2021 Alzheimer's Association Research Grant (AARG)

Aging in Down Syndrome: Cholinergic System and Alzheimer’s Pathology

What specific brain changes occur in individuals with Down syndrome that may be related to dementia?

Alexander Conley, Ph.D.
Vanderbilt University Medical Center
Nashville, TN - United States

Background

Past research has suggested that individuals with Down syndrome are at a high risk for developing brain changes associated with Alzheimer’s. By the early age of 40, most people with Down syndrome have a build-up of beta-amyloid plaques and tau protein tangles in their brains, both brain changes observed in Alzheimer’s. Studies show that individuals with Down syndrome and Alzheimer’s show similar changes in select brain regions that are interconnected; these regions are important for learning, memory, and attention. 

In the brains of persons with Alzheimer's, a class of nerve cells known as cholinergic neurons are more vulnerable to cell death, especially in the early stages of disease. Cholinergic neurons are nerve cells that use a chemical messenger called acetylcholine to communicate with one another, and they are a vital component of the brain's communication network. Studies show that the loss of cholinergic neurons negatively affects the formation of attention and new memories.  

The loss of cholinergic neurons has been shown to play a role in Alzheimer’s disease that occurs in individuals over the age of 65, but has not been evaluated in adults with Down syndrome. 

Research Plan

PET (positron emission tomography) is a type of brain imaging that when combined with a specific radiotracer helps to visualize disease- related brain changes, including those associated with Alzheimer’s. Dr. Sepideh Shokouhi and colleagues will study a new radiotracer that binds to and marks cholinergic neurons. The researchers will use this PET radiotracer to study the health of cholinergic neurons in adults with Down syndrome in relationship to their age, performance on cognitive tests, and other brain changes associated with Alzheimer’s. 

Dr. Shokouhi and team will study their new PET radiotracer in participants from the Trial-Ready Cohort-Down Syndrome study, a cohort of adults (age 35-55 years) with Down syndrome that do not have dementia. The researchers will also study five younger adults with Down syndrome (age 18-34) not included in the cohort. 

The research team will conduct PET scans and other brain imaging scans (magnetic resonance imaging), as well as cognitive and functional tests, to assess the associations between cholinergic neuron health, other brain changes associated with Alzheimer’s, and cognitive performance in this population.

Impact

The results may help determine whether cholinergic neuron decline is an early marker of dementia risk in Down syndrome. In addition, the findings may help identify individuals with Down syndrome who might respond better to pro-cholinergic treatments. If successful, the novel PET radiotracer may serve as a marker in future research projects aimed at understanding disease progression or tracking the effects of treatments in this population.