a study of LATE-NC. They plan to clarify its role in the brain and in mixed pathology. For their effort, the researchers will examine brain scan data from around 800 older adults (age 50 and older) who had or did not have Alzheimer’s and who participated in various studies of aging. First, using statistical analyses, Dr. Gaynor and team will identify how LATE-NC may affect brain cell loss in different brain regions. Preliminary studies suggest the most affected regions may include the medial temporal lobe and the anterior temporal lobe (regions behind your ears). Second, they will examine how LATE-NC may be related to specific types of cognitive decline, including executive function (a group of mental processes that include controlling attention and regulating impulsive behavior) and visuospatial memory (or the ability to navigate around an environment). The team will also examine how LATE-NC may accelerate cognitive decline in people with Alzheimer’s-related brain changes. Lastly, Dr. Gaynor’s group will develop a multi-pronged clinical signature (or scientific description) of the different ways LATE-NC alters brain structure and function, both in people with Alzheimer’s and without Alzheimer’s.     

Impact

Results from this project could shed new light on a little-known, but commonly detected, brain disorder linked to Alzheimer’s. They could also lead to improved methods of diagnosing and treating people with mixed dementia.